CAR T клеточная терапия в неврологических расстройствах, вызванных автоантибиозами: многообещающая стратегия.

Background

Autoimmune disease is a pathological process in which the body’s immune tolerance is disrupted, leading to a sustained pathological immune response to autoantigens and causing damage to normal cells or tissues, accompanied by the development of autoantibodies or autoreactive T cells [ 1 ]. In recent years, significant progress has been made in developing novel therapies for autoimmune diseases. Among these, autoimmune diseases that affect the nervous system present unique challenges due to their complex mechanisms, the distinctive anatomical locations, and the restrictive nature of the blood-brain barrier (BBB), which impedes the action of many therapeutic agents. Although an increasing number of innovative treatments have been developed with relapse rate significantly improved, there remains a substantial proportion of individuals with neuroimmunological disorders, such as myasthenia gravis (MG) or neuromyelitis optica spectrum disorders (NMOSD), that fail to achieve the expected disease improvement under current therapies [ 2 , 3 ]. This highlights the existence of a distinct subgroup of refractory clinical cases. Yet, the safety profile of antibody-based therapies for this group remains a matter of ongoing debate [ 4 ].

Humoral immunity-mediated autoimmune diseases associated with the nervous system include MG, NMOSD, multiple sclerosis (MS), anti-N-methyl-D-aspartate acid receptor (Anti-NMDAR) encephalitis, stiff-person syndrome (SPS), and myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD). The roles of self-reactive B cells and the autoantibodies produced in the progression of neuroimmunological diseases have been further elucidated. Specific mechanisms include: (1) generating antibodies that injure tissue by activating complement or antibody-dependent cell-mediated cytotoxicity [ 5 ]; (2) stimulating antigen-presenting cells (APCs), which activate self-reactive T cells and promote the production of cytokines [ 6 ]; (3) releasing pro-inflammatory cytokines that activate macrophages, thereby exacerbating tissue damage [ 7 ]; (4) blocking cell surface receptors (e.g., MG) [ 8 ]; (5) upregulating cell surface receptors (e.g., Graves’ disease) [ 9 ]; (6) disrupting cell adhesion (e.g. pemphigus vulgaris (PV)) [ 10 ]; (7) cell surface receptors internalization or downregulation (e.g., Anti-NMDAR encephalitis). These mechanisms primarily function through extracellular or membrane-bound targets. Consequently, for neurological autoimmune diseases with pathogenic antigens located extracellularly or on the cell membrane, such as NMOSD and Anti-NMDAR encephalitis, B cell depletion therapies have been validated by retrospective data and show robust clinical efficacy [ 11 , 12 ].

However, due to inherent limitations of traditional B-cell depletion therapies, such as incomplete elimination of pathogenic B-cell subsets and limited durability of response, the exploration of more effective approaches has gained momentum, particularly Chimeric Antigen Receptor (CAR) T cell therapy. CAR T cells have the potential to penetrate deeper tissues and are not restricted by major histocompatibility complex (MHC) binding [ 13 , 14 ]. The limited effectiveness of monoclonal antibody therapies in neurological autoimmune diseases such as NMOSD, MS, and Anti-NMDAR encephalitis is partly attributable to their inability to fully eliminate all pathogenic B cell subsets, especially long-lived plasma cells and memory B cells residing in secondary lymphoid tissues, which may escape CD20-based depletion and contribute to residual autoantibody production or relapse [ 15 , 16 ]. Meanwhile, CAR T cell therapy may allow for more efficient and thorough depletion of autoreactive B cells, thus forcing a complete reset of the immune system, even in patients who do not properly respond to B cell depletion therapy strategies [ 17 ].

Through its potential for precise and sustained B-cell elimination, CAR T cell therapy represents an innovative strategy that can complement and, in certain aspects, extend the benefits achieved with monoclonal antibody–mediated B-cell depletion. Several clinical trials in systemic autoimmune diseases have already demonstrated its promise [ 18 , 19 ]. For instance, in the case of systemic lupus erythematosus (SLE), CD19 CAR T cell therapy has been observed to induce a significant and rapid decline of dsDNA antibodies, suggesting that CAR T cell therapy can induce profound depletion of autoreactive B cells in tissues, accompanied by only a slight decrease in total immunoglobulin levels [ 20 ]. Moreover, long-term clinical follow-ups in various autoimmune diseases, such as SLE, systemic sclerosis (SS), and idiopathic inflammatory myopathies (IIM), have revealed that the side effects associated with CD19-targeted CAR T cell therapy are less severe than expected and remain manageable [ 21 ]. This reduction in symptoms is likely due to the considerably lower number of pathogenic B cells in autoimmune diseases than B cell-derived malignancies [ 22 , 23 ]. This can potentially reduce the risk of toxic reactions such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) linked to CAR T cell therapy.

Meanwhile, experimental results indicate a substantial reduction or even complete disappearance of autoantibodies, accompanied by relatively mild side effects and sufficient retention of immunoglobulin levels [ 24 – 30 ]. Some hypotheses have been proposed to address this paradox of comprehensive B cell depletion, suggesting that CD19 is still expressed on plasmablasts. At the same time, CD19 - and CD20 - long-lived plasma cells in the bone marrow can continue to produce adequate protective antibodies, which enables CD19-targeted therapy to achieve thorough elimination of pathogenic B cells without compromising the body’s normal immune function [ 31 , 32 ]. The different roles of short-lived and long-lived plasma cells in SLE have been revealed, with pathogenic anti-dsDNA antibodies predominantly originating from CD19 + short-lived plasma cells and plasmablasts [ 20 ]. This finding is closely related to their varying sensitivities to B cell-targeted therapies in SLE, and a similar approach holds promise for broader application to other neurological autoimmune diseases [ 33 ].

The efficacy of monoclonal antibodies targeting different B cell markers and CAR T cell therapies in depleting B cells can be helpful in deciphering the cellular origins of autoantibodies in various autoimmune diseases. Specifically, these therapies help determine the extent to which autoantibodies are derived from plasmablasts, short-lived, or long-lived plasma cells. Although current study cohorts remain limited in size, the preliminary findings are promising and support the potential safety of CAR T cell therapy for broader clinical application in neurologic autoimmune diseases [ 34 , 35 ]. Apart from the curative outcomes, the use of CAR T cell therapy has also shown the potential to bring the dysregulated immune system to a halt, which hints at the possibility of complete restoration of immune tolerance [ 36 ].

This article summarizes the latest advances of preclinical and clinical trials of CAR T cell therapy in neurological autoimmune diseases based on the classification of autoantibody targets. These targets are classified as extracellular antigen (MG, MOGAD, Lambert-Eaton Myasthenic Syndrome (LEMS), Aquaporin 4 (AQP4)-NMOSD, Anti-NMDAR encephalitis), intracellular antigen (SPS, Diacylglycerol lipase alpha (DAGLA) antibody associated encephalitis) and unspecified orgin (MS). Categories of CAR T cell therapies were further distinguished based on their target specificity, separating approaches directed at general B cell populations from those engineered to recognize specific autoantigens. The applications of CAR T cell in various autoimmune diseases have deepened our understanding of how aberrant B cell activation contributes to the disease pathogenesis.

Main text

Current therapies and their limitations

First-line therapies for autoimmune diseases consist of glucocorticoids, intravenous immunoglobulin (IVIG), and plasma exchange, while second-line therapies include B cell depletion therapy and cyclophosphamide administration. Glucocorticoids play a central role, as they not only suppress inflammatory cascades but also inhibit lymphocyte proliferation and antibody synthesis, thereby directly modulating the autoimmune responses [ 37 ]. Immunomodulatory therapies (e.g., plasma exchange and IVIG) and targeted immunosuppressive therapies (e.g., tumor necrosis factor (TNF) inhibitors, B cell depletion therapy, and T cell-targeted therapies) aim to regulate the immune system and promote beneficial immune responses in patients [ 38 ].

While biologics and small-molecule therapies have shown potential, they hardly account for the variability of the underlying pathophysiology and individualized medication responses of autoimmune disease. Monoclonal antibody therapy, which targets B cell surface molecules to disrupt aberrant B cell function, has also emerged as an effective immunotherapeutic approach for treating autoimmune diseases. Rituximab, a CD20-targeting monoclonal antibody, has been widely adopted as a second-line immunotherapy for refractory autoimmune encephalitis including Anti-NMDAR encephalitis [ 39 ]. Antibodies or agents targeting plasma cells (e.g., the proteasome inhibitor bortezomib), cytokines (e.g., the anti-IL-6 receptor antibody tocilizumab), or complement components (e.g., the anti-C5 antibody eculizumab) have been employed in clinical practice for refractory cases of autoimmune encephalitis and neuroimmunological conditions such as MG and NMOSD [ 40 , 41 ]. Bortezomib has been reported to reduce pathogenic antibody production and improve outcomes in refractory Anti-NMDAR encephalitis in several case series, while tocilizumab has shown benefit in rituximab-refractory autoimmune encephalitis cohorts [ 42 , 43 ]. Eculizumab has also gained robust evidence and regulatory approval for AQP4-IgG-positive NMOSD and for certain indications in MG. Besides, CD19-directed B-cell depletion with inebilizumab has been approved for AQP4-IgG-positive NMOSD, and anti-CD20 agents such as ocrelizumab and ofatumumab have gained approval by the FDA and EMA for MS, illustrating the expanding arsenal of B-cell-targeted therapies across neuroimmunological diseases [ 11 , 44 ].

Despite these advances, clinical practices still reveal certain limitations. For instance, in multiple sclerosis, emerging evidence suggests that while relapses may be temporarily suppressed, disease progression continues unabated after treatment of MS with monoclonal antibodies [ 45 ]. Similar challenges exist across neuroimmunological disorders, where pathogenic immune subsets are not completely eradicated, and relapses or residual deficits frequently persist. As seen in NMOSD where, despite substantial reductions in annualized relapse rate by monoclonal antibodies, a non-trivial proportion of patients still experience relapses during treatment with cumulative disability [ 16 ]. These observations highlight the need for next-generation strategies, such as cellular therapies of CAR T cells, that may potentially achieve deeper and more durable immune modulation with greater specificity.

The principles of car t cell therapy

CAR T cell therapy is a novel treatment that harnesses a patient’s immune system. By isolating T cells from the patient’s peripheral blood and modifying them through bioengineering and ex vivo expansion, T cells are redirected to recognize and eliminate target cells, achieving precision therapy specifically. Additionally, CAR T cells’ antigen recognition is not restricted by MHC, allowing them to be designed for various targets and address a broader range of antigens [ 46 ]. Currently, CAR T cell therapy mainly targets B cell-related tumor-associated antigens (TAAs), such as CD19, CD20 and BCMA, thereby combining T cell killing efficacy with antibody specificity [ 47 ].

Structurally, CAR T cell constructs comprise three parts: the extracellular domain, the transmembrane spacer region, and the intracellular domain. The extracellular domain fuses monoclonal antibody single-chain fragment variables (scFv) for antigen specificity followed by a hinge region. ScFv is the foundation for CAR T cell’s ability to specifically bind pathogenic antigens, comprising the light chain (V L ) and heavy chain (V H ) of monoclonal antibodies linked via a polypeptide chain. The transmembrane spacer region, often involving the CD3ζ (zeta), CD8, or CD28 chains, connects the extracellular region to the intracellular signaling domain. Meanwhile, the intracellular domain comprises the signaling domain of the T cell receptor (TCR) and co-stimulatory domains, usually derived from the CD28 receptor family or tumor necrosis factor receptor families such as 4-1BB and CD27. These are followed by the CD3ζ stimulatory domain, whose function is to achieve dual activation through co-stimulatory signaling and intracellular pathways, thereby enabling T cells to proliferate continuously, secrete cytokines, and enhance cytotoxic activity. Notably, all FDA-approved commercial CAR T cell products are based on second-generation designs that target CD19 or BCMA, with either CD28 or 4-1BB co-stimulatory domains and are used for treating relapsed or refractory hematologic malignancies. These therapies have shown outstanding therapeutic efficacy against B cell-mediated malignancies [ 48 – 50 ] (Fig. 1 ).

Fig. 1 The production and design of CAR T cell therapy process and its mechanism of action Six key steps are involved in CAR T cell production: (1) Phlebotomy, where peripheral blood is collected from the patient; (2) Apheresis, a process to isolate T cells; (3) CAR vector integration, where T cells are genetically modified to express CARs; (4) CAR T cell generation, where the modified T cells express CARs on their surface; (5) Expansion, where CAR T cells undergo in vitro proliferation; (6) Injection, where the expanded CAR T cells are infused back into the patient

The mechanism of CAR T cell targeting, and specific killing is attributed to its prototypical CAR construct, consisting of a scFv for antigen recognition, a hinge region, a transmembrane domain, a CD3ζ signaling domain, and a co-stimulatory domain. Upon target antigen recognition, CAR T cells become activated, leading to perforin-mediated cytotoxicity, cytokine release, and autocrine stimulation, ultimately inducing target cell apoptosis.

Remarkably, CAR design has expanded to include other engineered cell populations and additional targets besides the conventional B cell markers. CAR-regulatory T cells (CAR-Tregs) show promise in restoring immune tolerance and controlling autoimmune responses [ 51 ]. As Treg cells serve as the brakes to switch off the overreactive immune system, they are ideally suited to address autoimmune conditions. Therefore, engineering Treg cells with CARs enables them to acquire antigen specificity and traffic to areas of inflammation. In addition to CAR T cell therapies targeting broadly expressed B-cell antigens (e.g., CD19, CD20), the development of chimeric autoantigen receptor (CAAR) T cells, which selectively eliminate autoreactive B cells while sparing the non-pathogenic B-cell repertoire, highlights a strategy with the potential to achieve more precise targeting and improved immune tolerance in immune-mediated diseases [ 52 ].

In theory, CAR T cell therapy can be effective in diseases where a specific pathogenic cell population exists and can be precisely targeted. Therefore, autoimmune diseases characterized by partial aberrations of B cells that produce autoantibodies perfectly align with CAR T cell therapy’s application model. Particularly for the autoimmune diseases associated with central nervous system (CNS), which is isolated from the rest of the body by the BBB, CAR T cells represent an effective tool for deep penetration into the CNS compartment, due to T cells’ natural infiltration ability, high-affinity specific target binding, and anti-target effector functions. The prior clinical success of CAR T cell therapy has inspired exploration beyond the field of non-solid tumors, with recent advances in solid tumors and autoimmune diseases.

There are two hallmark clinical toxicities that affect patient outcomes and CAR T cell therapy function: CRS and ICANS. CRS arises from a high-level amplification and target cell lysis triggered shortly after CAR T cell binding to its target antigen, which results in a massive release of cytokines into the body [ 53 ]. ICANS, on the other hand, has a less well-defined pathogenesis. Some studies suggest it is associated with damage to the BBB, allowing CAR T cells and other immune cells to migrate into the cerebrospinal fluid (CSF), which leads to the release of intermediate-to-high levels of pro-inflammatory cytokines such as interleukin-6 (IL-6) and interleukin-8 (IL-8) [ 54 ]. Given the variability of adverse events reported across CAR T cell adoption, we outline the grading criteria used throughout this review (Table 1 ).

Table 1 CAR-T cell therapy related adverse events and grading criteria Complication Category Grade Specific Manifestations Cytokine Release Syndrome (CRS) (54) Grade 1 Fever only (≥ 38 °C) Grade 2 Hypotension; Hypoxia relieved by low-flow nasal cannula Grade 3 Hypotension requiring vasopressors; Hypoxia requiring high-flow nasal cannula Grade 4 Hypotension requiring multiple vasopressors; Hypoxia requiring mechanical ventilation Immune Effector Cell Associated Neurotoxicity Syndrome (ICANS) (54) Grade 1 ICE score 7–9; CAPD score 1–8; arousable spontaneously; no seizures; no motor impairment; no cerebral edema Grade 2 ICE score 3–6; CAPD score 1–8; arousable to voice; seizure responsive to intervention or non-convulsive seizures on EEG; no motor impairment; localized cerebral edema on imaging Grade 3 ICE score 0–2; CAPD ≥ 9; arousable only to tactile stimulus; life-threatening seizure ≥ 5 min or repetitive seizures; severe focal motor weakness (e.g., hemiparesis, paraparesis); diffuse cerebral edema involving cranial nerves/ optic disc Grade 4 ICE score 0 (unable to assess); CAPD not testable; unarousable/ coma; status epilepticus or uncontrolled electrographic seizures; profound focal motor deficits (e.g., hemiplegia); severe cerebral edema with brainstem involvement or herniation Infections / Bacterial, viral, fungal infections Other Complications / Allergic reactions or anaphylaxis (e.g., persistent skin rash) Hematological Complications / Prolonged cytopenia; B-cell aplasia and hypogammaglobulinemia Anemia (Hemoglobin, g/dL) Grade 1 < LLN-10.0 Grade 2 < 10.0–8.0 Grade 3 < 8.0; transfusion indicated Grade 4 Life-threatening; urgent intervention required Thrombocytopenia (Platelet count, ×10⁹/L) Grade 1 < LLN − 75 Grade 2 < 75 − 50 Grade 3 < 50 − 25; transfusion indicated Grade 4 < 25; life-threatening consequences; urgent intervention Neutropenia (Absolute neutrophil count, ×10⁹/L) Grade 1 < LLN-1.5 Grade 2 < 1.5-1.0 Grade 3 < 1.0-0.5 Grade 4 < 0.5; life-threatening; urgent intervention ICE score Immune effector Cell-Associated Encephalopathy score; lower scores indicate more severe neurotoxicity, CAPD score Cornell Assessment of Pediatric Delirium score; higher scores indicate more severe delirium, LLN Lower limit of normal Reference for hematologic grading: U.S. Department of Health and Human Services, National Institutes of Health, National Cancer Institute. Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0. Bethesda, MD: National Cancer Institute (Available at: https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_50 )

Therefore, finding a delicate balance between the side effects of CAR T cells and the management of disease progression in the field of autoimmune diseases strongly appeals for the support of more data and trials. However, the above side effects, in terms of their severity and incidence, are significantly less pronounced in noncancerous contexts, especially in autoimmune diseases, comparing with the challenges faced in the application of CART cell therapy in the field of solid tumors. The target cell population in autoimmune diseases is smaller, with a lower mutational burden and genetic heterogeneity, therefore the severity of side effects, such as CRS, resulting from the clearance of pathogenic B cells is much lower [ 55 ]. This has been supported by long-term clinical follow-up in patients with SLE, SSC, and IIM; however, these findings remain limited by small sample sizes [ 21 ]. Moreover, the risk of antigen mutation and subsequent immune escape, which represents a major challenge for CAR T cell therapy in oncology due to high antigen load and tumor heterogeneity, is not a concern in autoimmune diseases [ 56 ]. In these disorders, the pathogenic autoantigens are relatively stable, eliminating the problem of antigen variability. Particularly with CAAR T cell therapy, the approach achieves selective depletion of autoreactive B cells that express pathogenic autoantibodies, while sparing the protective B cell repertoire. This confers superior specificity and immune tolerance compared with applications in solid tumors, where both antigen escape and off-target cytotoxicity remain significant barriers [ 29 , 57 ].Thus, the concept of using CAR T cells to target autoimmune disorders is highly compelling and holds great potential for synergizing with endogenous immune functions to eliminate pathological cells. However, further data will be needed to provide a clearer and more convincing understanding moving forward [ 58 ].

Classifications of intracellular and extracellular antigens in neurological autoimmune diseases and car T cell therapy

Understanding the classification of intracellular and extracellular autoantibody-mediated neurological disorders

Neural autoantibodies play a vital role in various neurological autoimmune disorders. Therefore, autoantibodies specific to neuronal, glial, or muscle antigens can serve as diagnostic biomarkers or pathogenic factors in neuroimmunological diseases. These neural autoantibodies can be classified based on the location of their target antigens: (1) intracellular proteins such as nuclear proteins, cytoplasmic enzymes, and RNA-binding proteins, including ANNA-1 (Anti-Hu), ANNA-2 (Anti-Ri), ANNA-3, Ma1/Ma2, Purkinje Cell Antigen 1/2(PCA-1/2; Yo/Tr), Amphiphysin, Glutamic Acid Decarboxylase 65 (GAD65), and glial fibrillary acidic protein α (GFAPα); and (2) membrane and synaptic proteins (ion channels, water channels, and neurotransmitter receptors), such as AQP4, γ-aminobutyric acid receptors (GABA-R), MOG, NMDAR, anti-acetylcholine receptor (AChR), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR), Muscle-Specific Kinase (Musk), Voltage-Gated Calcium Channel (VGCC), N-Methyl-D-Aspartate Receptor Subunit 1 (NR1), and Glutamate Receptor 1/2 (GluR1/2) [ 59 , 60 ] (Table 2 ).

Table 2 Antibody-mediated neurological disorders Classification Antibodies Common Phenotypes Extracellular Antigens Muscle AChR MG Neuronal (α3) AChR Dysautonomia Neuronal (α7) AChR Encephalitis MuSK MG VGKC Reversible autoimmune encephalopathy VGCC LEMS AQP 4 NMOSD NMDAR LE, seizures, catatonia, subacute memory disturbance, abnormal movements Glycine receptor SPS, encephalomyelitis, seizures, rigidity, myoclonus, MOG ON, ADEM, myelitis LGI1 LE, faciobrachial dystonic seizures, neuromyotonia CASPR2 LGI1-like, neuromyotonia and Morvan’s syndrome, neuropathic pain GABA B receptor LE, seizures, memory loss GABA A receptor Encephalitis, seizures, catatonia mGluR5 LE, seizures, movement disorders Neurexin 3α Clinical overlap with Anti-NMDAR encephalitis Septin 7 Encephalitis Intracellular Antigens Striational muscle MG, myositis Amphiphysin SPS, encephalomyelitis Synapsin LE, neuropsychiatric disorders GFAP Meningoencephalomyelitis GAD65 LE, SPS, seizures Ma LE, diencephalic dysfunction, brainstem encephalopathy ANNA-1 (Anti-Hu) LE, sensory neuropathy ANNA-2 (Anti-Ri) Movement disorders, parkinsonism AK5 LE AGNA (SOX1) LEMS Abbreviations : AChR Nicotinic acetylcholine receptor, ADEM Acute disseminated encephalomyelitis, AGNA Antiglial nuclear antibody, AK5 Adenylate kinase 5, ANNA Antineuronal nuclear antibody, AQP4 Aquaporin-4 water channel, CASPR2 Contactin-associated protein-like 2, GABA γ-aminobutyric acid, GFAP Glial fibrillary acidic protein, LE Limbic encephalitis, LGI1 Leucine-rich glioma-inactivated 1, LEMS Lambert–Eaton myasthenic syndrome, MG Myasthenia gravis, mGluR5 Metabotropic glutamate receptor 5, MuSK Muscle-specific tyrosine kinase, NMDAR N-methyl-d-aspartate receptor, NMOSD Neuromyelitis optical spectrum disorder, ON Optic neuritis, SPS Stiff person syndrome, VGCC Voltage gated calcium channel, VGKC Voltage-gated potassium channels

Autoantibodies targeting intracellular antigens are generally considered diagnostic markers and are often associated with paraneoplastic neurological syndromes. In contrast, autoantibodies against extracellular antigens typically target specific extracellular domains, which usually exhibit direct pathogenic potential. These two classes of antibodies can coexist. Emerging evidence proposes a third subclassification, wherein specific intracellular antigens that are sometimes expressed on the cell surface are referred to as intracellular antigens with potential transient exposure on the plasma membrane [ 61 ]. Examples of this new category include amphiphysin and GAD65 associated with SPS [ 62 , 63 ]. For the purposes of this review, these antigens are categorized as intracellular, associated conditions are included under intracellular antigen-mediated neurological autoimmune disorders treated with CAR T cell therapy. While our focus centers on autoimmune diseases driven by neural autoantibodies and their therapeutic implications, we do not elaborate on the relevance of paraneoplastic or idiopathic neurological syndromes [ 64 ]. Notably, specific neuronal and glial antigens contribute directly to pathophysiology and serve as important diagnostic biomarkers across neuroimmunological diseases, thereby informing potential therapeutic strategies. In this context, CAAR T cell therapy aims to leverage known pathogenic epitopes by selectively depleting autoreactive B cells that recognize these antigens, although its clinical applicability remains to be fully defined [ 47 ].

As the mechanisms of intracellular and extracellular autoantigens differ and the therapeutic principles of CAR T cells targeting intracellular antigen-mediated neurological disorders remain largely undisclosed, we categorized neurological autoimmune disorders into three groups: extracellular antigen-mediated disorders (e.g., MG, MOGAD, NMOSD, LEMS, and Anti-NMDAR encephalitis), intracellular antigen-mediated disorders (e.g., SPS, DAGLA antibody associated encephalitis), and disorders with incompletely defined or heterogeneous antigenic targets (e.g., MS). While candidate autoantigens such as myelin basic protein (MBP), proteolipid protein (PLP), and MOG have been proposed in MS, their roles remain inconsistent across studies; thus, MS is provisionally included in this category to highlight the ongoing uncertainty in its antigenic drivers [ 65 , 66 ]. For each category, we detail known therapeutic targets, the current state of CAR T cell therapy in these diseases and propose potential mechanisms to develop a comprehensive understanding of the role of CAR T cell therapy in antigen-mediated neurological disorders (Table 3 ).

Table 3 CAR T cell therapy in neurological autoimmune disorders Abbreviations: AChR Anti-acetylcholine receptor, c/sMRI Cerebral and spinal magnetic resonance imaging, CRS Cytokine release syndrome, QMG Quantitative Myasthenia Gravis Score, MGC Myasthenia Gravis Composite, MG-ADL Myasthenia Gravis Activities of Daily Living Scale, CSF Cerebrospinal fluid, EAMG Experimental autoimmune myasthenia gravis, EAE Experimental autoimmune encephalomyelitis, EDSS Expanded disability status scale, GrB Granzyme B, ICANS Immune effector cell-associated neurotoxicity syndrome, IFNγ Interferon γ, MAS Modified Ashworth scale, NRS Numeric Rating Scale, MG Myasthenia gravis, MG-ADL Myasthenia gravis activities of daily living, MGFA Myasthenia Gravis Foundation of America, NMDA Anti-N-methyl-D-aspartate, NRS Numeric rating scale, CASE Clinical Assessment Scale in Autoimmune Encephalitis, ICARS International Cooperative Ataxia Rating Scale, MRC Medical Research Council, PPMS Primary-progressive Multiple sclerosis, QMG Quantitative myasthenia gravis, RRMS Relapsing-remitting Multiple sclerosis, VGCC Voltage-gated calcium channel

CAR T cell therapy for autoimmune neurological disorders based on antigen classification

CAR T cell therapy for extracellular antigen-mediated neurological disorders

Myasthenia gravis

MG is a prototypical antibody-mediated neuromuscular autoimmune disorder in which pathogenic autoantibodies, most commonly targeting the AChR, lead to impaired neuromuscular transmission and manifest as fluctuating muscle weakness and fatigue [ 67 , 68 ]. The severity of disease and treatment responses are clinically evaluated using standardized scales such as the Myasthenia Gravis Activities of Daily Living (MG-ADL) score, Quantitative Myasthenia Gravis (QMG) score, and Besinger disease activity score, where higher scores generally reflect greater functional impairment and disease burden. While antibodies against AChR, and less frequently MuSK or LRP4, provide valuable diagnostic and prognostic information, current therapies primarily modulate immune activity but do not adequately or specifically target the long-lived plasma cells responsible for sustained autoantibody production [ 69 , 70 ]. Consequently, a subset of patients, particularly those with persistent AChR-positive antibodies, may show limited or incomplete responses to B cell depletion with rituximab [ 71 , 72 ].

Even though new complement-targeting antibodies, such as eculizumab [ 40 ] and ravulizumab [ 73 ], have demonstrated effective treatment outcomes for highly active MG, their adoption is still accompanied by an incremental risk of infection. Additionally, up to 15% of patients show no response to complement therapy, likely due to C5 polymorphisms or alternative pathogenic mechanisms, such as antibody mediated AChR blockade or internalization. Neonatal Fc receptor (FcRn) inhibitors, which reduce circulating pathogenic antibody levels by disrupting IgG recycling and promoting its lysosomal degradation, have emerged as novel targeted immunotherapies in clinical practice. While FcRn antagonists have proven effective in alleviating autoantibody attacks on the neuromuscular junction (NMJ), these treatments still fail to eliminate harmful autoantibodies and avoid their downstream effects [ 74 , 75 ]. Therefore, an urgent need for novel and more durable immunotherapies persists, with the selective expression of B cell maturation antigen (BCMA) on the surface of mature plasma cells and CD19 on B cells providing promising therapeutic opportunities. These considerations provide the rationale for exploring CAR T and CAAR T cell therapies in MG.

Cartesian Therapeutics reported a 12-month follow-up data from a Phase 2a clinical trial, an anti-BCMA autologous RNA chimeric antigen receptor T cell (rCAR T) therapy, for patients with refractory generalized MG. Among the 14 enrolled patients, significant and sustained clinical improvements were observed across four validated MG disease scoring systems, with an average improvement of 6 or more points in the MG-ADL score. Notably, no typical adverse effects related to CAR T cell therapy, such as neurotoxicity, CRS, hematologic abnormalities, functional immunosuppression, or opportunistic infections, were reported, demonstrating excellent immune tolerance. Clinically meaningful improvements in MG disease severity were accompanied by reductions in circulating plasma cell markers and trends indicating partial plasma cell depletion and slight decreases in total IgG, vaccine antibodies, and autoantibody concentrations [ 24 ].

Subsequently, a CD19-targeted CAR T therapy has been reported in a patient with severe refractory anti-AChR + generalized MG. The patient showed substantial clinical improvement, evidenced by reductions in clinical multiparameter Besinger disease activity and QMG scores, correlated with serological elimination of CD19 B cells (cleared by day 8 and not reconstituted by day 62) and a marked decrease in pathogenic anti-AChR antibodies (from 2434 nmol/mL at day 0 to 718 nmol/mL at day 62). This study provided evidence that CD19 + plasmablasts together with short-lived plasma cells are responsible for producing most pathogenic anti-AChR autoantibodies. In contrast, protective autoantibodies are produced by long-lived CD19 - bone marrow plasma cells, unaffected by CD19 CAR T cells. The patient did not develop CRS, ICANS, hematopoietic insufficiency, or hypogammaglobulinemia but did experience self-limiting grade 1 transaminitis, which resolved without treatment [ 25 ].

For MuSK MG, MuSK-CAR T cells have also been specifically designed. In murine models, these cells exhibited efficacy comparable to CD19 CAR T therapy, with more stable retention times in the spleen. MuSK-CAR T cells specifically cleared anti-MuSK IgG without impacting overall IgG or B cell levels, thus circumventing the broad immunosuppressive limitations of current therapies. However, given the small sample sizes in these studies, the available evidence is limited in confirming the safety and efficacy of these therapies in MG patients, necessitating further experimental validation [ 57 ]. Nevertheless, the promising potential of CAR T therapy in achieving broad depletion of autoreactive cells and subsequent immune reset underscores its transformative role in neurological autoimmune diseases.

Lambert-Eaton myasthenic syndrome

LEMS is another neuromuscular autoimmune disease characterized by defective neurotransmitter release at the NMJ due to autoantibodies against presynaptic P/Q-type voltage-gated calcium channels (VGCCs) [ 76 , 77 ]. Autonomic dysfunction, diminished deep tendon reflexes, and proximal muscular weakness are common triad symptoms [ 78 ]. For LEMS patients, although symptomatic therapies such as 3,4-diaminopyridine and immunosuppressive regimens provide benefit, these approaches do not specifically eliminate the pathogenic B cell and plasma cell populations that drive autoantibody production [ 79 ]. As a result, disease activity often persists, underscoring the need for more targeted and durable immunotherapies.

CD19-targeted CAR T therapy (KYV-101) has shown great efficacy, achieving both serological and clinical remission in two patients with severe, refractory disease characterized by the coexistence of myasthenia gravis and Lambert–Eaton myasthenic syndrome, in whom conventional therapies had either failed to halt progression or were discontinued due to adverse effects. Notable improvements were observed in patients’ quality of life and daily activities, as reflected in MG-ADL scores, particularly in mobility and gait. A significant decline in pathogenic autoantibodies accompanied these clinical improvements: anti-AChR autoantibodies decreased by 53% in patient 1 and completely normalized in patient 2, whereas anti-VGCC autoantibodies decreased by 96% in patient 1 and 93% in patient 2, subsequently returning to normal levels. Both patients remained disease-free and off treatment during the 7-month follow-up after data publication. Mild cytokine release syndrome occurred in both cases, and Patient 1 additionally developed Grade 1 ICANS, both of which resolved with treatment [ 26 ].

In the pathophysiology of LEMS, it has been established that autoantibodies mediate chronic autoimmune attacks, resulting in damage to the presynaptic membrane and reduced VGCC function. CD19-CAR T cell therapy not only achieved remarkable functional recovery but also led to complete immune reset in the cases with both conditions of long-standing MG as well as LEMS, underscoring its therapeutic potential for refractory autoimmune neuromuscular diseases. However, it remains unclear whether NMJ damage is reversible and to what extent it can recover [ 80 ].

Neuromyelitis optica spectrum disorder

NMOSD commonly presents with either monophasic or recurrent attacks of optic neuritis and transverse myelitis. It is a phenocopy that has been identified as distinct from MS since the presence of specific AQP-4-IgG autoantibody signature and the detection of consequent complement activation [ 81 ]. In most NMOSD cases, pathogenic autoantibodies AQP4-IgG are produced by plasma cells and mature B cells, which target AQP4 abundantly expressed on the optic nerve and spinal cord, leading to complement activation, astrocyte injury, and subsequent neuroinflammation [ 82 ]. Although several FDA-approved monoclonal antibodies, including anti-CD19 B cell–depleting antibody inebilizumab [ 11 ], IL-6R inhibitor satralizumab, C5 complement inhibitor eculizumab and ravulizumab [ 41 ] have substantially advanced NMOSD management, a proportion of patients continue to experience relapses despite current treatments [ 3 , 83 ]. CAR T cell therapy, with its capacity to selectively and more thoroughly deplete autoreactive B cells thus eliminate pathogenic autoantibodies, offers a parallel yet potentially more durable approach, especially for patients with refractory symptoms.

Recently, a phase I pilot trial involving 12 adults with NMOSD treated with anti-BCMA CAR T cells showed that, over a 5.5-month follow-up period, 11 patients achieved drug-free remission without relapse. The decline in AQP4 antibody levels coincided with CAR T cell expansion, and improvements were generally reported in disability (Expanded Disability Status Scale (EDSS) scores), vision, walking ability, and bowel and bladder functions. All participants experienced grade 1–2 CRS and adverse events greater than grade 3, primarily manifesting as hematologic cytopenia and infections. Notably, when compared with the use of the exact same product of anti-BCMA CAR T cells in multiple myeloma, treatment in NMOSD patients was associated with significantly milder and shorter episodes of cytopenia, likely reflecting the absence of profound bone marrow involvement in this disease. The severity of CRS was also lower than typically reported in hematological settings, and infection rates were within the expected range for NMOSD patients receiving other immunotherapies. While established monoclonal antibody therapies have already provided substantial benefit and remain the current standard of care, these observations suggest that BCMA-CAR T cells may offer a comparatively favorable safety and tolerability profile in NMOSD, warranting further investigation [ 28 ].

Subsequently, the team conducted single-cell multi-omics analyses on both blood and CSF samples from AQP4 + NMOSD patients, revealing the evolution of CAR T cells in vivo at the cellular and molecular levels from a dynamic perspective. According to the study, CAR T cells with chemotactic characteristics can more readily cross the BBB, infiltrate the CNS, and directly eliminate autoreactive plasma cells, thereby reducing intrathecal autoantibody secretion and aberrant immune cell activation. At CSF immune microenvironment level, reductions were observed in pro-inflammatory cytokines, chemokines, and complement components, demonstrating that CAR T cells can regulate immune dysregulation of NMOSD patients especially within the CNS region. This reversal of immune dysfunction may underline the observed recovery following CAR T cell therapy. Thus, this discovery elucidates the crucial role of CAR T cells in correcting central immune abnormalities and reconstructing CNS immunity in patients, providing insights into potential applications for other autoimmune neurological disorders [ 27 ].

However, the adoption of CAR T cell therapy for NMOSD still remains in its early exploratory stage, likely attributed to its inherent complexities as a living drug and difficulties of recruiting less severe patients. In this context, it is important to acknowledge the considerably more mature clinical development of several monoclonal antibody therapies that have already achieved regulatory approval and demonstrated robust efficacy in NMOSD [ 11 , 84 – 86 ].

MOG antibody-associated disease

MOGAD is an autoimmune demyelinating disease characterized by perivenous demyelination, CD4⁺T cell infiltration and complement deposition in active lesions [ 87 ]. At present, due to the lack of high-quality clinical research evidence, the relapse prevention strategy of MOGAD and the treatment of refractory symptoms remains a challenge, while B cell depletion therapy is currently adopted in clinical practice, a substantial number of patients showed poor response to existing treatment [ 88 ].

A 25-year-old male patient with MOGAD had a long-standing history of recurrent optic neuritis and lower-limb sensory impairment, with an EDSS score of 7.5. Serum MOG-IgG remained persistently positive for six years (median titer 1:160). Following CD19-directed CAR T therapy, complete depletion of CD19⁺ B cells was achieved by day + 7 post-infusion, by day + 141, CD19⁺ B-cell reconstitution was noted, predominantly consisting of naïve CD19⁺CD27⁻IgD⁺ cells. During the one-year follow-up, CD19⁺CD27⁺IgD⁻ memory B cells gradually reappeared, while CD19⁺CD38⁺IgM⁺ plasmablasts remained persistently low (< 0.5%) or absent. MOG-IgG seroconversion occurred on day + 22 (< 1:80) and remained negative through the end of follow-up. Notably, an optic neuritis relapse developed on day 29, despite persistently negative MOG-IgG status. The patient remained relapse-free afterwards without maintenance immunotherapy, and no new or progressive abnormalities were detected on brain/spinal MRI or optical coherence tomography. No CAR T–related adverse events occurred throughout treatment and follow-up [ 89 ]. This single-case observational study demonstrates that CD19-targeted CAR T therapy is well tolerated in refractory MOGAD. The sustained MOG-IgG negativity paralleled the depletion of memory B cells and plasmablasts, suggesting that MOG-IgG is primarily derived from CD19⁺ memory B cells and plasmablasts, while long-lived CD19⁻ plasma cells maintain immune tolerance. These findings warrant confirmation in multicenter, large-scale studies.

Anti-NMDAR encephalitis

Anti-NMDAR encephalitis is currently the most prevalent type of AE. It is associated with autoantibodies targeting the NR1 subunit of NMDAR, an extracellular ionotropic glutamate receptor located on the neuronal cell surface. One crucial diagnostic criterion is the existence of IgG NMDAR antibodies in CSF, and the functions of B cells and plasma cells in disease progression have been well established. However, a subset of patients still experiences severe neurological sequelae despite receiving intensive immunosuppressive therapy [ 90 ].

Therefore, Reincke et al. proposed a more specific treatment to selectively deplete NMDAR autoantibody-producing B cells. They developed NMDAR-specific chimeric autoantibody receptor (NMDAR-CAAR) T cells, comprised of a 4-1BB/CD3 intracellular signaling domain fused to a fragment of the NMDAR autoantigen. In vitro , the CAAR T cells bound to various NMDAR autoantibodies generated from human patients and conducted effective target cell lysis. Effector molecules were secreted after being activated upon target cell encounter, then proliferation and specific killing took place. Notably, the NMDAR-CAAR T cells did not affect healthy donors’ primary B cells, meanwhile, a decrease in brain and serum autoantibodies was seen in a mouse model, indicating that CAR T cells successfully and precisely depleted pathogenic B cells expressing antibodies that are NMDAR-reactive, with no symptoms of adverse events or off-target toxicity [ 29 ]. However, this result is limited using a passive transfer B cell model that does not reproduce the full neuropathological or behavioral phenotype of Anti-NMDAR encephalitis, as well as by the restricted antibody diversity analyzed, necessitating future studies employing active immunization and broader patient-derived antibody panels.

In addition to its application in Anti-NMDAR encephalitis, preclinical studies for MuSK-MG, PV, and type 1 diabetes (T1D) have explored the adoption of CAAR T in autoimmune diseases. Subsequent sections discuss these studies in greater detail [ 57 , 91 – 93 ].

CAR T cell therapy for intracellular antigen-mediated neurological disorders

Stiff-Person syndrome

SPS is a prototypical autoimmune neuronal hyperexcitability condition associated with impaired GABAergic synaptic transmission. Autoantibodies produced by the immune system primarily target presynaptic GAD-65, amphiphysin, and postsynaptic GABA receptor-associated proteins, such as gephyrin. The recently proposed diagnostic criteria for SPS emphasize: (1) the presence of anti-GAD65 antibodies in serum and/or CSF (2), the presence of anti-GlyR antibodies in serum and/or CSF, or (3) the presence of anti-amphiphysin antibodies in serum and/or CSF. High-titer autoantibodies that target linear epitopes of GAD65 were found to correlate to the severity of the illness, indicating a strong T cell response to GAD65 [ 94 ], while anti-GlyR antibodies directly impair inhibitory neuronal signaling, and amphiphysin antibodies reduce presynaptic GABA release, both leading to neuronal hyperexcitability [ 95 ]. This underscored the importance of autoantibodies not only for diagnosis but also as evidence of their pathogenic contribution. Thus, eliminating pathogenic antibodies theoretically alleviates disease progression [ 96 – 98 ]. However, intracellular antigens are theoretically inaccessible to circulating antibodies, and the prevailing view is that antibodies targeting intracellular proteins such as GAD65 primarily serve as disease markers rather than direct pathogenic mediators [ 99 , 100 ]. Consequently, their pathogenic potential remains controversial. This discrepancy emphasizes the need for further studies to clarify their precise role in disease pathogenesis, to determine whether eliminating such antibodies can provide meaningful clinical benefit, and to elucidate the underlying mechanisms.

A female patient with a 9-year history of refractory SPS received CD19 CAR T cells (KYV101). The anti-GAD65 titer decreased from 1:3200 at baseline to 1:1000 at day + 56, then to 1:320 five months post-treatment. This was accompanied by significant clinical improvements in stiffness, pain relief and walking ability. Transient fever occurred, which resolved after treatment. Importantly, consistent with the experience of employing anti-CD19 CAR T cells for autoimmune disorders such as MG, MS, SLE, and RA, no severe safety signals (ICANS or CRS greater than grade 3) were observed in CAR T clinical outcomes. Severe neurotoxicity events were also substantially lower than those reported in B cell lymphoma, suggesting a potentially acceptable safety profile [ 101 ]. However, as this report represents only a single case, caution is required in drawing generalizable conclusions, and additional evidence is warranted. In this context, the ongoing clinical trial of CD19-CAR T therapy in SPS ( NCT06588491 ) will provide more data.

Diacylglycerol lipase alpha (DAGLA) antibody associated encephalitis

DAGLA antibody associated encephalitis is a novel type of autoimmune cerebellitis, characterized by autoantibodies against DAGLA being detected in CSF and serum samples [ 102 ]. DAGLA localizes as a multipass membrane protein expressed on the surface of the postsynaptic dendritic spines of hippocampus neurons and cerebellar Purkinje cells, where it regulates endocannabinoid signaling through the generation of 2-arachidonoylglycerol (2-AG) from the cytoplasmic side of the plasma membrane. It is indicated by epitope analyses that autoantibodies predominantly recognize intracellular linear epitopes [ 103 , 104 ]. The response to immunotherapy in previous study of four patients was limited, with only moderate or short-lived improvement observed. Initial corticosteroid treatment had minimal impact on the progression of clinical symptoms, and all patients exhibited persistent severe neurological deficits. Improvements following immunoadsorption, plasma exchange, and IVIG therapy were transient. Therefore, early diagnosis, along with more intensive and prolonged immunotherapy, may yield greater benefits and potentially prevent irreversible cerebellar damage [ 102 ].

In a recently published study in July 2025, CD19-directed CAR T-cell therapy successfully treated a case of refractory anti-DAGLA antibody-associated autoimmune encephalitis [ 105 ]. A 36-year-old patient, who had failed to respond to conventional therapies including corticosteroids, plasma exchange, and rituximab, received a single infusion of autologous anti-CD19 CAR T cells. Following treatment, the patient demonstrated marked clinical improvement, as assessed by the Clinical Assessment Scale in Autoimmune Encephalitis (CASE) and the International Cooperative Ataxia Rating Scale (ICARS). Levels of anti-DAGLA antibodies decreased in both serum and CSF. Complete depletion of B cells was observed in peripheral blood and CSF, accompanied by the elimination of anti-DAGLA antibodies in both compartments. It is of significant value to investigate whether anti-DAGLA autoantibodies exert direct pathogenic effects, potentially by inhibiting or activating protein function, triggering complement-mediated cytotoxicity, or promoting T cell–mediated processes. Further studies are needed to explore these mechanisms across different patient cohorts and to elucidate how DAGLA antibodies may affect neuronal function. For antibody-mediated CNS autoimmune diseases, this case offers early evidence that severe B-cell depletion with CD19-CAR T cell therapy may be a unique and effective therapeutic approach, especially in instances that are resistant to previous treatment.

CAR T cell therapy for neurological autoimmune disorders without identified antigen

Multiple sclerosis

MS is a chronic demyelinating disease of the CNS with no known specific cause, characterized by a diverse range of symptoms and signs due to varying involvement of autonomic, sensory, motor, and visual systems. The infiltration of immune cells into the CNS is a hallmark of MS, but traditional therapies have limited effects on these tissue-resident immune cells [ 106 ]. To date, no specific autoantibody has been confirmed as pathogenic or pathognomonic, and disease progression is thought to be driven instead by compartmentalized inflammation, microglial activation, and neurodegenerative processes [ 6 ]. This immunopathological complexity has made prevention of disease progression particularly challenging despite advances in disease-modifying therapies. Nevertheless, emerging research has provided deeper insights into the complex autoimmune and neurodegenerative mechanisms underlying MS, with particular emphasis on the pivotal role of B cells in disease pathophysiology and relapse reduction. B cells produce autoreactive antibodies and activate autoreactive T cells by presenting self-reactive peptides via MHC [ 6 ]. Although no therapy can completely prevent or reverse the progressive neurodegeneration, immune reconstitution therapy has demonstrated potential in inducing MS patients into long-term or possibly permanent drug-free remission [ 107 – 109 ], with selective B cell depletion therapies—such as rituximab, ocrelizumab, and ofatumumab, show promise in effectively reducing inflammation originating in the periphery, highlighting the crucial role of B cells in MS pathology [ 44 , 110 , 111 ]. However, growing evidence suggests that relapse prevention does not necessarily equate to control over disease progression [ 30 , 45 ].

The persistence of oligoclonal bands (OCBs) in CSF despite peripheral immunosuppression alongside B cell depletion in the CSF suggests that CNS-compartmentalized, tissue-resident B lymphocytes (including CD20⁻ long-lived plasma cells) may not be effectively eliminated. This observation is supported by studies showing ongoing intrathecal clonal B-cell / plasma-cell populations and persistent CSF OCBs following anti-CD20 therapy [ 112 , 113 ]. Therefore, using CAR T cells, which have shown the capacity to enter deeper tissue compartments, to eliminate pathogenic B cells may potentially alter the clinical outcomes of monoclonal antibody therapies, achieving more comprehensive immune reconstitution [ 30 ]. In B cell-dependent experimental autoimmune encephalomyelitis (EAE) mouse models, CD19 CAR T cell therapy improved EAE symptoms and delayed disease onset [ 114 ]. However, contradictory results were observed in another mouse model, where CD19 CAR T administration exacerbated EAE within two weeks, accompanied by widespread demyelination and axonal loss [ 115 ]. Observational evidence, however, has started to offer more realistic insights into CAR T cell therapy’s potential. In a recent case series, CAR T cell treatment demonstrated significant benefits in two progressive MS patients, resulting in the enrichment of CAR T cells in CSF along with reduced intrathecal antibody levels with no early signs of neurotoxicity, which underscores the advantages of CAR T cell therapy in penetrating immune-privileged compartments. The study also highlights the therapeutic potential of CD19 CAR T cells for advanced MS patients unresponsive to traditional B cell depletion therapies, as they more thoroughly eradicate CNS-resident B lymphocytes that responsible for accelerating the course of the disease and inflammatory relapses [ 116 ]. Notably, several registered trials (e.g. NCT06384976 , NCT06451159 , NCT07178431 , NCT06138132 , NCT06220201 ) are currently underway, which is expected to provide further supportive evidence to determine this therapy’s short- and long-term safety and efficacy of CAR-T cell therapy in patients with refractory or progressive MS.

It is worth mentioning that CAR Treg therapy has shown particularly promising results in MS. While Tregs naturally provide protective effects in EAE, their differentiation into Th17 cells in the absence of TGF-β contributes to MS pathology. To address this, Moa Fransson et al. engineered CARs expressing FoxP3 while targeting MOG in CD4 + T cells (CARαMOG-FoxP3). FoxP3 expression drives the Treg phenotype via transcriptional regulation, while CARαMOG promotes Treg binding to MOG-expressing oligodendrocytes [ 117 ]. The engineered Tregs efficiently penetrated brain regions following intranasal administration, suppressing EAE progression and reducing disease symptoms. In treated mice, improved myelination, reduced reactive astrogliosis, and increased levels of myelin basic protein (MBP) levels and GFAP confirmed CAR Treg efficacy. Additionally, brain tissues showed lower mRNA levels of IFN-γ and IL-12 [ 118 ]. The therapy of autoimmune diseases may benefit greatly from both CAR Treg and CAAR T treatments, as they provide antigen-specific targeting while minimizing systemic immunosuppression. Nonetheless, future studies must overcome challenges such as identifying optimal CAR targets, reducing costs, and developing scalable approaches for broader clinical applications. In this section, potential mechanisms regarding CAR T therapy in diseases mentioned above are shown in Fig. 2 . Fig. 2 Roles of aberrant B cells and autoantibody in the pathophysiology in autoimmune neurological disorders The pathogenic targets and mechanisms related to implicated autoantibodies of eight autoimmune disorders (NMOSD, MOGAD, MS, NMDAR encephalitis, DAGLA antibody-associated encephalitis, MG, LEMS, SPS) is summarized. NMOSD is mediated by AQP4 antibodies, leading to astrocyte damage. MOGAD, demyelinating disease induced by MOG-IgG binding to oligodendrocytes. MS involves T cell and B cell activation, releasing proinflammatory cytokines (IL-1, IL-6, TNF-α, IFN-γ) and inducing oligodendrocyte damage, resulting in demyelination. Anti-NMDAR encephalitis is characterized by autoantibodies targeting NMDAR at the synapse, disrupting glutamatergic neurotransmission. DAGLA antibody-associated encephalitis is caused by anti-DAGLA autoantibodies disrupting 2-AG–mediated endocannabinoid signaling at excitatory synapses. MG is caused by autoantibodies against AChR or MuSK at the neuromuscular junction, impairing synaptic transmission. LEMS is mediated by VGCC antibodies, reducing calcium influx and acetylcholine release. SPS is associated with antibodies against GAD65, gephyrin, and amphiphysin, affecting GABAergic inhibitory signaling. These autoimmune disorders underscore the critical role of B cell-mediated humoral immunity in neuroimmunological diseases and better our understanding for the principle of CAR T cell therapy upon these disorders

CAAR T cell and CAR-Treg therapy for wider autoimmune diseases

Beyond autoimmune disorders directly linked to the nervous system [ 119 , 120 ], researchers are also focusing on other autoimmune conditions, including SLE, rheumatoid arthritis (RA), SSC, IIM, anti-synthetase syndrome, PV, Crohn’s disease, and T1D. Among these, the application of CAR T cells has been extensively explored, with increasing data from follow-ups being summarized and presented [ 20 , 21 , 91 , 121 – 125 ]. Notably, various CAR T cell types are being adopted, including derivative approaches such as CAAR T and CAR Treg therapies, which have shown promising outcomes across multiple autoimmune diseases.

CAAR T cell therapy demonstrates superior specificity by selectively eliminating B cells that produce anti-autoantigen antibodies, which may theoretically lead to milder immunosuppressive side effects due to its limited clearance of components. Beyond NMDA receptor encephalitis and MuSK-MG discussed above, preclinical studies of CAAR T-cell therapy have also been conducted in PV and type 1 diabetes. In PV, where autoantibodies target desmoglein 3 (DSG3), DSG3-CAAR T cells were reported to have nearly eradicated all DSG3-specific B cells in both in vivo and in vitro mouse models, significantly reducing anti-DSG3 antibody levels together with novel symptoms improvements without evident toxicity, while preserving other B cell populations [ 91 ]. In terms of T1D, CAAR T cell therapy targeting I-Ag7-B:9–23(R3) was developed yet disappointing results indicated only week-long disease onset delay and failed to prevent disease progression [ 92 ], whereas InsB: R3-CAR Tregs effectively suppressed autoimmunity and demonstrated significant prevention of T1D progression [ 93 ]. In summary, these contrasting outcomes highlight the importance of precise epitope selection in CAAR T design, and that autoimmune diseases with well-defined epitopes could be effectively targeted through CAAR T or CAR-Treg therapies within correct recognition of pathogenic autoantibodies and design [ 47 ]. Moreover, therapeutic efficacy can serve as reverse evidence supporting the pathogenicity of disease-specific epitopes, a concept that may be extended to other neuroimmunological disorders, especially those with unclear pathological procedure.

On the other hand, Tregs, a CD4 + T cell-subset that regulates immune tolerance, was proven to be attractive tools for managing autoimmune disorders [ 126 , 127 ], especially when under redirection to focus on antigen-expressing targets, thus lowering the possibility of systemic immunosuppression. CAR Tregs have expanded application to animal models of T1D, MS, and vitiligo, based on preclinical and clinical results [ 118 , 125 , 128 , 129 ]. Tenspolde et al. first generated FOXP3-engineered insulin-specific CAR Tregs, but they failed to prevent diabetes in NOD mice [ 125 ]. Similarly, targeting the pancreatic marker HPi2 was unsuccessful due to its broad CD4⁺ T-cell expression, causing uncontrolled proliferation [ 130 ]. In contrast, GAD65-CAR Tregs in humanized T1D mice significantly improved glucose tolerance, along with β cell recovery and regeneration [ 131 ]. These findings highlighted the importance of precise antigen selection of optimal CAR targets.

Conclusion

Autoantibodies are produced by plasmablasts, short-lived plasma cells, and long-lived plasma cells. Targeting these cells offers the potential to eliminate the sources of autoantibody production, serving as a promising strategy for the treatment of B cell-mediated autoimmune diseases. CAR T cell therapy has demonstrated the ability to achieve thorough clearance of pathogenic target cells within tissues, effectively creating a “new” immune system, with the reconstituted system seemingly lacking the same predisposition to generate pathogenic B cells, thereby offering the prospect of a complete immune system reset. This could lead to long-term drug-free remission or even a complete cure for autoimmune diseases; however, extended follow-up durations and larger clinical samples are required to substantiate these findings.

Based on the antigenic sites of autoimmune neurological diseases, extracellular antigen-mediated conditions, such as MG, NMOSD, and Anti-NMDAR encephalitis, could potentially benefit from CAR T cell therapy under similar principles [ 132 ]. However, for neurological autoimmune disorders with intracellular antigenic sites, whose pathogenic mechanisms remain unclear, the limited development of targeted therapies highlights the significance of CAR T cell therapy as an emerging treatment, facilitating both therapeutic exploration and mechanistic research. The same principle applies to diseases like MS, where the pathogenic antigen has yet to be clearly identified. As seen in SLE, the role of aberrant B cell activation in SLE has been further elucidated based on the outcomes gained between the adoption of monoclonal antibodies and CAR T cell therapies, also revealing the concept of autoantibody production by distinct cell populations (short-lived versus long-lived plasma cells) with varying sensitivities to B cell depletion therapies [ 33 ]. Anti-dsDNA antibodies, for instance, are hypothesized to originate preferentially from CD19 + plasmablasts or short-lived plasma cells rather than an entire group of aberrant B cells. Similar mechanistic analyses can be applied to autoimmune neurological diseases. In MG, for example, autoantibodies appear to arise primarily from plasmablasts or short-lived plasma cells, as targeting CD19 and BCMA with CAR T cell therapies has shown favorable efficacy, while rituximab, which targets CD20 has also demonstrated to additionally decrease AChR autoantibody levels [ 33 , 133 ].

At the same time, target selection in CAR T cell therapy represents both an opportunity and a challenge. Especially in neurological autoimmune diseases where the pathogenic antigen is either intracellular or not clearly identified—as categorized in our review—evaluating the therapeutic responses of CAR T cells targeting different epitopes may help elucidate the actual disease-driving mechanisms. This approach may be particularly valuable for dissecting the pathogenic basis of neuroimmune autoimmune disorders and guiding the rational design of targeted immunotherapies in the future.

While any autoimmune diseases responsive to B cell depletion therapies could be considered as a potential candidate for CAR T cell therapy, differences in disease context must be acknowledged. Compared to relapsed end-stage cancer patients, individuals with autoimmune diseases tend to be younger, healthier, and exhibit significantly lower mortality rates. Therefore, for autoimmune patients in better health status with much lower mortality rates, it might not be worth it for them to undertake the risk of severe side effects from CAR T cell therapy. This reveals another challenge for further public adoption of CAR T cell therapy on autoimmune disease regardless of its previous outcomes gained, that a delicate balance between the cost of immunosuppression and the treatment efficacy must be carefully evaluated: the risk of excessively eliminating immune cells might lead to long-term immunodeficiency and more side effects. Therefore, CAR T cell therapy candidates are more likely to be patients with dominant B cell pathology and life-threatening disease severity who have failed to respond to safer and more effective treatments. Regarding CAR T cell therapy-related adverse effects, CRS, which occurs in 40% to 80% of hematologic malignancy patients receiving CAR T cell therapy, appears to be rarer and milder in autoimmune diseases [ 134 ]. Schett and his colleagues hypothesized that the lower risk of CRS may result from the lower circulating B cell counts in these patients compared to cancer patients, with the lower B cell burden in autoimmune diseases suggesting a better immune tolerance profile [ 135 ].

Building on the currently registered clinical trials summarized in Table 4 , several practical limitations must still be addressed before broader clinical translation can be realized. Recruitment remains a major hurdle, as identifying patients who are sufficiently treatment-refractory yet stable enough to tolerate a living-drug therapy requires careful calibration of inclusion criteria. Moreover, optimal dosing regimens, lymphodepletion strategies, and monitoring frameworks have not been standardized, leaving uncertainty about how to maximize therapeutic benefit while minimizing prolonged immunosuppression. Equally, long-term risks and durability of response require systematic evaluation and validation in larger and more diverse cohorts. These considerations underscore that, despite promising early signals, the field must continue refining trial design and safety assessment to support the responsible expansion of CAR T cell therapy in neurological autoimmune diseases.

Table 4 Ongoing and registered clinical trials investigating CAR T cell therapy in neurological autoimmune diseases Disease Phase Trial (Official Title) Intervention CAR T Target NCT number Status Myasthenia Gravis (MG) Phase IIb Autologous T-Cells Expressing A Chimeric Antigen Receptor Directed To BCMA In Patients With Generalized MG Descartes-08 BCMA NCT04146051 Active / not recruiting Phase II/III KYSA-6: A Phase 2/3, Open-Label, Randomized, Controlled, Multicenter Study of KYV-101, an Autologous Fully Human Anti CD19 CAR T Therapy, Versus Ongoing Standard-Of-Care Immunosuppressive Therapy in Patients with Generalized MG KYV-101 CD19 NCT06193889 Recruiting Phase I Evaluate the Safety and Efficacy of CD19-BCMA Targeted CAR T Therapy for Refractory, Generalized MG: A Single-center, Open-label, Single-arm, Dose-finding Study CD19-BCMA Targeted CAR T CD19-BCMA NCT06371040 Recruiting Stiff Person Syndrome (SPS) Phase II KYSA-8: A Phase 2 Open-Label, Single-Arm, Multicenter Study of KYV 101, an Autologous Fully Human Anti-CD19 CAR T Therapy, in Subjects with Treatment Refractory SPS KYV-101 CD19 NCT06588491 Recruiting Multiple sclerosis (MS) Phase II KYSA-7: A Phase 2, Open-Label, Randomized, Multicenter Study of KYV-101, an Autologous Fully Human Anti-CD19 CAR T Therapy, in Subjects with Refractory Primary and Secondary Progressive MS KYV-101 CD19 NCT06384976 Active / not recruiting Phase I Phase 1, Open-Label, Single Center Study of KYV-101, an Autologous Fully Human Anti-CD19 CAR T Therapy, in Participants with Treatment Refractory Progressive MS KYV-101 CD19 NCT06451159 Active / not recruiting Phase I/II An Open Label Phase I/IIa, Multicenter, Interventional Single-arm Trial of MB-CART 2019.1 in Patients with Refractory MS MB-CART2019.1 (industry CAR) / NCT07178431 Not yet recruiting Relapsing Forms of Multiple Sclerosis (RMS), Progressive Forms of Multiple Sclerosis (PMS), or Refractory MG. Phase I A Phase 1, Multicenter, Single-arm, Dose-escalation Study of CC-97,540 (BMS-986353), CD19-Targeted NEX-T CAR T Cells, Evaluating Safety and Tolerability in Participants with Autoimmune Neurological Diseases: Relapsing Forms of RMS, PMS, or Refractory MG. CC-97,540 (BMS-986353) CD19 NCT06220201 Recruiting NMOSD, MG, MS, Chronic Inflammatory Demyelinating Polyradiculoneuropathy (CIDP), Autoimmune Encephalitis Phase I A Clinical Study Evaluating the Safety and Preliminary Efficacy of Universal Allogeneic CAR T-cell Therapy Targeting CD19 and BCMA in Patients with Relapsed/ Refractory Neurological Autoimmune Diseases Universal CD19/BCMA CAR T CD19/BCMA NCT06939166 Not yet recruiting NMOSD, MG, CIDP, IIM, MS, autoimmune encephalitis, MOGAD and POEMS Syndrome. Early Phase I An Open Label Clinical Trial to Evaluate the Safety and Efficacy of CT103A Cells for the Treatment of Relapsed/ Refractory Antibody-associated Inflammatory Diseases of the Nervous System CT103A BCMA NCT04561557 Recruiting MS, NMOSD, MOGAD, MG Phase I An Open Clinical Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of LCAR-AIO CAR-T Cells for Treating Relapsed/Refractory Neurological Autoimmune Diseases LCAR-AIO / NCT06869278 Recruiting

We searched ClinicalTrials.gov for registered CAR T clinical trials in neurological autoimmune diseases. Table 4 lists the ongoing and registered trials we identified, along with NCT identifiers and sources. For several disease entities (LEMS, Anti-NMDAR encephalitis, DAGLA encephalitis) no dedicated CAR T registered trials were found at the time of search, indicating evidence gaps.

In summary, longer experimental durations, larger sample sizes, and rigorous long-term safety monitoring are crucial for advancing the application and maturation of CAR T cell therapy in autoimmune neurological diseases. Despite current challenges, CAR T cell therapy represents a highly promising and revolutionary approach with significant potential to improve patient outcomes.

Abbreviations

Acetylcholine Receptor

Acute Disseminated Encephalomyelitis

Antiglial Nuclear Antibody

Adenylate Kinase 5

α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid Receptor

Antineuronal Nuclear Antibody

Antigen-Presenting Cells

Aquaporin-4

Blood–Brain Barrier

B cell Maturation Antigen

Chimeric Autoantigen Receptor

Cornell Assessment of Pediatric Delirium score

Chimeric Antigen Receptor

Clinical Assessment Scale in Autoimmune Encephalitis

Contactin-Associated Protein-Like 2

Central Nervous System

Cytokine Release Syndrome

Cerebrospinal Fluid

Cerebral and Spinal Magnetic Resonance Imaging

Diacylglycerol Lipase Alpha

Desmoglein 3

Experimental Autoimmune Myasthenia Gravis

Experimental Autoimmune Encephalomyelitis

Expanded Disability Status Scale

Fc Receptor Neonatal Inhibitors

γ-aminobutyric Acid

Glutamic Acid Decarboxylase 65

Glial Fibrillary Acidic Protein

Glutamate Receptor 1/2

Granzyme B

Immune Effector Cell-Associated Neurotoxicity Syndrome

Immune Effector Cell-Associated Encephalopathy score

International Cooperative Ataxia Rating Scale

Interferon

Idiopathic Inflammatory Myopathies

Intravenous Immunoglobulin

Iimbic Encephalitis

Lambert-Eaton Myasthenic Syndrome

Leucine-Rich Glioma-Inactivated 1

Lower Limit of Normal

Modified Ashworth Scale

Myelin Basic Protein

Myasthenia Gravis

Myasthenia Gravis Activities of Daily Living

Myasthenia Gravis Foundation of America

Major Histocompatibility Complex

Metabotropic Glutamate Receptor 5

Myelin Oligodendrocyte Glycoprotein

Myelin Oligodendrocyte Glycoprotein Antibody-Associated Disease

Medical Research Council

Multiple Sclerosis

Muscle-Specific Tyrosine Kinase

N-Methyl-D-Aspartate Receptor

Neuromuscular Junction

Neuromyelitis Optica Spectrum Disorder

N-Methyl-D-Aspartate Receptor Subunit 1

Numeric Rating Scale / numeric rating scale

Oligoclonal Bands

Purkinje Cell Antigen 1/2

Proteolipid Protein

Primary-Progressive Multiple Sclerosis

Pemphigus Vulgaris

Quantitative Myasthenia Gravis

Rheumatoid Arthritis

Relapsing-Remitting Multiple Sclerosis

single-chain Fragment variables

Systemic Lupus Erythematosus

Stiff Person Syndrome

Sjögren’s Syndrome

Tumor-Associated Antigens

Type 1 Diabetes

T cell Receptor

Tumor Necrosis Factor

Regulatory T cells

Voltage Gated Calcium Channel

Voltage-Gated Potassium Channels

2-arachidonoylglycerol

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Muzi Wen, Ruoyi Zheng and Hanqing Zhang contributed equally to this work and share first authorship.

Change history

6/1/2026

Funding details has been updated

Acknowledgements

We thank Adobe Illustrator and Biorender.com for figure generation. We thank JW for providing valuable suggestions and professional support in the process of paper revision.

Authors’ contributions

PS conceptualized and drafted this manuscript. MZW, RYZ and HQZ contributed equally to this work and were responsible for the conceptualization, literature review, and drafting of the manuscript. SYG and SSK contributed to critical revision of the manuscript for important intellectual content.YG, RGC, LXW and YZ contributed to data collection, manuscript editing, refinement and formatting. MZW and ZYJ designed the figures. PS supervised the study, provided overall guidance, and reviewed the final version of the manuscript. All the authors participated in multiple rounds of revision of the paper.

Funding

The authors declare that financial support was received for the research and publication of this article. This work was supported by Fellowship from the China Postdoctoral Foundation (2023M741573) and Science and Technology Projects in Guangzhou (2023A04J2337).

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.

References

1. Pisetsky DS Pathogenesis of autoimmune disease Nat Rev Nephrol 2023 19 8 509 24 10.1038/s41581-023-00720-1 37165096 PMC10171171 Pisetsky DS. Pathogenesis of autoimmune disease. Nat Rev Nephrol. 2023;19(8):509–24. 37165096 10.1038/s41581-023-00720-1 PMC10171171

2. Cortés-Vicente E Álvarez-Velasco R Pla-Junca F Rojas-Garcia R Paradas C Sevilla T Drug-refractory myasthenia gravis: clinical characteristics, treatments, and outcome Ann Clin Transl Neurol 2022 9 2 122 31 10.1002/acn3.51492 35080153 PMC8862423 Cortés-Vicente E, Álvarez-Velasco R, Pla-Junca F, Rojas-Garcia R, Paradas C, Sevilla T, et al. Drug-refractory myasthenia gravis: clinical characteristics, treatments, and outcome. Ann Clin Transl Neurol. 2022;9(2):122–31. 35080153 10.1002/acn3.51492 PMC8862423

3. Pittock SJ Berthele A Fujihara K Kim HJ Levy M Palace J Eculizumab in Aquaporin-4-Positive neuromyelitis Optica spectrum disorder N Engl J Med 2019 381 7 614 25 10.1056/NEJMoa1900866 31050279 Pittock SJ, Berthele A, Fujihara K, Kim HJ, Levy M, Palace J, et al. Eculizumab in Aquaporin-4-Positive neuromyelitis Optica spectrum disorder. N Engl J Med. 2019;381(7):614–25. 31050279 10.1056/NEJMoa1900866

4. Damato V Evoli A Iorio R Efficacy and safety of rituximab therapy in neuromyelitis Optica spectrum disorders: A systematic review and Meta-analysis JAMA Neurol 2016 73 11 1342 8 10.1001/jamaneurol.2016.1637 27668357 Damato V, Evoli A, Iorio R. Efficacy and safety of rituximab therapy in neuromyelitis Optica spectrum disorders: A systematic review and Meta-analysis. JAMA Neurol. 2016;73(11):1342–8. 27668357 10.1001/jamaneurol.2016.1637

5. Ohishi K Kanoh M Shinomiya H Hitsumoto Y Utsumi S Complement activation by cross-linked B cell-membrane IgM J Immunol 1995 154 7 3173 9 10.4049/jimmunol.154.7.3173 7897206 Ohishi K, Kanoh M, Shinomiya H, Hitsumoto Y, Utsumi S. Complement activation by cross-linked B cell-membrane IgM. J Immunol. 1995;154(7):3173–9. 7897206

6. Zamvil SS Hauser SL Antigen presentation by B cells in multiple sclerosis N Engl J Med 2021 384 4 378 81 10.1056/NEJMcibr2032177 33503348 PMC8029120 Zamvil SS, Hauser SL. Antigen presentation by B cells in multiple sclerosis. N Engl J Med. 2021;384(4):378–81. 33503348 10.1056/NEJMcibr2032177 PMC8029120

7. Jain RW Yong VW B cells in central nervous system disease: diversity, locations and pathophysiology Nat Rev Immunol 2022 22 8 513 24 10.1038/s41577-021-00652-6 34903877 PMC8667979 Jain RW, Yong VW. B cells in central nervous system disease: diversity, locations and pathophysiology. Nat Rev Immunol. 2022;22(8):513–24. 34903877 10.1038/s41577-021-00652-6 PMC8667979

8. Koneczny I, Herbst R. Myasthenia gravis: pathogenic effects of autoantibodies on neuromuscular architecture. Cells. 2019;8(7):671. 10.3390/cells8070671 PMC6678492 31269763

9. Morshed SA, Davies TF. Graves’ disease mechanisms: the role of Stimulating, Blocking, and cleavage region TSH receptor antibodies. Hormone Metabolic Res = Hormon- Und Stoffwechselforschung = Horm Et Metab. 2015;47(10):727–34. 10.1055/s-0035-1559633 PMC5047290 26361259

10. Hammers CM Stanley JR Mechanisms of disease: pemphigus and bullous pemphigoid Annu Rev Pathol 2016 11 175 97 10.1146/annurev-pathol-012615-044313 26907530 PMC5560122 Hammers CM, Stanley JR. Mechanisms of disease: pemphigus and bullous pemphigoid. Annu Rev Pathol. 2016;11:175–97. 26907530 10.1146/annurev-pathol-012615-044313 PMC5560122

11. Cree BAC Bennett JL Kim HJ Weinshenker BG Pittock SJ Wingerchuk DM Inebilizumab for the treatment of neuromyelitis Optica spectrum disorder (N-MOmentum): a double-blind, randomised placebo-controlled phase 2/3 trial Lancet 2019 394 10206 1352 63 10.1016/S0140-6736(19)31817-3 31495497 Cree BAC, Bennett JL, Kim HJ, Weinshenker BG, Pittock SJ, Wingerchuk DM, et al. Inebilizumab for the treatment of neuromyelitis Optica spectrum disorder (N-MOmentum): a double-blind, randomised placebo-controlled phase 2/3 trial. Lancet. 2019;394(10206):1352–63. 31495497 10.1016/S0140-6736(19)31817-3

12. Seery N Wesselingh R Beech P McLaughlin L Rushen T Halliday AJ Rituximab use for relapse prevention in Anti-NMDAR Antibody-Mediated encephalitis: A multicenter cohort study Neurol Neuroimmunol Neuroinflamm 2025 12 4 e200395 10.1212/NXI.0000000000200395 40446185 PMC12153942 Seery N, Wesselingh R, Beech P, McLaughlin L, Rushen T, Halliday AJ, et al. Rituximab use for relapse prevention in Anti-NMDAR Antibody-Mediated encephalitis: A multicenter cohort study. Neurol Neuroimmunol Neuroinflamm. 2025;12(4):e200395. 40446185 10.1212/NXI.0000000000200395 PMC12153942

13. von Baumgarten L, Stauss HJ, Lünemann JD. Synthetic Cell-Based Immunotherapies for Neurologic Diseases. Neurology(R) neuroimmunology & neuroinflammation. 2023;10(5):e200139. 10.1212/NXI.0000000000200139 PMC10474853 37385738

14. Siddiqi T Wang X Blanchard MS Wagner JR Popplewell LL Budde LE CD19-directed CAR T-cell therapy for treatment of primary CNS lymphoma Blood Adv 2021 5 20 4059 63 10.1182/bloodadvances.2020004106 34492703 PMC8945630 Siddiqi T, Wang X, Blanchard MS, Wagner JR, Popplewell LL, Budde LE, et al. CD19-directed CAR T-cell therapy for treatment of primary CNS lymphoma. Blood Adv. 2021;5(20):4059–63. 34492703 10.1182/bloodadvances.2020004106 PMC8945630

15. Häusler D Häusser-Kinzel S Feldmann L Torke S Lepennetier G Bernard CCA Functional characterization of reappearing B cells after anti-CD20 treatment of CNS autoimmune disease Proc Natl Acad Sci U S A 2018 115 39 9773 8 10.1073/pnas.1810470115 30194232 PMC6166805 Häusler D, Häusser-Kinzel S, Feldmann L, Torke S, Lepennetier G, Bernard CCA, et al. Functional characterization of reappearing B cells after anti-CD20 treatment of CNS autoimmune disease. Proc Natl Acad Sci U S A. 2018;115(39):9773–8. 30194232 10.1073/pnas.1810470115 PMC6166805

16. Cao S Zhou X Du J Zhang J Zhu Y Wei L Relapses during treatment with monoclonal antibodies targeting B-cells in NMOSD J Neurol 2025 272 6 406 10.1007/s00415-025-13118-9 40383834 Cao S, Zhou X, Du J, Zhang J, Zhu Y, Wei L, et al. Relapses during treatment with monoclonal antibodies targeting B-cells in NMOSD. J Neurol. 2025;272(6):406. 40383834 10.1007/s00415-025-13118-9

17. Lee DSW Rojas OL Gommerman JL B cell depletion therapies in autoimmune disease: advances and mechanistic insights Nat Rev Drug Discov 2021 20 3 179 99 10.1038/s41573-020-00092-2 33324003 PMC7737718 Lee DSW, Rojas OL, Gommerman JL. B cell depletion therapies in autoimmune disease: advances and mechanistic insights. Nat Rev Drug Discov. 2021;20(3):179–99. 33324003 10.1038/s41573-020-00092-2 PMC7737718

18. Danaher P Hasle N Nguyen ED Roberts JE Rosenwasser N Rickert C Childhood-onset lupus nephritis is characterized by complex interactions between kidney stroma and infiltrating immune cells Sci Transl Med 2024 16 775 eadl1666 10.1126/scitranslmed.adl1666 39602512 PMC11708815 Danaher P, Hasle N, Nguyen ED, Roberts JE, Rosenwasser N, Rickert C, et al. Childhood-onset lupus nephritis is characterized by complex interactions between kidney stroma and infiltrating immune cells. Sci Transl Med. 2024;16(775):eadl1666. 39602512 10.1126/scitranslmed.adl1666 PMC11708815

19. Schett G Mackensen A Mougiakakos D CAR T-cell therapy in autoimmune diseases Lancet (London England) 2023 402 10416 2034 44 10.1016/S0140-6736(23)01126-1 37748491 Schett G, Mackensen A, Mougiakakos D. CAR T-cell therapy in autoimmune diseases. Lancet (London England). 2023;402(10416):2034–44. 37748491 10.1016/S0140-6736(23)01126-1

20. Mougiakakos D Krönke G Völkl S Kretschmann S Aigner M Kharboutli S CD19-Targeted CAR T cells in refractory systemic lupus erythematosus N Engl J Med 2021 385 6 567 9 10.1056/NEJMc2107725 34347960 Mougiakakos D, Krönke G, Völkl S, Kretschmann S, Aigner M, Kharboutli S, et al. CD19-Targeted CAR T cells in refractory systemic lupus erythematosus. N Engl J Med. 2021;385(6):567–9. 34347960 10.1056/NEJMc2107725

21. Müller F Taubmann J Bucci L Wilhelm A Bergmann C Völkl S CD19 CAR T-Cell therapy in autoimmune Disease - A case series with Follow-up N Engl J Med 2024 390 8 687 700 10.1056/NEJMoa2308917 38381673 Müller F, Taubmann J, Bucci L, Wilhelm A, Bergmann C, Völkl S, et al. CD19 CAR T-Cell therapy in autoimmune Disease - A case series with Follow-up. N Engl J Med. 2024;390(8):687–700. 38381673 10.1056/NEJMoa2308917

22. Koff JL Cashman KS Warren V Smith K Flowers CR Sanz I Circulating B cell subsets from untreated diffuse large B cell lymphoma (DLBCL) patients resemble those of patients with autoimmune disease Blood 2018 132 Supplement 1 4221 10.1182/blood-2018-99-119031 Koff JL, Cashman KS, Warren V, Smith K, Flowers CR, Sanz I. Circulating B cell subsets from untreated diffuse large B cell lymphoma (DLBCL) patients resemble those of patients with autoimmune disease. Blood. 2018;132(Supplement 1):4221.

23. Pecher AC Hensen L Lengerke C Henes J The future of CAR T therapeutics to treat autoimmune disorders Mol Diagn Ther 2024 28 5 593 600 10.1007/s40291-024-00730-0 39078456 PMC11349844 Pecher AC, Hensen L, Lengerke C, Henes J. The future of CAR T therapeutics to treat autoimmune disorders. Mol Diagn Ther. 2024;28(5):593–600. 39078456 10.1007/s40291-024-00730-0 PMC11349844

24. Granit V Benatar M Kurtoglu M Miljković MD Chahin N Sahagian G Safety and clinical activity of autologous RNA chimeric antigen receptor T-cell therapy in myasthenia Gravis (MG-001): a prospective, multicentre, open-label, non-randomised phase 1b/2a study Lancet Neurol 2023 22 7 578 90 10.1016/S1474-4422(23)00194-1 37353278 PMC10416207 Granit V, Benatar M, Kurtoglu M, Miljković MD, Chahin N, Sahagian G, et al. Safety and clinical activity of autologous RNA chimeric antigen receptor T-cell therapy in myasthenia Gravis (MG-001): a prospective, multicentre, open-label, non-randomised phase 1b/2a study. Lancet Neurol. 2023;22(7):578–90. 37353278 10.1016/S1474-4422(23)00194-1 PMC10416207

25. Haghikia A Hegelmaier T Wolleschak D Böttcher M Desel C Borie D Anti-CD19 CAR T cells for refractory myasthenia Gravis Lancet Neurol 2023 22 12 1104 5 10.1016/S1474-4422(23)00375-7 37977704 Haghikia A, Hegelmaier T, Wolleschak D, Böttcher M, Desel C, Borie D, et al. Anti-CD19 CAR T cells for refractory myasthenia Gravis. Lancet Neurol. 2023;22(12):1104–5. 37977704 10.1016/S1474-4422(23)00375-7

26. Motte J Sgodzai M Schneider-Gold C Steckel N Mika T Hegelmaier T Treatment of concomitant myasthenia Gravis and Lambert-Eaton myasthenic syndrome with autologous CD19-targeted CAR T cells Neuron 2024 112 11 1757 e632 10.1016/j.neuron.2024.04.014 38697115 Motte J, Sgodzai M, Schneider-Gold C, Steckel N, Mika T, Hegelmaier T, et al. Treatment of concomitant myasthenia Gravis and Lambert-Eaton myasthenic syndrome with autologous CD19-targeted CAR T cells. Neuron. 2024;112(11):1757–e632. 38697115 10.1016/j.neuron.2024.04.014

27. Qin C Zhang M Mou DP Zhou LQ Dong MH Huang L Single-cell analysis of anti-BCMA CAR T cell therapy in patients with central nervous system autoimmunity Sci Immunol 2024 9 95 eadj9730 10.1126/sciimmunol.adj9730 38728414 Qin C, Zhang M, Mou DP, Zhou LQ, Dong MH, Huang L, et al. Single-cell analysis of anti-BCMA CAR T cell therapy in patients with central nervous system autoimmunity. Sci Immunol. 2024;9(95):eadj9730. 38728414 10.1126/sciimmunol.adj9730

28. Qin C Tian DS Zhou LQ Shang K Huang L Dong MH Anti-BCMA CAR T-cell therapy CT103A in relapsed or refractory AQP4-IgG seropositive neuromyelitis Optica spectrum disorders: phase 1 trial interim results Signal Transduct Target Ther 2023 8 1 5 10.1038/s41392-022-01278-3 36596762 PMC9810610 Qin C, Tian DS, Zhou LQ, Shang K, Huang L, Dong MH, et al. Anti-BCMA CAR T-cell therapy CT103A in relapsed or refractory AQP4-IgG seropositive neuromyelitis Optica spectrum disorders: phase 1 trial interim results. Signal Transduct Target Ther. 2023;8(1):5. 36596762 10.1038/s41392-022-01278-3 PMC9810610

29. Reincke SM von Wardenburg N Homeyer MA Kornau HC Spagni G Li LY Chimeric autoantibody receptor T cells deplete NMDA receptor-specific B cells Cell 2023 186 23 5084 e9718 10.1016/j.cell.2023.10.001 37918394 Reincke SM, von Wardenburg N, Homeyer MA, Kornau HC, Spagni G, Li LY, et al. Chimeric autoantibody receptor T cells deplete NMDA receptor-specific B cells. Cell. 2023;186(23):5084–e9718. 37918394 10.1016/j.cell.2023.10.001

30. Monson NL Cravens PD Frohman EM Hawker K Racke MK Effect of rituximab on the peripheral blood and cerebrospinal fluid B cells in patients with primary progressive multiple sclerosis Arch Neurol 2005 62 2 258 64 10.1001/archneur.62.2.258 15710854 Monson NL, Cravens PD, Frohman EM, Hawker K, Racke MK. Effect of rituximab on the peripheral blood and cerebrospinal fluid B cells in patients with primary progressive multiple sclerosis. Arch Neurol. 2005;62(2):258–64. 15710854 10.1001/archneur.62.2.258

31. Bhoj VG Arhontoulis D Wertheim G Capobianchi J Callahan CA Ellebrecht CT Persistence of long-lived plasma cells and humoral immunity in individuals responding to CD19-directed CAR T-cell therapy Blood 2016 128 3 360 70 10.1182/blood-2016-01-694356 27166358 PMC4957161 Bhoj VG, Arhontoulis D, Wertheim G, Capobianchi J, Callahan CA, Ellebrecht CT, et al. Persistence of long-lived plasma cells and humoral immunity in individuals responding to CD19-directed CAR T-cell therapy. Blood. 2016;128(3):360–70. 27166358 10.1182/blood-2016-01-694356 PMC4957161

32. Halliley JL Tipton CM Liesveld J Rosenberg AF Darce J Gregoretti IV Long-Lived plasma cells are contained within the CD19(-)CD38(hi)CD138(+) subset in human bone marrow Immunity 2015 43 1 132 45 10.1016/j.immuni.2015.06.016 26187412 PMC4680845 Halliley JL, Tipton CM, Liesveld J, Rosenberg AF, Darce J, Gregoretti IV, et al. Long-Lived plasma cells are contained within the CD19(-)CD38(hi)CD138(+) subset in human bone marrow. Immunity. 2015;43(1):132–45. 26187412 10.1016/j.immuni.2015.06.016 PMC4680845

33. Taubmann J Müller F Yalcin Mutlu M Völkl S Aigner M Bozec A CD19 chimeric antigen receptor T cell treatment: unraveling the role of B cells in systemic lupus erythematosus 2024 Hoboken, NJ Arthritis & rheumatology 497 504 10.1002/art.42784 38114423 Taubmann J, Müller F, Yalcin Mutlu M, Völkl S, Aigner M, Bozec A, et al. CD19 chimeric antigen receptor T cell treatment: unraveling the role of B cells in systemic lupus erythematosus. Volume 76. Hoboken, NJ: Arthritis & rheumatology; 2024. pp. 497–504. 4. 10.1002/art.42784 38114423

34. Mullard A CAR T cell therapies Raise hopes - and questions - for lupus and autoimmune disease Nat Rev Drug Discov 2023 22 11 859 61 10.1038/d41573-023-00166-x 37833555 Mullard A. CAR T cell therapies Raise hopes - and questions - for lupus and autoimmune disease. Nat Rev Drug Discov. 2023;22(11):859–61. 37833555 10.1038/d41573-023-00166-x

35. Grant SJ Grimshaw AA Silberstein J Murdaugh D Wildes TM Rosko AE Clinical Presentation, risk Factors, and outcomes of immune effector cell-Associated neurotoxicity syndrome following chimeric antigen receptor T cell therapy: A systematic review Transplantation Cell Therapy 2022 28 6 294 302 10.1016/j.jtct.2022.03.006 PMC9197870 35288347 Grant SJ, Grimshaw AA, Silberstein J, Murdaugh D, Wildes TM, Rosko AE, et al. Clinical Presentation, risk Factors, and outcomes of immune effector cell-Associated neurotoxicity syndrome following chimeric antigen receptor T cell therapy: A systematic review. Transplantation Cell Therapy. 2022;28(6):294–302. 10.1016/j.jtct.2022.03.006 PMC9197870 35288347

36. Ferreira LMR Muller YD Bluestone JA Tang Q Next-generation regulatory T cell therapy Nat Rev Drug Discov 2019 18 10 749 69 10.1038/s41573-019-0041-4 31541224 PMC7773144 Ferreira LMR, Muller YD, Bluestone JA, Tang Q. Next-generation regulatory T cell therapy. Nat Rev Drug Discov. 2019;18(10):749–69. 31541224 10.1038/s41573-019-0041-4 PMC7773144

37. Abboud H Probasco JC Irani S Ances B Benavides DR Bradshaw M Autoimmune encephalitis: proposed best practice recommendations for diagnosis and acute management J Neurol Neurosurg Psychiatry 2021 92 7 757 68 10.1136/jnnp-2020-325300 33649022 PMC8223680 Abboud H, Probasco JC, Irani S, Ances B, Benavides DR, Bradshaw M, et al. Autoimmune encephalitis: proposed best practice recommendations for diagnosis and acute management. J Neurol Neurosurg Psychiatry. 2021;92(7):757–68. 33649022 10.1136/jnnp-2020-325300 PMC8223680

38. Ramírez-Valle F Maranville JC Roy S Plenge RM Sequential immunotherapy: towards cures for autoimmunity Nat Rev Drug Discov 2024 23 7 501 24 10.1038/s41573-024-00959-8 38839912 Ramírez-Valle F, Maranville JC, Roy S, Plenge RM. Sequential immunotherapy: towards cures for autoimmunity. Nat Rev Drug Discov. 2024;23(7):501–24. 38839912 10.1038/s41573-024-00959-8

39. Thaler FS, Zimmermann L, Kammermeier S, Strippel C, Ringelstein M, Kraft A, et al. Rituximab treatment and long-term outcome of patients with autoimmune encephalitis: real-world evidence from the GENERATE registry. Neurol Neuroimmunol Neuroinflamm. 2021;8(6):e1088. 10.1212/NXI.0000000000001088 PMC8488759 34599001

40. Howard JF Jr Utsugisawa K Benatar M Murai H Barohn RJ Illa I Safety and efficacy of Eculizumab in anti-acetylcholine receptor antibody-positive refractory generalised myasthenia Gravis (REGAIN): a phase 3, randomised, double-blind, placebo-controlled, multicentre study Lancet Neurol 2017 16 12 976 86 10.1016/S1474-4422(17)30369-1 29066163 Howard JF Jr., Utsugisawa K, Benatar M, Murai H, Barohn RJ, Illa I, et al. Safety and efficacy of Eculizumab in anti-acetylcholine receptor antibody-positive refractory generalised myasthenia Gravis (REGAIN): a phase 3, randomised, double-blind, placebo-controlled, multicentre study. Lancet Neurol. 2017;16(12):976–86. 29066163 10.1016/S1474-4422(17)30369-1

41. Pittock SJ Barnett M Bennett JL Berthele A de Sèze J Levy M Ravulizumab in Aquaporin-4-Positive neuromyelitis Optica spectrum disorder Ann Neurol 2023 93 6 1053 68 10.1002/ana.26626 36866852 Pittock SJ, Barnett M, Bennett JL, Berthele A, de Sèze J, Levy M, et al. Ravulizumab in Aquaporin-4-Positive neuromyelitis Optica spectrum disorder. Ann Neurol. 2023;93(6):1053–68. 36866852 10.1002/ana.26626

42. Scheibe F Prüss H Mengel AM Kohler S Nümann A Köhnlein M Bortezomib for treatment of therapy-refractory anti-NMDA receptor encephalitis Neurology 2017 88 4 366 70 10.1212/WNL.0000000000003536 28003505 Scheibe F, Prüss H, Mengel AM, Kohler S, Nümann A, Köhnlein M, et al. Bortezomib for treatment of therapy-refractory anti-NMDA receptor encephalitis. Neurology. 2017;88(4):366–70. 28003505 10.1212/WNL.0000000000003536

43. Lee WJ Lee ST Moon J Sunwoo JS Byun JI Lim JA Tocilizumab in autoimmune encephalitis refractory to rituximab: an institutional cohort study Neurotherapeutics 2016 13 4 824 32 10.1007/s13311-016-0442-6 27215218 PMC5081109 Lee WJ, Lee ST, Moon J, Sunwoo JS, Byun JI, Lim JA, et al. Tocilizumab in autoimmune encephalitis refractory to rituximab: an institutional cohort study. Neurotherapeutics. 2016;13(4):824–32. 27215218 10.1007/s13311-016-0442-6 PMC5081109

44. Hauser SL Bar-Or A Comi G Giovannoni G Hartung HP Hemmer B Ocrelizumab versus interferon Beta-1a in relapsing multiple sclerosis N Engl J Med 2017 376 3 221 34 10.1056/NEJMoa1601277 28002679 Hauser SL, Bar-Or A, Comi G, Giovannoni G, Hartung HP, Hemmer B, et al. Ocrelizumab versus interferon Beta-1a in relapsing multiple sclerosis. N Engl J Med. 2017;376(3):221–34. 28002679 10.1056/NEJMoa1601277

45. Tur C Carbonell-Mirabent P Cobo-Calvo Á Otero-Romero S Arrambide G Midaglia L Association of early progression independent of relapse activity with Long-term disability after a first demyelinating event in multiple sclerosis JAMA Neurol 2023 80 2 151 60 10.1001/jamaneurol.2022.4655 36534392 PMC9856884 Tur C, Carbonell-Mirabent P, Cobo-Calvo Á, Otero-Romero S, Arrambide G, Midaglia L, et al. Association of early progression independent of relapse activity with Long-term disability after a first demyelinating event in multiple sclerosis. JAMA Neurol. 2023;80(2):151–60. 36534392 10.1001/jamaneurol.2022.4655 PMC9856884

46. Maus MV Plotkin J Jakka G Stewart-Jones G Rivière I Merghoub T An MHC-restricted antibody-based chimeric antigen receptor requires TCR-like affinity to maintain antigen specificity Mol Therapy Oncolytics 2016 3 1 9 10.1038/mto.2016.23 PMC5904357 29675462 Maus MV, Plotkin J, Jakka G, Stewart-Jones G, Rivière I, Merghoub T, et al. An MHC-restricted antibody-based chimeric antigen receptor requires TCR-like affinity to maintain antigen specificity. Mol Therapy Oncolytics. 2016;3:1–9. 10.1038/mto.2016.23 PMC5904357 29675462

47. Zhang P Zhang G Wan X Challenges and new technologies in adoptive cell therapy J Hematol Oncol 2023 16 1 97 10.1186/s13045-023-01492-8 37596653 PMC10439661 Zhang P, Zhang G, Wan X. Challenges and new technologies in adoptive cell therapy. J Hematol Oncol. 2023;16(1):97. 37596653 10.1186/s13045-023-01492-8 PMC10439661

48. Aghajanian H Rurik JG Epstein JA CAR-based therapies: opportunities for immuno-medicine beyond cancer Nat Metabolism 2022 4 2 163 9 10.1038/s42255-022-00537-5 PMC9947862 35228742 Aghajanian H, Rurik JG, Epstein JA. CAR-based therapies: opportunities for immuno-medicine beyond cancer. Nat Metabolism. 2022;4(2):163–9. 10.1038/s42255-022-00537-5 PMC9947862 35228742

49. Labanieh L Mackall CL CAR immune cells: design principles, resistance and the next generation Nature 2023 614 7949 635 48 10.1038/s41586-023-05707-3 36813894 Labanieh L, Mackall CL. CAR immune cells: design principles, resistance and the next generation. Nature. 2023;614(7949):635–48. 36813894 10.1038/s41586-023-05707-3

50. June CH Sadelain M Chimeric antigen receptor therapy N Engl J Med 2018 379 1 64 73 10.1056/NEJMra1706169 29972754 PMC7433347 June CH, Sadelain M. Chimeric antigen receptor therapy. N Engl J Med. 2018;379(1):64–73. 29972754 10.1056/NEJMra1706169 PMC7433347

51. Sun Y Yuan Y Zhang B Zhang X CARs: a new approach for the treatment of autoimmune diseases Sci China Life Sci 2023 66 4 711 28 10.1007/s11427-022-2212-5 36346550 PMC9641699 Sun Y, Yuan Y, Zhang B, Zhang X. CARs: a new approach for the treatment of autoimmune diseases. Sci China Life Sci. 2023;66(4):711–28. 36346550 10.1007/s11427-022-2212-5 PMC9641699

52. Sadeqi Nezhad M Seifalian A Bagheri N Yaghoubi S Karimi MH Adbollahpour-Alitappeh M Chimeric antigen receptor based therapy as a potential approach in autoimmune diseases: how close are we to the treatment? Front Immunol 2020 11 603237 10.3389/fimmu.2020.603237 33324420 PMC7727445 Sadeqi Nezhad M, Seifalian A, Bagheri N, Yaghoubi S, Karimi MH, Adbollahpour-Alitappeh M. Chimeric antigen receptor based therapy as a potential approach in autoimmune diseases: how close are we to the treatment? Front Immunol. 2020;11:603237. 33324420 10.3389/fimmu.2020.603237 PMC7727445

53. Santomasso BD Nastoupil LJ Adkins S Lacchetti C Schneider BJ Anadkat M Management of Immune-Related adverse events in patients treated with chimeric antigen receptor T-Cell therapy: ASCO guideline J Clin Oncol 2021 39 35 3978 92 10.1200/JCO.21.01992 34724386 Santomasso BD, Nastoupil LJ, Adkins S, Lacchetti C, Schneider BJ, Anadkat M, et al. Management of Immune-Related adverse events in patients treated with chimeric antigen receptor T-Cell therapy: ASCO guideline. J Clin Oncol. 2021;39(35):3978–92. 34724386 10.1200/JCO.21.01992

54. Lee DW Santomasso BD Locke FL Ghobadi A Turtle CJ Brudno JN ASTCT consensus grading for cytokine release syndrome and neurologic toxicity associated with immune effector cells Biol Blood Marrow Transpl 2019 25 4 625 38 10.1016/j.bbmt.2018.12.758 PMC12180426 30592986 Lee DW, Santomasso BD, Locke FL, Ghobadi A, Turtle CJ, Brudno JN, et al. ASTCT consensus grading for cytokine release syndrome and neurologic toxicity associated with immune effector cells. Biol Blood Marrow Transpl. 2019;25(4):625–38. 10.1016/j.bbmt.2018.12.758 PMC12180426 30592986

55. Kattamuri L Mohan Lal B Vojjala N Jain M Sharma K Jain S Safety and efficacy of CAR-T cell therapy in patients with autoimmune diseases: a systematic review Rheumatol Int 2025 45 1 18 10.1007/s00296-024-05772-5 39754644 Kattamuri L, Mohan Lal B, Vojjala N, Jain M, Sharma K, Jain S, et al. Safety and efficacy of CAR-T cell therapy in patients with autoimmune diseases: a systematic review. Rheumatol Int. 2025;45(1):18. 39754644 10.1007/s00296-024-05772-5

56. Majzner RG Mackall CL Tumor antigen escape from CAR T-cell therapy Cancer Discov 2018 8 10 1219 26 10.1158/2159-8290.CD-18-0442 30135176 Majzner RG, Mackall CL. Tumor antigen escape from CAR T-cell therapy. Cancer Discov. 2018;8(10):1219–26. 30135176 10.1158/2159-8290.CD-18-0442

57. Oh S Mao X Manfredo-Vieira S Lee J Patel D Choi EJ Precision targeting of autoantigen-specific B cells in muscle-specific tyrosine kinase myasthenia Gravis with chimeric autoantibody receptor T cells Nat Biotechnol 2023 41 9 1229 38 10.1038/s41587-022-01637-z 36658341 PMC10354218 Oh S, Mao X, Manfredo-Vieira S, Lee J, Patel D, Choi EJ, et al. Precision targeting of autoantigen-specific B cells in muscle-specific tyrosine kinase myasthenia Gravis with chimeric autoantibody receptor T cells. Nat Biotechnol. 2023;41(9):1229–38. 36658341 10.1038/s41587-022-01637-z PMC10354218

58. Baker DJ Arany Z Baur JA Epstein JA June CH CAR T therapy beyond cancer: the evolution of a living drug Nature 2023 619 7971 707 15 10.1038/s41586-023-06243-w 37495877 PMC12522170 Baker DJ, Arany Z, Baur JA, Epstein JA, June CH. CAR T therapy beyond cancer: the evolution of a living drug. Nature. 2023;619(7971):707–15. 37495877 10.1038/s41586-023-06243-w PMC12522170

59. Prüss H Autoantibodies in neurological disease Nat Rev Immunol 2021 21 12 798 813 10.1038/s41577-021-00543-w 33976421 PMC8111372 Prüss H. Autoantibodies in neurological disease. Nat Rev Immunol. 2021;21(12):798–813. 33976421 10.1038/s41577-021-00543-w PMC8111372

60. Burbelo PD Iadarola MJ Keller JM Warner BM Autoantibodies targeting intracellular and extracellular proteins in autoimmunity Front Immunol 2021 12 548469 10.3389/fimmu.2021.548469 33763057 PMC7982651 Burbelo PD, Iadarola MJ, Keller JM, Warner BM. Autoantibodies targeting intracellular and extracellular proteins in autoimmunity. Front Immunol. 2021;12:548469. 33763057 10.3389/fimmu.2021.548469 PMC7982651

61. Segal Y Zekeridou A Interest of rare autoantibodies in autoimmune encephalitis and paraneoplastic neurological syndromes: the utility (or futility) of rare antibody discovery Curr Opin Neurol 2024 37 3 295 304 10.1097/WCO.0000000000001261 38533672 Segal Y, Zekeridou A. Interest of rare autoantibodies in autoimmune encephalitis and paraneoplastic neurological syndromes: the utility (or futility) of rare antibody discovery. Curr Opin Neurol. 2024;37(3):295–304. 38533672 10.1097/WCO.0000000000001261

62. Dubey D Jitprapaikulsan J Bi H Do Campo RV McKeon A Pittock SJ Amphiphysin-IgG autoimmune neuropathy: A recognizable clinicopathologic syndrome Neurology 2019 93 20 e1873 80 10.1212/WNL.0000000000008472 31624089 Dubey D, Jitprapaikulsan J, Bi H, Do Campo RV, McKeon A, Pittock SJ, et al. Amphiphysin-IgG autoimmune neuropathy: A recognizable clinicopathologic syndrome. Neurology. 2019;93(20):e1873–80. 31624089 10.1212/WNL.0000000000008472

63. Madlener M Strippel C Thaler FS Doppler K Wandinger KP Lewerenz J Glutamic acid decarboxylase antibody-associated neurological syndromes: clinical and antibody characteristics and therapy response J Neurol Sci 2023 445 120540 10.1016/j.jns.2022.120540 36608627 Madlener M, Strippel C, Thaler FS, Doppler K, Wandinger KP, Lewerenz J, et al. Glutamic acid decarboxylase antibody-associated neurological syndromes: clinical and antibody characteristics and therapy response. J Neurol Sci. 2023;445:120540. 36608627 10.1016/j.jns.2022.120540

64. Pittock SJ Kryzer TJ Lennon VA Paraneoplastic antibodies coexist and predict cancer, not neurological syndrome Ann Neurol 2004 56 5 715 9 10.1002/ana.20269 15468074 Pittock SJ, Kryzer TJ, Lennon VA. Paraneoplastic antibodies coexist and predict cancer, not neurological syndrome. Ann Neurol. 2004;56(5):715–9. 15468074 10.1002/ana.20269

65. Hemmer B Kerschensteiner M Korn T Role of the innate and adaptive immune responses in the course of multiple sclerosis Lancet Neurol 2015 14 4 406 19 10.1016/S1474-4422(14)70305-9 25792099 Hemmer B, Kerschensteiner M, Korn T. Role of the innate and adaptive immune responses in the course of multiple sclerosis. Lancet Neurol. 2015;14(4):406–19. 25792099 10.1016/S1474-4422(14)70305-9

66. Dendrou CA Fugger L Friese MA Immunopathology of multiple sclerosis Nat Rev Immunol 2015 15 9 545 58 10.1038/nri3871 26250739 Dendrou CA, Fugger L, Friese MA. Immunopathology of multiple sclerosis. Nat Rev Immunol. 2015;15(9):545–58. 26250739 10.1038/nri3871

67. Verschuuren JJ Palace J Murai H Tannemaat MR Kaminski HJ Bril V Advances and ongoing research in the treatment of autoimmune neuromuscular junction disorders Lancet Neurol 2022 21 2 189 202 10.1016/S1474-4422(21)00463-4 35065041 Verschuuren JJ, Palace J, Murai H, Tannemaat MR, Kaminski HJ, Bril V. Advances and ongoing research in the treatment of autoimmune neuromuscular junction disorders. Lancet Neurol. 2022;21(2):189–202. 35065041 10.1016/S1474-4422(21)00463-4

68. Lazaridis K Tzartos SJ Autoantibody specificities in myasthenia Gravis; implications for improved diagnostics and therapeutics Front Immunol 2020 11 212 10.3389/fimmu.2020.00212 32117321 PMC7033452 Lazaridis K, Tzartos SJ. Autoantibody specificities in myasthenia Gravis; implications for improved diagnostics and therapeutics. Front Immunol. 2020;11:212. 32117321 10.3389/fimmu.2020.00212 PMC7033452

69. Binks S Vincent A Palace J Myasthenia gravis: a clinical-immunological update J Neurol 2016 263 4 826 34 10.1007/s00415-015-7963-5 26705120 PMC4826656 Binks S, Vincent A, Palace J. Myasthenia gravis: a clinical-immunological update. J Neurol. 2016;263(4):826–34. 26705120 10.1007/s00415-015-7963-5 PMC4826656

70. Uyen Dao TM Barbeau S Messéant J Della-Gaspera B Bouceba T Semprez F The collagen ColQ binds to LRP4 and regulates the activation of the Muscle-Specific Kinase-LRP4 receptor complex by Agrin at the neuromuscular junction J Biol Chem 2023 299 8 104962 10.1016/j.jbc.2023.104962 37356721 PMC10382678 Uyen Dao TM, Barbeau S, Messéant J, Della-Gaspera B, Bouceba T, Semprez F, et al. The collagen ColQ binds to LRP4 and regulates the activation of the Muscle-Specific Kinase-LRP4 receptor complex by Agrin at the neuromuscular junction. J Biol Chem. 2023;299(8):104962. 37356721 10.1016/j.jbc.2023.104962 PMC10382678

71. Marino M Bartoccioni E Alboini PE Evoli A Rituximab in myasthenia gravis: a to be or not to be inhibitor of T cell function Ann N Y Acad Sci 2018 1413 1 41 8 10.1111/nyas.13562 29369382 Marino M, Bartoccioni E, Alboini PE, Evoli A. Rituximab in myasthenia gravis: a to be or not to be inhibitor of T cell function. Ann N Y Acad Sci. 2018;1413(1):41–8. 29369382 10.1111/nyas.13562

72. Jiang R, Fichtner ML, Hoehn KB, Pham MC, Stathopoulos P, Nowak RJ, et al. Single-cell repertoire tracing identifies rituximab-resistant B cells during myasthenia Gravis relapses. JCI Insight. 2020;5(14):e136471. 10.1172/jci.insight.136471 PMC7453893 32573488

73. Vu T Meisel A Mantegazza R Annane D Katsuno M Aguzzi R Terminal complement inhibitor ravulizumab in generalized myasthenia Gravis NEJM Evid 2022 1 5 EVIDoa2100066 10.1056/EVIDoa2100066 38319212 Vu T, Meisel A, Mantegazza R, Annane D, Katsuno M, Aguzzi R, et al. Terminal complement inhibitor ravulizumab in generalized myasthenia Gravis. NEJM Evid. 2022;1(5):EVIDoa2100066. 38319212 10.1056/EVIDoa2100066

74. Iorio R Myasthenia gravis: the changing treatment landscape in the era of molecular therapies Nat Rev Neurol 2024 20 2 84 98 10.1038/s41582-023-00916-w 38191918 Iorio R. Myasthenia gravis: the changing treatment landscape in the era of molecular therapies. Nat Rev Neurol. 2024;20(2):84–98. 38191918 10.1038/s41582-023-00916-w

75. Crisafulli S Boccanegra B Carollo M Bottani E Mantuano P Trifirò G Myasthenia Gravis treatment: from old drugs to innovative therapies with a glimpse into the future CNS Drugs 2024 38 1 15 32 10.1007/s40263-023-01059-8 38212553 Crisafulli S, Boccanegra B, Carollo M, Bottani E, Mantuano P, Trifirò G, et al. Myasthenia Gravis treatment: from old drugs to innovative therapies with a glimpse into the future. CNS Drugs. 2024;38(1):15–32. 38212553 10.1007/s40263-023-01059-8

76. Lennon VA Kryzer TJ Griesmann GE O’Suilleabhain PE Windebank AJ Woppmann A Calcium-channel antibodies in the Lambert-Eaton syndrome and other paraneoplastic syndromes N Engl J Med 1995 332 22 1467 74 10.1056/NEJM199506013322203 7739683 Lennon VA, Kryzer TJ, Griesmann GE, O’Suilleabhain PE, Windebank AJ, Woppmann A, et al. Calcium-channel antibodies in the Lambert-Eaton syndrome and other paraneoplastic syndromes. N Engl J Med. 1995;332(22):1467–74. 7739683 10.1056/NEJM199506013322203

77. Motomura M Lang B Johnston I Palace J Vincent A Newsom-Davis J Incidence of serum anti-P/O-type and anti-N-type calcium channel autoantibodies in the Lambert-Eaton myasthenic syndrome J Neurol Sci 1997 147 1 35 42 10.1016/S0022-510X(96)05303-8 9094058 Motomura M, Lang B, Johnston I, Palace J, Vincent A, Newsom-Davis J. Incidence of serum anti-P/O-type and anti-N-type calcium channel autoantibodies in the Lambert-Eaton myasthenic syndrome. J Neurol Sci. 1997;147(1):35–42. 9094058 10.1016/s0022-510x(96)05303-8

78. Titulaer MJ Lang B Verschuuren JJ Lambert-Eaton myasthenic syndrome: from clinical characteristics to therapeutic strategies Lancet Neurol 2011 10 12 1098 107 10.1016/S1474-4422(11)70245-9 22094130 Titulaer MJ, Lang B, Verschuuren JJ. Lambert-Eaton myasthenic syndrome: from clinical characteristics to therapeutic strategies. Lancet Neurol. 2011;10(12):1098–107. 22094130 10.1016/S1474-4422(11)70245-9

79. Skeie GO Apostolski S Evoli A Gilhus NE Illa I Harms L Guidelines for treatment of autoimmune neuromuscular transmission disorders Eur J Neurol 2010 17 7 893 902 10.1111/j.1468-1331.2010.03019.x 20402760 Skeie GO, Apostolski S, Evoli A, Gilhus NE, Illa I, Harms L, et al. Guidelines for treatment of autoimmune neuromuscular transmission disorders. Eur J Neurol. 2010;17(7):893–902. 20402760 10.1111/j.1468-1331.2010.03019.x

80. Meriggioli MN Sanders DB Autoimmune myasthenia gravis: emerging clinical and biological heterogeneity Lancet Neurol 2009 8 5 475 90 10.1016/S1474-4422(09)70063-8 19375665 PMC2730933 Meriggioli MN, Sanders DB. Autoimmune myasthenia gravis: emerging clinical and biological heterogeneity. Lancet Neurol. 2009;8(5):475–90. 19375665 10.1016/S1474-4422(09)70063-8 PMC2730933

81. Wingerchuk DM Lennon VA Pittock SJ Lucchinetti CF Weinshenker BG Revised diagnostic criteria for neuromyelitis Optica Neurology 2006 66 10 1485 9 10.1212/01.wnl.0000216139.44259.74 16717206 Wingerchuk DM, Lennon VA, Pittock SJ, Lucchinetti CF, Weinshenker BG. Revised diagnostic criteria for neuromyelitis Optica. Neurology. 2006;66(10):1485–9. 16717206 10.1212/01.wnl.0000216139.44259.74

82. Pittock SJ Zekeridou A Weinshenker BG Hope for patients with neuromyelitis Optica spectrum disorders - from mechanisms to trials Nat Rev Neurol 2021 17 12 759 73 10.1038/s41582-021-00568-8 34711906 Pittock SJ, Zekeridou A, Weinshenker BG. Hope for patients with neuromyelitis Optica spectrum disorders - from mechanisms to trials. Nat Rev Neurol. 2021;17(12):759–73. 34711906 10.1038/s41582-021-00568-8

83. Jeong IH Park B Kim SH Hyun JW Joo J Kim HJ Comparative analysis of treatment outcomes in patients with neuromyelitis Optica spectrum disorder using multifaceted endpoints Mult Scler 2016 22 3 329 39 10.1177/1352458515587752 26041804 Jeong IH, Park B, Kim SH, Hyun JW, Joo J, Kim HJ. Comparative analysis of treatment outcomes in patients with neuromyelitis Optica spectrum disorder using multifaceted endpoints. Mult Scler. 2016;22(3):329–39. 26041804 10.1177/1352458515587752

84. Traboulsee A Greenberg BM Bennett JL Szczechowski L Fox E Shkrobot S Safety and efficacy of satralizumab monotherapy in neuromyelitis Optica spectrum disorder: a randomised, double-blind, multicentre, placebo-controlled phase 3 trial Lancet Neurol 2020 19 5 402 12 10.1016/S1474-4422(20)30078-8 32333898 PMC7935419 Traboulsee A, Greenberg BM, Bennett JL, Szczechowski L, Fox E, Shkrobot S, et al. Safety and efficacy of satralizumab monotherapy in neuromyelitis Optica spectrum disorder: a randomised, double-blind, multicentre, placebo-controlled phase 3 trial. Lancet Neurol. 2020;19(5):402–12. 32333898 10.1016/S1474-4422(20)30078-8 PMC7935419

85. Velasco M Zarco LA Agudelo-Arrieta M Torres-Camacho I Garcia-Cifuentes E Muñoz O Effectiveness of treatments in neuromyelitis Optica to modify the course of disease in adult patients. Systematic review of literature Mult Scler Relat Disord 2021 50 102869 10.1016/j.msard.2021.102869 33711580 Velasco M, Zarco LA, Agudelo-Arrieta M, Torres-Camacho I, Garcia-Cifuentes E, Muñoz O. Effectiveness of treatments in neuromyelitis Optica to modify the course of disease in adult patients. Systematic review of literature. Mult Scler Relat Disord. 2021;50:102869. 33711580 10.1016/j.msard.2021.102869

86. Zhang C Zhang M Qiu W Ma H Zhang X Zhu Z Safety and efficacy of Tocilizumab versus azathioprine in highly relapsing neuromyelitis Optica spectrum disorder (TANGO): an open-label, multicentre, randomised, phase 2 trial Lancet Neurol 2020 19 5 391 401 10.1016/S1474-4422(20)30070-3 32333897 PMC7935423 Zhang C, Zhang M, Qiu W, Ma H, Zhang X, Zhu Z, et al. Safety and efficacy of Tocilizumab versus azathioprine in highly relapsing neuromyelitis Optica spectrum disorder (TANGO): an open-label, multicentre, randomised, phase 2 trial. Lancet Neurol. 2020;19(5):391–401. 32333897 10.1016/S1474-4422(20)30070-3 PMC7935423

87. Al-Ani A Chen JJ Costello F Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD): current Understanding and challenges J Neurol 2023 270 8 4132 50 10.1007/s00415-023-11737-8 37154894 PMC10165591 Al-Ani A, Chen JJ, Costello F. Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD): current Understanding and challenges. J Neurol. 2023;270(8):4132–50. 37154894 10.1007/s00415-023-11737-8 PMC10165591

88. Kwon YN Kim B Kim JS Park KS Seo DY Kim H Time to treat first acute attack of Myelin oligodendrocyte glycoprotein Antibody-Associated disease JAMA Neurol 2024 81 10 1073 84 10.1001/jamaneurol.2024.2811 39226035 PMC11372657 Kwon YN, Kim B, Kim JS, Park KS, Seo DY, Kim H, et al. Time to treat first acute attack of Myelin oligodendrocyte glycoprotein Antibody-Associated disease. JAMA Neurol. 2024;81(10):1073–84. 39226035 10.1001/jamaneurol.2024.2811 PMC11372657

89. Cabrera-Maqueda JM Sepulveda M García RR Muñoz-Sánchez G Martínez-Cibrian N Ortíz-Maldonado V CD19-Directed CAR T-Cells in a patient with refractory MOGAD: clinical and Immunologic Follow-Up for 1 year Neurol Neuroimmunol Neuroinflamm 2024 11 5 e200292 10.1212/NXI.0000000000200292 39106426 PMC11309560 Cabrera-Maqueda JM, Sepulveda M, García RR, Muñoz-Sánchez G, Martínez-Cibrian N, Ortíz-Maldonado V, et al. CD19-Directed CAR T-Cells in a patient with refractory MOGAD: clinical and Immunologic Follow-Up for 1 year. Neurol Neuroimmunol Neuroinflamm. 2024;11(5):e200292. 39106426 10.1212/NXI.0000000000200292 PMC11309560

90. Dalmau J Gleichman AJ Hughes EG Rossi JE Peng X Lai M Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies Lancet Neurol 2008 7 12 1091 8 10.1016/S1474-4422(08)70224-2 18851928 PMC2607118 Dalmau J, Gleichman AJ, Hughes EG, Rossi JE, Peng X, Lai M, et al. Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies. Lancet Neurol. 2008;7(12):1091–8. 18851928 10.1016/S1474-4422(08)70224-2 PMC2607118

91. Lee J Lundgren DK Mao X Manfredo-Vieira S Nunez-Cruz S Williams EF Antigen-specific B cell depletion for precision therapy of mucosal pemphigus vulgaris J Clin Invest 2020 130 12 6317 24 10.1172/JCI138416 32817591 PMC7685721 Lee J, Lundgren DK, Mao X, Manfredo-Vieira S, Nunez-Cruz S, Williams EF, et al. Antigen-specific B cell depletion for precision therapy of mucosal pemphigus vulgaris. J Clin Invest. 2020;130(12):6317–24. 32817591 10.1172/JCI138416 PMC7685721

92. Zhang L Sosinowski T Cox AR Cepeda JR Sekhar NS Hartig SM Chimeric antigen receptor (CAR) T cells targeting a pathogenic MHC class ii:peptide complex modulate the progression of autoimmune diabetes J Autoimmun 2019 96 50 8 10.1016/j.jaut.2018.08.004 30122420 PMC6541442 Zhang L, Sosinowski T, Cox AR, Cepeda JR, Sekhar NS, Hartig SM, et al. Chimeric antigen receptor (CAR) T cells targeting a pathogenic MHC class ii:peptide complex modulate the progression of autoimmune diabetes. J Autoimmun. 2019;96:50–8. 30122420 10.1016/j.jaut.2018.08.004 PMC6541442

93. Obarorakpor N Patel D Boyarov R Amarsaikhan N Cepeda JR Eastes D Regulatory T cells targeting a pathogenic MHC class II: insulin peptide epitope postpone spontaneous autoimmune diabetes Front Immunol 2023 14 1207108 10.3389/fimmu.2023.1207108 37593744 PMC10428008 Obarorakpor N, Patel D, Boyarov R, Amarsaikhan N, Cepeda JR, Eastes D, et al. Regulatory T cells targeting a pathogenic MHC class II: insulin peptide epitope postpone spontaneous autoimmune diabetes. Front Immunol. 2023;14:1207108. 37593744 10.3389/fimmu.2023.1207108 PMC10428008

94. Newsome SD Johnson T Stiff person syndrome spectrum disorders; more than Meets the eye J Neuroimmunol 2022 369 577915 10.1016/j.jneuroim.2022.577915 35717735 PMC9274902 Newsome SD, Johnson T. Stiff person syndrome spectrum disorders; more than Meets the eye. J Neuroimmunol. 2022;369:577915. 35717735 10.1016/j.jneuroim.2022.577915 PMC9274902

95. Werner C Pauli M Doose S Weishaupt A Haselmann H Grünewald B Human autoantibodies to amphiphysin induce defective presynaptic vesicle dynamics and composition Brain 2016 139 Pt 2 365 79 10.1093/brain/awv324 26582558 Werner C, Pauli M, Doose S, Weishaupt A, Haselmann H, Grünewald B, et al. Human autoantibodies to amphiphysin induce defective presynaptic vesicle dynamics and composition. Brain. 2016;139(Pt 2):365–79. 26582558 10.1093/brain/awv324

96. Dalakas MC Stiff-person syndrome and related disorders - diagnosis, mechanisms and therapies Nat Rev Neurol 2024 20 10 587 601 10.1038/s41582-024-01012-3 39227464 Dalakas MC. Stiff-person syndrome and related disorders - diagnosis, mechanisms and therapies. Nat Rev Neurol. 2024;20(10):587–601. 39227464 10.1038/s41582-024-01012-3

97. Hadavi S Noyce AJ Leslie RD Giovannoni G Stiff person syndrome Pract Neurol 2011 11 5 272 82 10.1136/practneurol-2011-000071 21921002 Hadavi S, Noyce AJ, Leslie RD, Giovannoni G. Stiff person syndrome. Pract Neurol. 2011;11(5):272–82. 21921002 10.1136/practneurol-2011-000071

98. Chia NH McKeon A Dalakas MC Flanagan EP Bower JH Klassen BT Stiff person spectrum disorder diagnosis, misdiagnosis, and suggested diagnostic criteria Ann Clin Transl Neurol 2023 10 7 1083 94 10.1002/acn3.51791 37212351 PMC10351653 Chia NH, McKeon A, Dalakas MC, Flanagan EP, Bower JH, Klassen BT, et al. Stiff person spectrum disorder diagnosis, misdiagnosis, and suggested diagnostic criteria. Ann Clin Transl Neurol. 2023;10(7):1083–94. 37212351 10.1002/acn3.51791 PMC10351653

99. Rakocevic G Raju R Dalakas MC Anti-glutamic acid decarboxylase antibodies in the serum and cerebrospinal fluid of patients with stiff-person syndrome: correlation with clinical severity Arch Neurol 2004 61 6 902 4 10.1001/archneur.61.6.902 15210528 Rakocevic G, Raju R, Dalakas MC. Anti-glutamic acid decarboxylase antibodies in the serum and cerebrospinal fluid of patients with stiff-person syndrome: correlation with clinical severity. Arch Neurol. 2004;61(6):902–4. 15210528 10.1001/archneur.61.6.902

100. Gresa-Arribas N Ariño H Martínez-Hernández E Petit-Pedrol M Sabater L Saiz A Antibodies to inhibitory synaptic proteins in neurological syndromes associated with glutamic acid decarboxylase autoimmunity PLoS ONE 2015 10 3 e0121364 10.1371/journal.pone.0121364 25774787 PMC4361655 Gresa-Arribas N, Ariño H, Martínez-Hernández E, Petit-Pedrol M, Sabater L, Saiz A, et al. Antibodies to inhibitory synaptic proteins in neurological syndromes associated with glutamic acid decarboxylase autoimmunity. PLoS ONE. 2015;10(3):e0121364. 25774787 10.1371/journal.pone.0121364 PMC4361655

101. Faissner S Motte J Sgodzai M Geis C Haghikia A Mougiakakos D Successful use of anti-CD19 CAR T cells in severe treatment-refractory stiff-person syndrome Proc Natl Acad Sci U S A 2024 121 26 e2403227121 10.1073/pnas.2403227121 38885382 PMC11214089 Faissner S, Motte J, Sgodzai M, Geis C, Haghikia A, Mougiakakos D, et al. Successful use of anti-CD19 CAR T cells in severe treatment-refractory stiff-person syndrome. Proc Natl Acad Sci U S A. 2024;121(26):e2403227121. 38885382 10.1073/pnas.2403227121 PMC11214089

102. Miske R Scharf M Borowski K Specht I Corty M Loritz MJ Identification of DAGLA as an autoantibody target in cerebellar ataxia J Neurol Neurosurg Psychiatry 2024 95 11 1064 76 10.1136/jnnp-2024-333458 38663995 PMC11503208 Miske R, Scharf M, Borowski K, Specht I, Corty M, Loritz MJ, et al. Identification of DAGLA as an autoantibody target in cerebellar ataxia. J Neurol Neurosurg Psychiatry. 2024;95(11):1064–76. 38663995 10.1136/jnnp-2024-333458 PMC11503208

103. Yoshida T Fukaya M Uchigashima M Miura E Kamiya H Kano M Localization of Diacylglycerol lipase-alpha around postsynaptic spine suggests close proximity between production site of an endocannabinoid, 2-arachidonoyl-glycerol, and presynaptic cannabinoid CB1 receptor J Neurosci 2006 26 18 4740 51 10.1523/JNEUROSCI.0054-06.2006 16672646 PMC6674155 Yoshida T, Fukaya M, Uchigashima M, Miura E, Kamiya H, Kano M, et al. Localization of Diacylglycerol lipase-alpha around postsynaptic spine suggests close proximity between production site of an endocannabinoid, 2-arachidonoyl-glycerol, and presynaptic cannabinoid CB1 receptor. J Neurosci. 2006;26(18):4740–51. 16672646 10.1523/JNEUROSCI.0054-06.2006 PMC6674155

104. Vorasoot N Isitan-Alkawadri C Pillai B Miske R Dubey D Gilligan M DAGLA autoantibody experience at Mayo clinic J Neurol 2025 272 7 460 10.1007/s00415-025-13197-8 40512252 PMC12165888 Vorasoot N, Isitan-Alkawadri C, Pillai B, Miske R, Dubey D, Gilligan M, et al. DAGLA autoantibody experience at Mayo clinic. J Neurol. 2025;272(7):460. 40512252 10.1007/s00415-025-13197-8 PMC12165888

105. Hegelmaier T Wolleschak D Pappa V Wickel J Geis C Miske R Chimeric antigen receptor T cells in treatment-refractory DAGLA antibody-associated encephalitis Med 2025 6 9 100776 10.1016/j.medj.2025.100776 40706586 Hegelmaier T, Wolleschak D, Pappa V, Wickel J, Geis C, Miske R, et al. Chimeric antigen receptor T cells in treatment-refractory DAGLA antibody-associated encephalitis. Med. 2025;6(9):100776. 40706586 10.1016/j.medj.2025.100776

106. Hauser SL Cree BAC Treatment of multiple sclerosis: A review Am J Med 2020 133 12 1380 e902 10.1016/j.amjmed.2020.05.049 32682869 PMC7704606 Hauser SL, Cree BAC. Treatment of multiple sclerosis: A review. Am J Med. 2020;133(12):1380–e902. 32682869 10.1016/j.amjmed.2020.05.049 PMC7704606

107. Brownlee WJ Hardy TA Fazekas F Miller DH Diagnosis of multiple sclerosis: progress and challenges Lancet (London England) 2017 389 10076 1336 46 10.1016/S0140-6736(16)30959-X 27889190 Brownlee WJ, Hardy TA, Fazekas F, Miller DH. Diagnosis of multiple sclerosis: progress and challenges. Lancet (London England). 2017;389(10076):1336–46. 27889190 10.1016/S0140-6736(16)30959-X

108. Cree BA Gourraud PA Oksenberg JR Bevan C Crabtree-Hartman E Gelfand JM Long-term evolution of multiple sclerosis disability in the treatment era Ann Neurol 2016 80 4 499 510 10.1002/ana.24747 27464262 PMC5105678 Cree BA, Gourraud PA, Oksenberg JR, Bevan C, Crabtree-Hartman E, Gelfand JM, et al. Long-term evolution of multiple sclerosis disability in the treatment era. Ann Neurol. 2016;80(4):499–510. 27464262 10.1002/ana.24747 PMC5105678

109. Lünemann JD Ruck T Muraro PA Bar-Or A Wiendl H Immune reconstitution therapies: concepts for durable remission in multiple sclerosis Nat Rev Neurol 2020 16 1 56 62 10.1038/s41582-019-0268-z 31649335 Lünemann JD, Ruck T, Muraro PA, Bar-Or A, Wiendl H. Immune reconstitution therapies: concepts for durable remission in multiple sclerosis. Nat Rev Neurol. 2020;16(1):56–62. 31649335 10.1038/s41582-019-0268-z

110. Cencioni MT Mattoscio M Magliozzi R Bar-Or A Muraro PA B cells in multiple sclerosis - from targeted depletion to immune reconstitution therapies Nat Rev Neurol 2021 17 7 399 414 10.1038/s41582-021-00498-5 34075251 Cencioni MT, Mattoscio M, Magliozzi R, Bar-Or A, Muraro PA. B cells in multiple sclerosis - from targeted depletion to immune reconstitution therapies. Nat Rev Neurol. 2021;17(7):399–414. 34075251 10.1038/s41582-021-00498-5

111. Kalincik T Sharmin S Roos I Freedman MS Atkins H Burman J Comparative effectiveness of autologous hematopoietic stem cell transplant vs Fingolimod, Natalizumab, and Ocrelizumab in highly active Relapsing-Remitting multiple sclerosis JAMA Neurol 2023 80 7 702 13 10.1001/jamaneurol.2023.1184 37437240 PMC10186210 Kalincik T, Sharmin S, Roos I, Freedman MS, Atkins H, Burman J, et al. Comparative effectiveness of autologous hematopoietic stem cell transplant vs Fingolimod, Natalizumab, and Ocrelizumab in highly active Relapsing-Remitting multiple sclerosis. JAMA Neurol. 2023;80(7):702–13. 37437240 10.1001/jamaneurol.2023.1184 PMC10186210

112. Greenfield AL, Dandekar R, Ramesh A, Eggers EL, Wu H, Laurent S, et al. Longitudinally persistent cerebrospinal fluid B cells can resist treatment in multiple sclerosis. JCI Insight. 2019;4(6):e126599. 10.1172/jci.insight.126599 PMC6482992 30747723

113. Bogers L Engelenburg HJ Janssen M Unger PA Melief MJ Wierenga-Wolf AF Selective emergence of antibody-secreting cells in the multiple sclerosis brain EBioMedicine 2023 89 104465 10.1016/j.ebiom.2023.104465 36796230 PMC9958261 Bogers L, Engelenburg HJ, Janssen M, Unger PA, Melief MJ, Wierenga-Wolf AF, et al. Selective emergence of antibody-secreting cells in the multiple sclerosis brain. EBioMedicine. 2023;89:104465. 36796230 10.1016/j.ebiom.2023.104465 PMC9958261

114. Gupta S, Simic M, Sagan SA, Shepherd C, Duecker J, Sobel RA, et al. CAR-T Cell-Mediated B-Cell depletion in central nervous system autoimmunity. Neurology(R) Neuroimmunol Neuroinflammation. 2023;10(2):e200080. 10.1212/NXI.0000000000200080 PMC9853314 36657993

115. Mitsdoerffer M Di Liberto G Dötsch S Sie C Wagner I Pfaller M Formation and Immunomodulatory function of meningeal B cell aggregates in progressive CNS autoimmunity Brain 2021 144 6 1697 710 10.1093/brain/awab093 33693558 Mitsdoerffer M, Di Liberto G, Dötsch S, Sie C, Wagner I, Pfaller M, et al. Formation and Immunomodulatory function of meningeal B cell aggregates in progressive CNS autoimmunity. Brain. 2021;144(6):1697–710. 33693558 10.1093/brain/awab093

116. Fischbach F Richter J Pfeffer LK Fehse B Berger SC Reinhardt S CD19-targeted chimeric antigen receptor T cell therapy in two patients with multiple sclerosis Med (New York NY) 2024 5 6 550 e82 10.1016/j.medj.2024.03.002 38554710 Fischbach F, Richter J, Pfeffer LK, Fehse B, Berger SC, Reinhardt S, et al. CD19-targeted chimeric antigen receptor T cell therapy in two patients with multiple sclerosis. Med (New York NY). 2024;5(6):550–e82. 10.1016/j.medj.2024.03.002 38554710

117. Wing K Sakaguchi S Regulatory T cells exert checks and balances on self tolerance and autoimmunity Nat Immunol 2010 11 1 7 13 10.1038/ni.1818 20016504 Wing K, Sakaguchi S. Regulatory T cells exert checks and balances on self tolerance and autoimmunity. Nat Immunol. 2010;11(1):7–13. 20016504 10.1038/ni.1818

118. Fransson M Piras E Burman J Nilsson B Essand M Lu B CAR/FoxP3-engineered T regulatory cells target the CNS and suppress EAE upon intranasal delivery J Neuroinflammation 2012 9 112 10.1186/1742-2094-9-112 22647574 PMC3403996 Fransson M, Piras E, Burman J, Nilsson B, Essand M, Lu B, et al. CAR/FoxP3-engineered T regulatory cells target the CNS and suppress EAE upon intranasal delivery. J Neuroinflammation. 2012;9:112. 22647574 10.1186/1742-2094-9-112 PMC3403996

119. Brittain G Roldan E Alexander T Saccardi R Snowden JA Sharrack B The role of chimeric antigen receptor T-Cell therapy in Immune-Mediated neurological diseases Ann Neurol 2024 96 3 441 52 10.1002/ana.27029 39015040 Brittain G, Roldan E, Alexander T, Saccardi R, Snowden JA, Sharrack B, et al. The role of chimeric antigen receptor T-Cell therapy in Immune-Mediated neurological diseases. Ann Neurol. 2024;96(3):441–52. 39015040 10.1002/ana.27029

120. Haghikia A Schett G Mougiakakos D B cell-targeting chimeric antigen receptor T cells as an emerging therapy in neuroimmunological diseases Lancet Neurol 2024 23 6 615 24 10.1016/S1474-4422(24)00140-6 38760099 Haghikia A, Schett G, Mougiakakos D. B cell-targeting chimeric antigen receptor T cells as an emerging therapy in neuroimmunological diseases. Lancet Neurol. 2024;23(6):615–24. 38760099 10.1016/S1474-4422(24)00140-6

121. Zhang B Wang Y Yuan Y Sun J Liu L Huang D In vitro elimination of autoreactive B cells from rheumatoid arthritis patients by universal chimeric antigen receptor T cells Ann Rheum Dis 2021 80 2 176 84 10.1136/annrheumdis-2020-217844 32998865 Zhang B, Wang Y, Yuan Y, Sun J, Liu L, Huang D, et al. In vitro elimination of autoreactive B cells from rheumatoid arthritis patients by universal chimeric antigen receptor T cells. Ann Rheum Dis. 2021;80(2):176–84. 32998865 10.1136/annrheumdis-2020-217844

122. Bergmann C Müller F Distler JHW Györfi AH Völkl S Aigner M Treatment of a patient with severe systemic sclerosis (SSc) using CD19-targeted CAR T cells Ann Rheum Dis 2023 82 8 1117 20 10.1136/ard-2023-223952 37147112 PMC10359520 Bergmann C, Müller F, Distler JHW, Györfi AH, Völkl S, Aigner M, et al. Treatment of a patient with severe systemic sclerosis (SSc) using CD19-targeted CAR T cells. Ann Rheum Dis. 2023;82(8):1117–20. 37147112 10.1136/ard-2023-223952 PMC10359520

123. Pecher AC Hensen L Klein R Schairer R Lutz K Atar D CD19-Targeting CAR T cells for myositis and interstitial lung disease associated with antisynthetase syndrome JAMA 2023 329 24 2154 62 10.1001/jama.2023.8753 37367976 PMC10300719 Pecher AC, Hensen L, Klein R, Schairer R, Lutz K, Atar D, et al. CD19-Targeting CAR T cells for myositis and interstitial lung disease associated with antisynthetase syndrome. JAMA. 2023;329(24):2154–62. 37367976 10.1001/jama.2023.8753 PMC10300719

124. Cui Y, David M, Bouchareychas L, Rouquier S, Sajuthi S, Ayrault M, et al. IL23R-specific CAR Tregs for the treatment of Crohn’s disease. Journal of Crohn’s & colitis; 2024. 10.1093/ecco-jcc/jjae135 PMC11945296 39252592

125. Tenspolde M Zimmermann K Weber LC Hapke M Lieber M Dywicki J Regulatory T cells engineered with a novel insulin-specific chimeric antigen receptor as a candidate immunotherapy for type 1 diabetes J Autoimmun 2019 103 102289 10.1016/j.jaut.2019.05.017 31176558 Tenspolde M, Zimmermann K, Weber LC, Hapke M, Lieber M, Dywicki J, et al. Regulatory T cells engineered with a novel insulin-specific chimeric antigen receptor as a candidate immunotherapy for type 1 diabetes. J Autoimmun. 2019;103:102289. 31176558 10.1016/j.jaut.2019.05.017

126. Dawson NAJ, Rosado-Sánchez I, Novakovsky GE, Fung VCW, Huang Q, McIver E, et al. Functional effects of chimeric antigen receptor co-receptor signaling domains in human regulatory T cells. Sci Transl Med. 2020;12(557):eaaz3866. 10.1126/scitranslmed.aaz3866 32817364

127. Yeh WI Seay HR Newby B Posgai AL Moniz FB Michels A Avidity and bystander suppressive capacity of human regulatory T cells expressing de Novo autoreactive T-Cell receptors in type 1 diabetes Front Immunol 2017 8 1313 10.3389/fimmu.2017.01313 29123516 PMC5662552 Yeh WI, Seay HR, Newby B, Posgai AL, Moniz FB, Michels A, et al. Avidity and bystander suppressive capacity of human regulatory T cells expressing de Novo autoreactive T-Cell receptors in type 1 diabetes. Front Immunol. 2017;8:1313. 29123516 10.3389/fimmu.2017.01313 PMC5662552

128. Mukhatayev Z Dellacecca ER Cosgrove C Shivde R Jaishankar D Pontarolo-Maag K Antigen specificity enhances disease control by Tregs in vitiligo Front Immunol 2020 11 581433 10.3389/fimmu.2020.581433 33335528 PMC7736409 Mukhatayev Z, Dellacecca ER, Cosgrove C, Shivde R, Jaishankar D, Pontarolo-Maag K, et al. Antigen specificity enhances disease control by Tregs in vitiligo. Front Immunol. 2020;11:581433. 33335528 10.3389/fimmu.2020.581433 PMC7736409

129. Raffin C Vo LT Bluestone JA T(reg) cell-based therapies: challenges and perspectives Nat Rev Immunol 2020 20 3 158 72 10.1038/s41577-019-0232-6 31811270 PMC7814338 Raffin C, Vo LT, Bluestone JA. T(reg) cell-based therapies: challenges and perspectives. Nat Rev Immunol. 2020;20(3):158–72. 31811270 10.1038/s41577-019-0232-6 PMC7814338

130. Radichev IA Yoon J Scott DW Griffin K Savinov AY Towards antigen-specific Tregs for type 1 diabetes: construction and functional assessment of pancreatic endocrine marker, HPi2-based chimeric antigen receptor Cell Immunol 2020 358 104224 10.1016/j.cellimm.2020.104224 33068914 PMC7655659 Radichev IA, Yoon J, Scott DW, Griffin K, Savinov AY. Towards antigen-specific Tregs for type 1 diabetes: construction and functional assessment of pancreatic endocrine marker, HPi2-based chimeric antigen receptor. Cell Immunol. 2020;358:104224. 33068914 10.1016/j.cellimm.2020.104224 PMC7655659

131. Imam, Shahnawaz and Dar, Pervaiz and Alfonso-Jaume, Maria and Al-Khudhair, Ahmed and Jaume, Juan Carlos. Spontaneous Type-1-Diabetes Humanized Transgenics Help Unveil Pathophysiology of Human Diabetes and Allow for Disease-Reverting CAR-Treg Immunotherapy. CR-MEDICINE-D-21-00036. Available at SSRN: https://ssrn.com/abstract=3778362 or http://dx.doi.org/10.2139/ssrn.3778362 .

132. Ismail FS Gallus M Meuth SG Okada H Hartung HP Melzer N Current and future roles of chimeric antigen receptor T-Cell therapy in neurology: A review JAMA Neurol 2025 82 1 93 103 10.1001/jamaneurol.2024.3818 39585688 Ismail FS, Gallus M, Meuth SG, Okada H, Hartung HP, Melzer N. Current and future roles of chimeric antigen receptor T-Cell therapy in neurology: A review. JAMA Neurol. 2025;82(1):93–103. 39585688 10.1001/jamaneurol.2024.3818

133. Stathopoulos P Kumar A Nowak RJ O’Connor KC Autoantibody-producing plasmablasts after B cell depletion identified in muscle-specific kinase myasthenia Gravis JCI Insight 2017 2 17 10.1172/jci.insight.94263 PMC5621905 28878127 Stathopoulos P, Kumar A, Nowak RJ, O’Connor KC. Autoantibody-producing plasmablasts after B cell depletion identified in muscle-specific kinase myasthenia Gravis. JCI Insight. 2017;2:17. 10.1172/jci.insight.94263 PMC5621905 28878127

134. Mueller F Schwingen NR Stabel L Aigner M Taubmann J Kretschmann S CAR-T cell therapy in patients with refractory systemic autoimmune diseases exhibits less Inflammation, toxicities and different cellular dynamics compared to patients with B cell lymphoma Blood 2023 142 Supplement 1 6871 10.1182/blood-2023-188830 Mueller F, Schwingen NR, Stabel L, Aigner M, Taubmann J, Kretschmann S, et al. CAR-T cell therapy in patients with refractory systemic autoimmune diseases exhibits less Inflammation, toxicities and different cellular dynamics compared to patients with B cell lymphoma. Blood. 2023;142(Supplement 1):6871.

135. Arnold C Autoimmune disease is the next frontier for CAR T cell therapy Nat Med 2024 30 1 6 9 10.1038/s41591-023-02716-7 38212433 Arnold C. Autoimmune disease is the next frontier for CAR T cell therapy. Nat Med. 2024;30(1):6–9. 38212433 10.1038/s41591-023-02716-7