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Effect of chorioamnionitis on the levels of serum proteins in the cord blood of premature infants.

OBJECTIVE: To determine the relationships among complements, other serum proteins (including acute-phase reactant), and the cytokine interleukin-6. DESIGN: Prospective observational study. SETTING: A perinatal center, children's hospital, and research institute in Osaka, Japan. PATIENTS: Two hundred fifteen newborn infants ranging from 17 to 42 weeks in gestational age. MAIN OUTCOME MEASURES: We measured the serum levels of several proteins and complements in the cord blood of neonates with and without chorioamnionitis by immunological assays. RESULTS: The levels of C3d, haptoglobin, inte

Eculizumab in myasthenia gravis: A review.

Eculizumab, a monoclonal antibody against complement C5, is a novel therapy to treat refractory myasthenia gravis (MG). The present review was undertaken to study the role of eculizumab in MG. This includes the drug's mechanism, pharmacokinetics, clinical trial findings, tolerability, side effects, safety, dosage, administration, and cost. An English-language search for relevant items was undertaken using Embase and PubMed from 1946 to present. Clinical trial registries/databases and websites were also searched for relevant data. Keywords were eculizumab and MG. The present review found 103 ar…

Case report: Short-term eculizumab use in atypical HUS associated with Lemierre's syndrome and post-infectious glomerulonephritis.

Atypical hemolytic uremic syndrome (aHUS) is a rare disease caused by genetic abnormalities, infections, autoimmune diseases, drugs, and malignancies. Anti-C5 monoclonal antibody eculizumab is the mainstay of treatment of aHUS caused by the genetic defects of the alternative complement pathway. However, the utility of eculizumab in non-genetic forms of aHUS and the timing of treatment discontinuation remain controversial. Here, we report successful short-term eculizumab use in two young adult patients with aHUS due to rare infectious and autoimmune etiologies: Lemierre's syndrome and post-infe

Scleroderma Renal Crisis With Thrombotic Microangiopathy Treated With Eculizumab.

We herein report the unusual case of a 52-year-old female with systemic scleroderma who was admitted to the emergency department (ED) with renal dysfunction and hypertension. Following a decline in hemoglobin (Hb) and platelet (Plt) count, the diagnosis of scleroderma renal crisis (SRC) with associated microangiopathic hemolytic anemia was made. Renal replacement therapy using hemodialysis was required. Systemic scleroderma is a chronic autoimmune multisystem vasculopathy affecting several vessel beds, including distal extremities, kidneys, and lungs. Microangiopathic hemolytic anemia occurs i

Lymphocyte alterations and elevated complement signaling are key features of refractory myasthenia gravis.

BACKGROUND: A significant proportion of patients with myasthenia gravis (MG) remain refractory to standard immunosuppressive therapy, and biomarkers to help guide treatment decisions are lacking. We investigated whether refractory disease is associated with a distinct circulating immune profile. METHODS: We performed comprehensive immune phenotyping of peripheral blood from patients with acetylcholine-receptor-antibody-positive MG with differing treatment requirements and compared them with healthy controls. In a subset of refractory patients treated with anti-CD20 therapy, B cell reconstitut

Early anti-C5 therapy in NMOSD: rationale and clinical evidence.

Complement-mediated astrocyte injury is central to aquaporin-4 immunoglobulin G-positive neuromyelitis optica spectrum disorder (AQP4-IgG+ NMOSD). Although C5 inhibitors are approved for relapse prevention, their role as rescue therapy during severe acute attacks remains unclear.We describe a 39-year-old woman with AQP4-IgG+ NMOSD presenting with longitudinally extensive myelitis, optic neuropathy, and a basal ganglia lesion. Despite two courses of intravenous methylprednisolone, five plasma exchanges, and intravenous immunoglobulin, disability progressed to an Expanded Disability Status Scale

Ravulizumab in the Management of Refractory Myasthenic Crisis: Clinical and Ventilatory Evidence of Early Recovery-A Case Report.

INTRODUCTION: Generalized myasthenia gravis (gMG) is an autoimmune disorder impairing neuromuscular transmission, most commonly through anti-AChR antibodies that activate the complement cascade. This can lead to severe complications such as myasthenic crisis (MC), which often requires intensive care. While plasma exchange (PLEX) and intravenous immunoglobulins (IVIG) are standard first-line therapies, approximately 30% of patients may show suboptimal response. Ravulizumab, a long-acting C5 complement inhibitor, has been approved for anti-AChR-positive gMG, but data on its use in MC remain limi

Characterizing the association between complement-mediated TMA and cognitive dysfunction using MRI and neurocognitive assessment.

Complement-mediated thrombotic microangiopathy (CM-TMA) is a rare, life-threatening thrombotic microangiopathy caused by a defect in the alternative complement pathway. It is associated with renal failure and acute encephalopathy, but long-term neurocognitive effects are uncertain. Using magnetic resonance imaging (MRI) and neurocognitive tests, we can further evaluate the long-term neurocognitive complications in CM-TMA and compare them with controls. In this study, we analyzed microstructural changes in the cerebral white matter and neurocognitive testing results of patients with CM-TMA. Sev

Atypical hemolytic uremic syndrome triggered by mRNA vaccination against SARS-CoV-2: Case report.

Atypical hemolytic uremic syndrome (aHUS), also called complement-mediated hemolytic uremic syndrome (CM-HUS), is a rare disease caused by dysregulation in the alternative complement activation pathway. It is a life-threatening condition causing ischemia of a number of organs, and it typically causes acute kidney injury. This disorder may be triggered by various factors including viral or bacterial infections, pregnancy, surgery, and injuries. In about 60% of cases, the genetic origin of the disease can be identified-commonly mutations affecting complementary factor H and MCP protein. Eculizum

C5a/C5aR pathway is essential for the pathogenesis of murine viral fulminant hepatitis by way of potentiating Fgl2/fibroleukin expression.

UNLABELLED: Viral fulminant hepatitis (FH) remains a serious clinical problem with very high mortality. Lacking understanding of FH pathogenesis has in essence hindered efficient clinical treatment. Inferring from a correlation observed between the genetic differences in the complement component 5 (C5) and the susceptibility of mouse strains to murine hepatitis virus strain-3 (MHV-3) infections, we propose that excessive complement activation plays a critical role in the development of FH. We show that MHV-3 infection causes massive complement activation, along with a rapid increase in serum C

Complement factor I deficiency associated with recurrent meningitis coinciding with menstruation.

BACKGROUND: Complement (C) factor I deficiency is a rare immunodeficiency state frequently associated with recurrent pyogenic infections in early infancy. This deficiency causes a permanent uncontrolled activation of the alternative pathway resulting in massive consumption of C3. PATIENT: A 23-year-old woman with monthly recurrent meningitis episodes, mostly in the perimenstrual period, since August 1999. Previously, at age 16 years, she had meningococcal sepsis, also coinciding with menstruation. OBJECTIVES: To study the patient and her family to elucidate the molecular defects in the pedig

Аберрантная дополняющая активация связана со структурным повреждением мозга при множественном склерозе.

Уровни активированных дополнительных белков в CSF увеличиваются у людей с множественным склерозом (MS) и связаны с остротой клинических заболеваний. В этом исследовании мы определили, следует ли дополнять профили активации количественными показателями МРТ и жидкими биомаркерами, указывающими на активность и прогресс в области заболеваний.МЕТОДЫ: Дополняющие компоненты и продукты активации (Factor H и I, C1q, C3, C4, C5, Ba, Bb, C3a, C4a, C5a и sC5b-9) и жидкие биомаркеры (белковая цепочка накаливания, глиальный фибриллярный кислотный белок [GFAP], CXCL-13, CXCL-9, и IL-12b), были количественно

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… Complement C5 in experimental autoimmune encephalomyelitis (EAE) facilitates remyelination and prevents gliosis . Am J Pathol . 2003 ; 163 ( 3 ): 1069 - 1080 . doi: 10.1016/S0002-9440(10)63466-9 12937147 PMC1868269 …

A systematic review of the role of eculizumab in systemic lupus erythematosus-associated thrombotic microangiopathy.

BACKGROUND: Lupus nephritis (LN) is a severe consequence of systemic lupus erythematosus (SLE) that affects approximately 40% of patients. Pathogenic immune complexes that are characteristic of LN deposit in the kidney and activate immune mediated pathways including the complement system. Complete remission rates in LN are approximately 44% highlighting the need for new treatment strategies in these patients. Eculizumab is a fully humanised IgG2/IgG4 monoclonal antibody directed at C5 and thus prevents the formation of the terminal complement complex. Eculizumab is successfully used in atypica

Association of TNFAIP3 polymorphism with rheumatic heart disease in Chinese Han population.

In a pair-matched case-control study (239 versus 478) conducted in Chinese Han population, we investigated the association between tumor necrosis factor-alpha-induced protein 3 (TNFAIP3) gene, tumor necrosis factor receptor-associated factor 1 (TRAF1) gene, complement component 5 (C5) gene, and rheumatic heart disease (RHD). We observed no association with RHD for the five tagging single nucleotide polymorphisms (tSNP) in the C5 gene, the three tSNPs in the TNFAIP3 gene, or the two tSNPs in the TRAF1 gene. However, we determined that the tSNP, rs582757, located at intron_5 of the TNFAIP3 gene,

Model-Informed Precision Dosing of Eculizumab in Patients with Paroxysmal Nocturnal Hemoglobinuria.

BACKGROUND AND OBJECTIVE: Eculizumab is an expensive therapeutic monoclonal antibody inhibiting complement C5 and approved for various indications, including the rare disease paroxysmal nocturnal hemoglobinuria. Eculizumab is administered in a "one-dose-fits-all" dosing paradigm in adults, which is inflexible and suboptimal in some patients. Therefore, the aim of this study was to develop alternative dosing regimens that may improve patient friendliness or improve cost effectiveness. METHODS: A prospective observational pharmacokinetic study was conducted in 27 patients with paroxysmal noctur…

Factor H-dependent alternative pathway inhibition mediated by porin B contributes to virulence of Neisseria meningitidis.

UNLABELLED: The identification of "factor H binding protein (fHbp)-null" invasive meningococcal isolates and the realization that widespread use of fHbp-based vaccines could herald selection of such strains prompted us to characterize novel mechanisms of alternative pathway (AP) inhibition on meningococci. Of seven strains engineered to lack four known AP-inhibiting molecules, capsular polysaccharide, lipooligosaccharide sialic acid, fHbp, and neisserial surface protein A (quadruple mutants), four strains inhibited human AP-mediated C3 deposition. All four expressed the porin B2 (PorB2) molecu

[Immunopathology of dermatitis herpetiformis and bullous pemphigoid (author's transl)].

Dermatitis herpetiformis and bullous pemphigoid are similar enough clinically to have been considered for some time as two forms of the same disease. Their histologic and ultrastructural characteristics are a more accurate mean of differenciation: employed essentially with respect to early lesions and the mode of bullous formation. But immunologic analysis is especially helpful in distinguishing the two. This study involves the analysis of acquired data concerning these two entities: 1) The nature, form, and topography of immunoglobulin and complement deposits examined under the light microsco

C5a induced tracheal contraction: a histamine independent mechanism.

C5a, a peptide derived from the fifth component of complement, caused significant prolonged smooth muscle contraction in isolated guinea pig trachea. Diphenhydramine, a histamine receptor antagonist of the H1 type, had no effect on either the rate, amplitude or duration of C5a induced tracheal contraction, whereas it significantly inhibited the tracheal response to exogenous histamine. Diphenhydramine also caused a significant delay in the response to compound 48/80 in normal guinea pig trachea and to antigen in actively sensitized trachea, indicating that the antihistamine was capable of inhi

Deregulated cellular circuits driving immunoglobulins and complement consumption associate with the severity of COVID-19 patients.

SARS-CoV-2 infection causes an abrupt response by the host immune system, which is largely responsible for the outcome of COVID-19. We investigated whether the specific immune responses in the peripheral blood of 276 patients were associated with the severity and progression of COVID-19. At admission, dramatic lymphopenia of T, B, and NK cells is associated with severity. Conversely, the proportion of B cells, plasmablasts, circulating follicular helper T cells (cTfh) and CD56- CD16+ NK-cells increased. Regarding humoral immunity, levels of IgM, IgA, and IgG were unaffected, but when degrees o

Complement functional tests for monitoring eculizumab treatment in patients with atypical hemolytic uremic syndrome.

BACKGROUND: Atypical hemolytic uremic syndrome (aHUS) is a thrombotic microangiopathy characterized by hemolysis, platelet consumption, and renal injury. Eculizumab, a mAb that blocks complement activity, has been successfully used in aHUS. OBJECTIVES: To optimize eculizumab therapy in aHUS patients by monitoring complement functional tests and markers of disease activity. PATIENTS/METHODS: We studied 18 patients with aHUS (10 males; eight females; age range, 2-40 years) treated with eculizumab to induce and/or maintain disease remission. Patients were followed up for a cumulative observatio