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Emerging Technologies Tackling Adeno-Associated Viruses (AAV) Immunogenicity in Gene Therapy Applications.

Adeno-associated viral vectors have proven to be a safe and effective gene therapy delivery system. Over the past decade, the approval of AAV gene therapies made a revolution in treatment of severe hereditary diseases, including spinal muscular atrophy, AADC deficiency, and others. Recombinant AAV-based therapeutics are currently intended for single administration. Safety concerns arise from immune responses to AAV and the resulting transgene, which can render subsequent injections ineffective. It remains unclear whether patients who have received an AAV-based gene therapy will need re-adminis

Reduced Neutrophil Extracellular Trap Formation During Ischemia Reperfusion Injury in C3 KO Mice: C3 Requirement for NETs Release.

Complement C3 plays a prominent role in inflammatory processes, and its increase exacerbates ischemia reperfusion injury (IRI)-induced acute kidney injury (AKI). Infiltrated neutrophils can be stimulated to form neutrophil extracellular traps (NETs), leading to renal injury. However, the relationship between the increase of C3 and the release of NETs in AKI was not clear. Here we found that IRI in the mouse kidney leads to increased neutrophils infiltration and NET formation. Furthermore, neutrophils depletion by anti-Ly6G IgG (1A8) did not reduce C3 activation but reduced kidney injury and in

Emicizumab: a novel drug in hemophilia A prophylaxis - a narrative review.

INTRODUCTION: Hemophilia A is a genetically conditioned disease leading to hemostatic disorders due to factor VIII (FVIII) deficiency. The treatment of hemophilia has evolved throughout the past years and has significantly changed. One of the newest drugs for prophylactic treatment is the humanized bispecific IgG antibody - emicizumab, which binds with factor IXa and factor X, bridging those factors and thus mimicking the activity of factor VIII. AREAS COVERED: The literature search was done via the PubMed database, with the emphasis on clinical trials and case reports, describing the off-lab

Controversies about immunoglobulin replacement therapy in HSCT recipients with hypogammaglobulinemia.

The efficacy of immunoglobulin replacement therapy (IgRT) has been demonstrated for primary immune deficiency diseases and hematological malignancies such as chronic lymphocytic leukemia (CLL) or multiple myeloma with hypogammaglobulinemia. Clinical development of anti-B cell therapies including a monoclonal antibody, bispecific antibody, or chimeric antigen receptor T-cell therapy which could result in severe hypogammaglobulinemia accelerates the argument of prophylactic use of IgRT. Clinical guidelines for CLL describe immunoglobulin administration in patients with a low IgG who have experie

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… IgG deficiency is divided into primary immunodeficiency (PID) and secondary immunodeficiency (SID) [ 5 ]. A representative PID is X-linked agammaglobulinemia (XLA) harboring pathogenic variants in Bruton’s tyrosine kinase ( BTK ) gene [ 7 ]. … SID accounts for most of the IgG deficiency, and derives from both primary disease (e.g., chronic lymphocytic leukemia (CLL) or multiple myeloma (MM)), and anti-cancer therapy (e.g., anti-B cell monoclonal antibody, genetically engineered chimeric antigen receptor (CAR) T-cell therapy) [ 6 ]. …

Intravenous Immunoglobulins Promote an Expansion of Monocytic Myeloid-Derived Suppressor Cells (MDSC) in CVID Patients.

Common variable immunodeficiency disorders (CVID), the most common primary immune deficiency, includes heterogeneous syndromes characterized by hypogammaglobulinemia and impaired antibody responses. CVID patients frequently suffer from recurrent infections and inflammatory conditions. Currently, immunoglobulin replacement therapy (IgRT) is the first-line treatment to prevent infections and aminorate immune alterations in CVID patients. Intravenous Immunoglobulin (IVIg), a preparation of highly purified poly-specific IgG, is used for treatment of immunodeficiencies as well as for autoimmune and

Application of the diagnostic criteria for Common Variable Immunodeficiency in resource-limited settings.

INTRODUCTION: Common variable immunodeficiency (CVID) is the most prevalent symptomatic humoral deficiency; however, its heterogeneous presentation makes the diagnosis difficult. The present study is aimed to verify the CVID diagnostic criteria as established by the European Society for Immunodeficiencies in 42 CVID patients from our outpatient clinic. METHODS: Information was collected from their medical records and when needed, lymphocyte subpopulations in peripheral blood (PB) were performed by flow cytometry. RESULTS: All the patients fulfilled the clinical working definition for CVID an

CVID Associated with Systemic Amyloidosis.

Common variable immunodeficiency (CVID) is a frequent primary immune deficiency (PID), which consists of a heterogeneous group of disorders and can present with recurrent infections, chronic diarrhea, autoimmunity, chronic pulmonary and gastrointestinal diseases, and malignancy. Secondary amyloidosis is an uncommon complication of CVID. We report an unusual case of a 27-year-old male patient who presented with recurrent sinopulmonary infections, chronic diarrhea, and hypogammaglobulinemia and was diagnosed with CVID. The patient was treated with intravenous immunoglobulin (IVIg) therapy once e

Thrombophilia Profile in Budd-Chiari Syndrome and Splanchnic Vein Thrombosis: A Study from Western India.

AIM: To estimate the prevalence of inherited prothrombotic risk factors in patients with splanchnic venous thrombosis (SVT) and Budd-Chiari syndrome (BCS) and to compare the risk factor profiles between these two groups. METHODS: In this prospective study, patients with abdominal venous thrombosis were studied. The patients were divided into two groups on the basis of the veins involved; splanchnic venous thrombosis group [portal (PVT), splenic, superior mesenteric veins (SMV)] and Budd-Chiari group (hepatic vein, IVC thrombosis). Thrombophilia profile including protein C, protein S, antithro

Assessing humoral immune response of 4 recombinant antigens for serodiagnosis of tuberculosis.

Serodiagnostic potential of four recombinant proteins (38 kDa[Rv0934], MPT64[Rv1980c], Adk[Rv0733], and BfrB[Rv3874]) was evaluated in Healthy control subjects (HCS), Healthy household contacts (HHC), Pulmonary tuberculosis patients (PTB), and Human immuno deficiency virus & Tuberculosis co-infected patients (HIV-TB). All the antigens tested individually for the detection of serum IgG by indirect ELISA. All the four antigens have a significantly higher antibody response in PTB compared to healthy controls (P < 0.05). The sensitivity of individual antigens ranged from 20% to 52.5% for the prefi

The many faces of common variable immunodeficiency.

Common variable immunodeficiency (CVID) is a rare immune deficiency characterized by low levels of serum IgG, IgA, and/or IgM, with a loss of Ab production. The diagnosis is most commonly made in adults between the ages of 20 and 40 years, but both children and much older adults can be found to have this immune defect. The range of clinical manifestations is broad, including acute and chronic infections, inflammatory and autoimmune diseases, and an increased incidence of cancer and lymphoma. For all of these reasons, the disease phenotype is both heterogeneous and complex. In the past few year

The 752delG26 mutation in the RFXANK gene associated with major histocompatibility complex class II deficiency: evidence for a founder effect in the Moroccan population.

Major histocompatibility complex class II plays a key role in the immune response, by presenting processed antigens to CD4+ lymphocytes. Major histocompatibility complex class II expression is controlled at the transcriptional level by at least four trans-acting genes: CIITA, RFXANK, RFX5 and RFXAP. Defects in these regulatory genes cause MHC class II immunodeficiency, which is frequent in North Africa. The aim of this study was to describe the immunological and molecular characteristics of ten unrelated Moroccan patients with MHC class II deficiency. Immunological examinations revealed a lack

Conjunctival effects of canine distemper virus-induced keratoconjunctivitis sicca.

OBJECTIVE: This study compared the histopathology of canine distemper virus (CDV)-induced keratoconjunctivitis sicca (KCS) to non-infectious KCS in conjunctival tissues. ANIMALS STUDIED: Forty mongrel dogs were assigned to three distinct groups: (i) non-infectious KCS (G1, n = 10), (ii) CDV-induced KCS (G2, n = 20), and (iii) healthy animals without any ocular alterations (G3, n = 10). PROCEDURE: IgG titers and physical and ophthalmic examinations (e.g. Schirmer tear test [STT], tonometry, biomicroscopy, indirect biomicroscopy, and fluorescein test) were performed on all dogs. Conjunctival b

A severe form of human combined immunodeficiency due to mutations in DNA ligase IV.

DNA ligase IV (LigIV) deficiency was identified as the molecular basis for a severe form of combined immunodeficiency in two microcephalic siblings with cellular radiosensitivity. In one patient the diagnosis was made directly after birth, allowing analysis of the role of LigIV in the development of specific immune cells. Absolute numbers of B cells were reduced 100-fold and alphabeta T cells 10-fold, whereas gammadelta T cells were normal. Spectratyping of all three cell populations showed a diverse repertoire, but sequencing of IgH V(D)J junctions revealed shorter CDR3 regions due to more ex

Evaluation of short stature, carbohydrate metabolism and other endocrinopathies in Bloom's syndrome.

AIMS: To obtain an understanding of the etiology of proportional dwarfism and endocrinopathies of Bloom's syndrome BS. METHODS: Admission for 5-day periods to an NIH-supported Clinical Research Center of a randomly selected population of persons with BS (n = 11; mean age 11.5 years, range 9 months to 28.5 years) for clinical and genetic history-taking, physical examination, and endocrinological, gastroenterological and immunological testing. RESULTS: An oral glucose tolerance test was performed in all participants. Impaired glucose tolerance was present in 4 individuals, insulin resistance w

Rheumatoid arthritis in a patient with common variable immunodeficiency: difficulty in diagnosis and therapy.

Common variable immunodeficiency (CVID) is the most frequent primary immunodeficiency syndrome in adults with equal sex prevalence. The syndrome typically presents as recurrent infections, with onset in childhood or young adulthood (between 20 and 30 years). CVID patients also have a higher prevalence of autoimmune diseases. A 38-year-old woman presented to the Rheumatology Department with polyarthralgia and fever of 39 degrees C of several months' duration. She had recurrent respiratory and gastrointestinal tract infections and pernicious anemia. Immunological studies showed decreased levels

Enzyme replacement therapy in mucopolysaccharidosis type I.

UNLABELLED: Mucopolysaccharidosis (MPS) type I is a lysosomal storage disorder caused by deficiency of the enzyme alpha-L-iduronidase (IDUA), which presents with a wide spectrum of phenotypes. Recently, enzyme replacement therapy (ERT) became available for patients with MPS I and has been demonstrated to be safe and effective in patients with the milder Hurler-Scheie and Scheie phenotypes. Treatment for 26 weeks with recombinant human IDUA (laronidase) has been shown to significantly increase the percentage of predicted normal forced vital capacity and the distance walked in the 6-minute walk

The role of humoral mucosal immunity in the induction and maintenance of chronic airway infections.

The respiratory mucosa is protected primarily by a secretory immune system that is under complex and only partly understood immunoregulatory control. Secretory immunoglobulins (SIgA and SIgM) protect the mucosal surface by immune exclusion of antigens. However, the fact that most IgA produced in the respiratory tract belongs to the IgA1 subclass renders SIgA in this region susceptible to IgA-specific proteases produced by Haemophilus influenzae, Streptococcus pneumonia, and Neisseria meningitidis. Immunoglobulin G can also perform immune exclusion at respiratory surfaces but, like IgE, it reac

The reversibility of phenytoin-induced IgA deficiency.

Phenytoin has been shown to induce serum IgA deficiency in patients with epilepsy. We have followed 37 phenytoin-treated patients with reduced serum IgA concentrations for 2-7 years. All anti-epileptic drug treatment was withdrawn in 8 patients. Phenytoin was substituted by other anti-epileptic drugs in 13 patients. Sixteen patients received phenytoin unchanged. The mean serum IgA concentration increased from 0.14 g/l to 0.71 g/l in the patients off drug treatment, and from 0.20 g/l to 0.84 g/l in the patients changing to other drugs. The mean IgA concentration increased from 0.21 g/l to 0.37

Protective effects of supplemental vitamin E against infection.

Vitamin E supplementation (dl-alpha-tocopheryl acetate except where noted) in excess of requirement significantly increased humoral immune response or disease resistance. Mice immunized with sheep red blood cells or tetanus toxoid and fed the supplemental vitamin demonstrated increased plaque-forming cells (PFC) and hemagglutinin (HA) titers. A vitamin E deficiency resulted in decreased PFC and little IgG which was partially corrected by N,N-diphenyl-p-phenylenediamine but not as effectively as by vitamin E. Hens immunized with Brucella abortus and fed different levels of the vitamin produced

Kcnn4 Knockout Induces Salivary Gland Fibrosis, Immune Cell Infiltration, and B-Cell Dysfunction in Mice.

Kcnn4 (KCa3.1) is a calcium-activated potassium channel involved in cell volume regulation and immune cell function, but its role in salivary gland homeostasis remains poorly understood. In this study, we generated constitutive Kcnn4 knockout (Kcnn4-/-) mice to investigate the impact of Kcnn4 loss on salivary glands and systemic inflammation. Histological examination revealed that Kcnn4-/- mice had enlarged salivary glands with increased collagen deposition (fibrosis) but no major disorganization on H&E staining. mRNA-seq identified 473 differentially expressed genes (DEGs), with significant e