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Brain, Behavior, and Immunity Mar 2024Autoantibodies against the potassium voltage-gated channel subfamily A member 2 (KCNA2) have been described in a few cases of neuropsychiatric disorders, but their...
BACKGROUND
Autoantibodies against the potassium voltage-gated channel subfamily A member 2 (KCNA2) have been described in a few cases of neuropsychiatric disorders, but their diagnostic and pathophysiological role is currently unknown, imposing challenges to medical practice.
DESIGN / METHODS
We retrospectively collected comprehensive clinical and paraclinical data of 35 patients with KCNA2 IgG autoantibodies detected in cell-based and tissue-based assays. Patients' sera and cerebrospinal fluid (CSF) were used for characterization of the antigen, clinical-serological correlations, and determination of IgG subclasses.
RESULTS
KCNA2 autoantibody-positive patients (n = 35, median age at disease onset of 65 years, range of 16-83 years, 74 % male) mostly presented with cognitive impairment and/or epileptic seizures but also ataxia, gait disorder and personality changes. Serum autoantibodies belonged to IgG3 and IgG1 subclasses and titers ranged from 1:32 to 1:10,000. KCNA2 IgG was found in the CSF of 8/21 (38 %) patients and in the serum of 4/96 (4.2 %) healthy blood donors. KCNA2 autoantibodies bound to characteristic anatomical areas in the cerebellum and hippocampus of mammalian brain and juxtaparanodal regions of peripheral nerves but reacted exclusively with intracellular epitopes. A subset of four KCNA2 autoantibody-positive patients responded markedly to immunotherapy alongside with conversion to seronegativity, in particular those presenting an autoimmune encephalitis phenotype and receiving early immunotherapy. An available brain biopsy showed strong immune cell invasion. KCNA2 autoantibodies occurred in less than 10 % in association with an underlying tumor.
CONCLUSION
Our data suggest that KCNA2 autoimmunity is clinically heterogeneous. Future studies should determine whether KCNA2 autoantibodies are directly pathogenic or develop secondarily. Early immunotherapy should be considered, in particular if autoantibodies occur in CSF or if clinical or diagnostic findings suggest ongoing inflammation. Suspicious clinical phenotypes include autoimmune encephalitis, atypical dementia, new-onset epilepsy and unexplained epileptic seizures.
Topics: Animals; Humans; Male; Adolescent; Young Adult; Adult; Middle Aged; Aged; Aged, 80 and over; Female; Autoimmunity; Retrospective Studies; Autoantibodies; Seizures; Autoimmune Diseases of the Nervous System; Mammals; Kv1.2 Potassium Channel; Encephalitis; Hashimoto Disease
PubMed: 38309639
DOI: 10.1016/j.bbi.2024.01.220 -
World Journal of Gastroenterology Feb 2024Autoimmune pancreatitis (AIP) is an autoimmune subtype of chronic pancreatitis resulting from the aberrant immune response against the pancreas, leading to inflammation... (Review)
Review
Autoimmune pancreatitis (AIP) is an autoimmune subtype of chronic pancreatitis resulting from the aberrant immune response against the pancreas, leading to inflammation and fibrosis. Although AIP is rare, its incidence is increasing and is often misdiagnosed as other pancreatic diseases. AIP is commonly classified into two types. Type 1 AIP (AIP-1) is typically associated with elevated serum immunoglobulin G4 (IgG4) levels and systemic manifestations, while type 2 AIP is typically a more localized form of the disease, and may coexist with other autoimmune disorders, especially inflammatory bowel diseases. Additionally, there is emerging recognition of a third type (type 3 AIP), which refers to immunotherapy-triggered AIP, although this classification is still gaining acceptance in medical literature. The clinical manifestations of AIP mainly include painless jaundice and weight loss. Elevated serum IgG4 levels are particularly characteristic of AIP-1. Diagnosis relies on a combination of clinical, laboratory, radiological, and histological findings, given the similarity of AIP symptoms to other pancreatic disorders. The mainstay of treatment for AIP is steroid therapy, which is effective in most cases. Severe cases might require additional imm-unosuppressive agents. This review aims to summarize the current knowledge of AIP, encompassing its epidemiology, etiology, clinical presentation, diagnosis, and treatment options. We also address the challenges and controversies in diagnosing and treating AIP, such as distinguishing it from pancreatic cancer and managing long-term treatment, highlighting the need for increased awareness and knowledge of this complex disease.
Topics: Humans; Autoimmune Pancreatitis; Autoimmune Diseases; Immunoglobulin G; Diagnosis, Differential; Pancreas
PubMed: 38516247
DOI: 10.3748/wjg.v30.i8.817 -
Frontiers in Immunology 2023Autoimmune diseases are heterogeneous disorders believed to stem from the immune system's inability to distinguish between auto- and foreign- antigens. B lymphocytes... (Review)
Review
Autoimmune diseases are heterogeneous disorders believed to stem from the immune system's inability to distinguish between auto- and foreign- antigens. B lymphocytes serve a crucial role in humoral immunity as they generate antibodies and present antigens. Dysregulation of B cell function induce the onset of autoimmune disorders by generating autoantibodies and pro-inflammatory cytokines, resulting in an imbalance in immune regulation. New research in immunometabolism shows that cellular metabolism plays an essential role in controlling B lymphocytes immune reactions by providing the energy and substrates for B lymphocytes activation, differentiation, and function. However, dysregulated immunometabolism lead to autoimmune diseases by disrupting self-tolerance mechanisms. This review summarizes the latest research on metabolic reprogramming of B lymphocytes in autoimmune diseases, identifying crucial pathways and regulatory factors. Moreover, we consider the potential of metabolic interventions as a promising therapeutic strategy. Understanding the metabolic mechanisms of B cells brings us closer to developing novel therapies for autoimmune disorders.
Topics: Humans; Autoimmune Diseases; B-Lymphocytes; Autoantibodies; Immunity, Humoral; Signal Transduction
PubMed: 37680644
DOI: 10.3389/fimmu.2023.1232820 -
Frontiers in Pediatrics 2023In last decades a simultaneous increase in the prevalence of atopic and autoimmune disorders in pediatric population has been observed. Despite the Th1-Th2 paradigm,... (Review)
Review
In last decades a simultaneous increase in the prevalence of atopic and autoimmune disorders in pediatric population has been observed. Despite the Th1-Th2 paradigm, supporting the polarization of the immune system with Th1 response involved in autoimmune diseases and Th2 response leading to hypersensitivity reactions, recent evidence suggests a possible coexistence of common pathogenic pathways as result of shared immune dysregulation. Similar genes and other mechanisms such as epithelial barrier damage, gut microbiota dysbiosis and reduced number of T regs and IL-10 contribute to the onset of allergy and autoimmunity. IgA deficiency is also hypothesized to be the crosslink between celiac disease and allergy by lowering gut mucous membrane protection from antigens and allergens. The present narrative review aims to give an overview of the co-occurrence of allergic and autoimmune disorders (celiac disease, inflammatory bowel diseases, type 1 diabetes mellitus, thyroid disease, juvenile idiopathic arthritis) in pediatric population, based on the available evidence. We also highlighted the common pathogenic pathways that may underpin both. Our findings confirm that allergic and autoimmune diseases are commonly associated, and clinicians should therefore be aware of the possible coexistence of these conditions in order to ameliorate disease management and patient care. Particular attention should be paid to the association between atopic dermatitis or asthma and celiac disease or type 1 diabetes and vice versa, for therapeutic interventions. Further studies are needed to better clarify mechanisms involved in the pathogenesis and eventually identify new therapeutic strategies.
PubMed: 38027278
DOI: 10.3389/fped.2023.1239365 -
International Journal of Molecular... Dec 2023Natural killer (NK) cells and CD8 T cells can clear infected and transformed cells and generate tolerance to themselves, which also prevents autoimmune diseases. Natural... (Review)
Review
Natural killer (NK) cells and CD8 T cells can clear infected and transformed cells and generate tolerance to themselves, which also prevents autoimmune diseases. Natural killer group 2 member D (NKG2D) is an important activating immune receptor that is expressed on NK cells, CD8 T cells, γδ T cells, and a very small percentage of CD4 T cells. In contrast, the NKG2D ligand (NKG2D-L) is generally not expressed on normal cells but is overexpressed under stress. Thus, the inappropriate expression of NKG2D-L leads to the activation of self-reactive effector cells, which can trigger or exacerbate autoimmunity. In this review, we discuss the role of NKG2D and NKG2D-L in systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), multiple sclerosis (MS), type I diabetes (T1DM), inflammatory bowel disease (IBD), and celiac disease (CeD). The data suggest that NKG2D and NKG2D-L play a pathogenic role in some autoimmune diseases. Therefore, the development of strategies to block the interaction of NKG2D and NKG2D-L may have therapeutic effects in some autoimmune diseases.
Topics: Humans; NK Cell Lectin-Like Receptor Subfamily K; CD8-Positive T-Lymphocytes; Ligands; Autoimmune Diseases; Killer Cells, Natural; Immunotherapy
PubMed: 38139373
DOI: 10.3390/ijms242417545 -
Frontiers in Immunology 2023Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that predominantly affects women of childbearing age and is characterized by the damage to multiple... (Review)
Review
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that predominantly affects women of childbearing age and is characterized by the damage to multiple target organs. The pathogenesis of SLE is complex, and its etiology mainly involves genetic and environmental factors. At present, there is still a lack of effective means to cure SLE. In recent years, growing evidence has shown that gut microbiota, as an environmental factor, triggers autoimmunity through potential mechanisms including translocation and molecular mimicry, leads to immune dysregulation, and contributes to the development of SLE. Dietary intervention, drug therapy, probiotics supplement, fecal microbiome transplantation and other ways to modulate gut microbiota appear to be a potential treatment for SLE. In this review, the dysbiosis of gut microbiota in SLE, potential mechanisms linking gut microbiota and SLE, and immune dysregulation associated with gut microbiota in SLE are summarized.
Topics: Humans; Female; Gastrointestinal Microbiome; Lupus Erythematosus, Systemic; Autoimmunity; Fecal Microbiota Transplantation; Probiotics
PubMed: 37533870
DOI: 10.3389/fimmu.2023.1202850 -
Science (New York, N.Y.) Mar 2024We describe humans with rare biallelic loss-of-function variants impairing pre-α T cell receptor (pre-TCRα) expression. Low circulating naive αβ T cell counts at...
We describe humans with rare biallelic loss-of-function variants impairing pre-α T cell receptor (pre-TCRα) expression. Low circulating naive αβ T cell counts at birth persisted over time, with normal memory αβ and high γδ T cell counts. Their TCRα repertoire was biased, which suggests that noncanonical thymic differentiation pathways can rescue αβ T cell development. Only a minority of these individuals were sick, with infection, lymphoproliferation, and/or autoimmunity. We also report that 1 in 4000 individuals from the Middle East and South Asia are homozygous for a common hypomorphic variant. They had normal circulating naive αβ T cell counts but high γδ T cell counts. Although residual pre-TCRα expression drove the differentiation of more αβ T cells, autoimmune conditions were more frequent in these patients compared with the general population.
Topics: Humans; Autoimmunity; Cell Differentiation; Homozygote; Intraepithelial Lymphocytes; Receptors, Antigen, T-Cell, alpha-beta; Membrane Glycoproteins; Loss of Function Mutation; Lymphocyte Count; Alleles; Infections; Lymphoproliferative Disorders; Pedigree; Male; Female; Middle Aged; Aged; Aged, 80 and over
PubMed: 38422122
DOI: 10.1126/science.adh4059 -
Frontiers in Cardiovascular Medicine 2023
PubMed: 37534278
DOI: 10.3389/fcvm.2023.1249525 -
Genes and Immunity Oct 2023FOXP3 regulatory T cells (T) are indispensable for immune homoeostasis and for the prevention of autoimmune diseases. Interleukin-2 (IL-2) signalling is critical in all... (Review)
Review
FOXP3 regulatory T cells (T) are indispensable for immune homoeostasis and for the prevention of autoimmune diseases. Interleukin-2 (IL-2) signalling is critical in all aspects of T biology. Consequences of defective IL-2 signalling are insufficient numbers or dysfunction of T and hence autoimmune disorders in human and mouse. The restoration and maintenance of immune homoeostasis remain central therapeutic aims in the field of autoimmunity. Historically, broadly immunosuppressive drugs with serious side-effects have been used for the treatment of autoimmune diseases or prevention of organ-transplant rejection. More recently, ex vivo expanded or in vivo stimulated T have been shown to induce effective tolerance in clinical trials supporting the clinical benefit of targeting natural immunosuppressive mechanisms. Given the central role of exogenous IL-2 in T homoeostasis, a new and promising focus in drug development are IL-2-based approaches for in vivo targeted expansion of T or for enhancement of their suppressive activity. In this review, we summarise the role of IL-2 in T biology and consequences of dysfunctional IL-2 signalling pathways. We then examine evidence of efficacy of IL-2-based biological drugs targeting T with specific focus on therapeutic candidates in clinical trials and discuss their limitations.
Topics: Humans; Mice; Animals; T-Lymphocytes, Regulatory; Autoimmunity; Interleukin-2; Autoimmune Diseases; Immunotherapy; Immunosuppressive Agents
PubMed: 37741949
DOI: 10.1038/s41435-023-00221-y -
The Journal of Experimental Medicine Oct 2023Th17 cells play a critical role in both tissue homeostasis and inflammation during clearance of infections as well as autoimmune and inflammatory disorders. Despite...
Th17 cells play a critical role in both tissue homeostasis and inflammation during clearance of infections as well as autoimmune and inflammatory disorders. Despite numerous efforts to distinguish the homeostatic and inflammatory roles of Th17 cells, the mechanism underlying the divergent functions of inflammatory Th17 cells remains poorly understood. In this study, we demonstrate that the inflammatory Th17 cells involved in autoimmune colitis and those activated during colitogenic infection are distinguishable populations characterized by their differential responses to the pharmacological molecule, clofazimine (CLF). Unlike existing Th17 inhibitors, CLF selectively inhibits proautoimmune Th17 cells while preserving the functional state of infection-elicited Th17 cells partially by reducing the enzyme ALDH1L2. Overall, our study identifies two distinct subsets within the inflammatory Th17 compartment with distinct regulatory mechanisms. Furthermore, we highlight the feasibility to develop disease-promoting Th17 selective inhibitor for treating autoimmune diseases.
Topics: Humans; Autoimmunity; Th17 Cells; Autoimmune Diseases; Inflammation; Colitis
PubMed: 37367944
DOI: 10.1084/jem.20221911