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Journal of Translational Autoimmunity Jun 2024Autoimmune diseases (ADs) are one of the groups of chronic illnesses that impose a significant burden of disease and health costs worldwide. Age is a crucial risk factor... (Review)
Review
Autoimmune diseases (ADs) are one of the groups of chronic illnesses that impose a significant burden of disease and health costs worldwide. Age is a crucial risk factor for the onset of ADs. Theoretically, it is inferred that with organic and immune system aging, the loss of immune tolerance and specificity of immune activity becomes more intense, the probability of autoimmunity is increasing. However, there is a group of individuals whose prevalence of ADs is very low or non-existent, despite the biological aging. This paradox in autoimmunity raises questions. Centenarians, individuals who are over 100 years old, are possibly the most successful model of biological aging in humans. Most of these individuals exhibit a favorable health phenotype. To date, primary data evidence and potential hypotheses explaining this phenomenon are lacking globally, even though this paradox could provide valuable, original, and relevant information regarding the understanding of risk or protective factors, biological drivers, and biomarkers related to autoimmunity. Herein we discuss some hypothesis that may explain the absence of ADs in centenarians, including inflammaging, immunosenescence and immune resilience, immune system hyperstimulation, proteodynamics, and genetics.
PubMed: 38468861
DOI: 10.1016/j.jtauto.2024.100237 -
Frontiers in Immunology 2024For many decades viral infections have been suspected as 'triggers' of autoimmune disease, but mechanisms for how this could occur have been difficult to establish.... (Review)
Review
For many decades viral infections have been suspected as 'triggers' of autoimmune disease, but mechanisms for how this could occur have been difficult to establish. Recent studies have shown that viral infections that are commonly associated with viral myocarditis and other autoimmune diseases such as coxsackievirus B3 (CVB3) and SARS-CoV-2 target mitochondria and are released from cells in mitochondrial vesicles that are able to activate the innate immune response. Studies have shown that Toll-like receptor (TLR)4 and the inflammasome pathway are activated by mitochondrial components. Autoreactivity against cardiac myosin and heart-specific immune responses that occur after infection with viruses where the heart is not the primary site of infection (e.g., CVB3, SARS-CoV-2) may occur because the heart has the highest density of mitochondria in the body. Evidence exists for autoantibodies against mitochondrial antigens in patients with myocarditis and dilated cardiomyopathy. Defects in tolerance mechanisms like autoimmune regulator gene (AIRE) may further increase the likelihood of autoreactivity against mitochondrial antigens leading to autoimmune disease. The focus of this review is to summarize current literature regarding the role of viral infection in the production of extracellular vesicles containing mitochondria and virus and the development of myocarditis.
Topics: Humans; Myocarditis; Autoimmunity; Coxsackievirus Infections; Enterovirus B, Human; Autoimmune Diseases; Mitochondria; Extracellular Vesicles
PubMed: 38550582
DOI: 10.3389/fimmu.2024.1374796 -
Nature Feb 2024Guillain-Barré syndrome (GBS) is a rare heterogenous disorder of the peripheral nervous system, which is usually triggered by a preceding infection, and causes a...
Guillain-Barré syndrome (GBS) is a rare heterogenous disorder of the peripheral nervous system, which is usually triggered by a preceding infection, and causes a potentially life-threatening progressive muscle weakness. Although GBS is considered an autoimmune disease, the mechanisms that underlie its distinct clinical subtypes remain largely unknown. Here, by combining in vitro T cell screening, single-cell RNA sequencing and T cell receptor (TCR) sequencing, we identify autoreactive memory CD4 cells, that show a cytotoxic T helper 1 (T1)-like phenotype, and rare CD8 T cells that target myelin antigens of the peripheral nerves in patients with the demyelinating disease variant. We characterized more than 1,000 autoreactive single T cell clones, which revealed a polyclonal TCR repertoire, short CDR3β lengths, preferential HLA-DR restrictions and recognition of immunodominant epitopes. We found that autoreactive TCRβ clonotypes were expanded in the blood of the same patient at distinct disease stages and, notably, that they were shared in the blood and the cerebrospinal fluid across different patients with GBS, but not in control individuals. Finally, we identified myelin-reactive T cells in the nerve biopsy from one patient, which indicates that these cells contribute directly to disease pathophysiology. Collectively, our data provide clear evidence of autoreactive T cell immunity in a subset of patients with GBS, and open new perspectives in the field of inflammatory peripheral neuropathies, with potential impact for biomedical applications.
Topics: Humans; Autoimmunity; Biopsy; CD8-Positive T-Lymphocytes; Guillain-Barre Syndrome; HLA-DR Antigens; Immunodominant Epitopes; Myelin Sheath; Peripheral Nerves; Peripheral Nervous System Diseases; Receptors, Antigen, T-Cell; Th1 Cells; T-Lymphocytes, Cytotoxic; Immunologic Memory
PubMed: 38233524
DOI: 10.1038/s41586-023-06916-6 -
International Journal of Molecular... Sep 2023Autoimmunity is defined by the presence of antibodies and/or T cells directed against self-components. Although of unknown etiology, autoimmunity commonly is associated... (Review)
Review
Autoimmunity is defined by the presence of antibodies and/or T cells directed against self-components. Although of unknown etiology, autoimmunity commonly is associated with environmental factors such as infections, which have been reported to increase the risk of developing autoimmune diseases. Occasionally, similarities between infectious non-self and self-tissue antigens may contribute to immunological cross-reactivity in autoimmune diseases. These reactions may be interpreted as molecular mimicry, which describes cross-reactivity between foreign pathogens and self-antigens that have been reported to cause tissue damage and to contribute to the development of autoimmunity. By focusing on the nature of antibodies, cross-reactivity in general, and antibody-antigen interactions, this review aims to characterize the nature of potential cross-reactive immune reactions between infectious non-self and self-tissue antigens which may be associated with autoimmunity but may not actually be the cause of disease onset.
Topics: Humans; Antibodies; Immune System Diseases; Autoimmune Diseases; Autoimmunity; Autoantigens
PubMed: 37686415
DOI: 10.3390/ijms241713609 -
Journal of Autoimmunity Sep 2023Infectious diseases are commonly implicated as potential initiators of autoimmune diseases (ADs) and represent the most commonly known factor in the development of... (Review)
Review
Infectious diseases are commonly implicated as potential initiators of autoimmune diseases (ADs) and represent the most commonly known factor in the development of autoimmunity in susceptible individuals. Epidemiological data and animal studies on multiple ADs suggest that molecular mimicry is one of the likely mechanisms for the loss of peripheral tolerance and the development of clinical disease. Besides molecular mimicry, other mechanisms such as defects in central tolerance, nonspecific bystander activation, epitope-determinant spreading, and/or constant antigenic stimuli, may also contribute for breach of tolerance and to the development of ADs. Linear peptide homology is not the only mechanism by which molecular mimicry is established. Peptide modeling (i.e., 3D structure), molecular docking analyses, and affinity estimation for HLAs are emerging as critical strategies when studying the links of molecular mimicry in the development of autoimmunity. In the current pandemic, several reports have confirmed an influence of SARS-CoV-2 on subsequent autoimmunity. Bioinformatic and experimental evidence support the potential role of molecular mimicry. Peptide dimensional analysis requires more research and will be increasingly important for designing and distributing vaccines and better understanding the role of environmental factors related to autoimmunity.
Topics: Animals; Autoimmunity; Molecular Mimicry; Molecular Docking Simulation; COVID-19; SARS-CoV-2; Autoimmune Diseases
PubMed: 37390745
DOI: 10.1016/j.jaut.2023.103070 -
Frontiers in Pharmacology 2023Autoimmune hepatitis (AIH) is the inflammation of the liver with clear-cut interface hepatitis and piecemeal necrosis located at the boundary between portal areas and...
Autoimmune hepatitis (AIH) is the inflammation of the liver with clear-cut interface hepatitis and piecemeal necrosis located at the boundary between portal areas and periportal hepatocytes, and characterized by autoimmunity to hepatocytes with an increase in the antinuclear antibody. After the disastrous SARS-CoV-2 pandemic flagellated several countries, several vaccines have been commercialized and have become a ground for social responsibility. The mRNA vaccines, issued by Pfizer-BioNTech (BNT162b2) and Moderna (mRNA-1273), do not use prebuilt viruses to supply the antigen in the subject's body and are not perfect but have been useful in tackling the pandemic. Nevertheless, both myocarditis and AIH have been reported as side effects of the vaccination programs in addition to thromboembolic events. Here, we explore this topic and give a data-based perspective, gathering a comparison between the titin protein of the sarcomere and myocarditis. The isolation of a gene using the serum from a patient with autoimmune scleroderma recognized an epitope on chromosomes (condensed mitotic form) in both human cultured cells and early embryos. It revealed that this gene encodes a homolog of the vertebrate titin (D-Titin). Moreover, anti-titin antibodies have been found in a subset of patients with , a neuromuscular junction disease that is mostly associated with autoimmune antibodies, such as the anti-acetylcholine receptor antibody. The co-existence of and autoimmune hepatitis is rare, and a cohort of patients with anti-titin antibodies seems to be highly relevant. In consideration of these data and the number of patients who may not be symptomatic, we postulated that autoimmune phenomena may not be exceedingly rare, following the administration of mRNA technology-based vaccines, and a balance between pros and cons in administrating boosters is critical.
PubMed: 37601060
DOI: 10.3389/fphar.2023.1190367 -
Nature Feb 2024Plasma cells produce large quantities of antibodies and so play essential roles in immune protection. Plasma cells, including a long-lived subset, reside in the bone...
Plasma cells produce large quantities of antibodies and so play essential roles in immune protection. Plasma cells, including a long-lived subset, reside in the bone marrow where they depend on poorly defined microenvironment-linked survival signals. We show that bone marrow plasma cells use the ligand-gated purinergic ion channel P2RX4 to sense extracellular ATP released by bone marrow osteoblasts through the gap-junction protein pannexin 3 (PANX3). Mutation of Panx3 or P2rx4 each caused decreased serum antibodies and selective loss of bone marrow plasma cells. Compared to their wild-type counterparts, PANX3-null osteoblasts secreted less extracellular ATP and failed to support plasma cells in vitro. The P2RX4-specific inhibitor 5-BDBD abrogated the impact of extracellular ATP on bone marrow plasma cells in vitro, depleted bone marrow plasma cells in vivo and reduced pre-induced antigen-specific serum antibody titre with little posttreatment rebound. P2RX4 blockade also reduced autoantibody titre and kidney disease in two mouse models of humoral autoimmunity. P2RX4 promotes plasma cell survival by regulating endoplasmic reticulum homeostasis, as short-term P2RX4 blockade caused accumulation of endoplasmic reticulum stress-associated regulatory proteins including ATF4 and B-lineage mutation of the pro-apoptotic ATF4 target Chop prevented bone marrow plasma cell demise on P2RX4 inhibition. Thus, generating mature protective and pathogenic plasma cells requires P2RX4 signalling controlled by PANX3-regulated extracellular ATP release from bone marrow niche cells.
Topics: Animals; Mice; Adenosine Triphosphate; Autoantibodies; Autoimmunity; Bone Marrow Cells; Cell Lineage; Connexins; Endoplasmic Reticulum; Endoplasmic Reticulum Stress; Mutation; Osteoblasts; Plasma Cells; Receptors, Purinergic P2X4; Signal Transduction
PubMed: 38355795
DOI: 10.1038/s41586-024-07047-2 -
Cells Oct 2023Immune surveillance and adaptive immune responses, involving continuously circulating and tissue-resident T-lymphocytes, provide host defense against infectious agents... (Review)
Review
Immune surveillance and adaptive immune responses, involving continuously circulating and tissue-resident T-lymphocytes, provide host defense against infectious agents and possible malignant transformation while avoiding autoimmune tissue damage. Activation, migration, and deployment of T-cells to affected tissue sites are crucial for mounting an adaptive immune response. An effective adaptive immune defense depends on the ability of T-cells to dynamically reprogram their metabolic requirements in response to environmental cues. Inability of the T-cells to adapt to specific metabolic demands may skew cells to become either hyporesponsive (creating immunocompromised conditions) or hyperactive (causing autoimmune tissue destruction). Here, we review maladaptive T-cell metabolic fitness that can cause autoimmune diseases and discuss how T-cell metabolic programs can potentially be modulated to achieve therapeutic benefits.
Topics: Humans; T-Lymphocytes; Autoimmune Diseases; Adaptive Immunity
PubMed: 37947619
DOI: 10.3390/cells12212541 -
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