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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 -
Seminars in Immunology Aug 2021Autoimmune diseases, caused by cellularly and molecularly complex immune responses against self-antigens, are largely treated with broad-acting, non-disease-specific... (Review)
Review
Autoimmune diseases, caused by cellularly and molecularly complex immune responses against self-antigens, are largely treated with broad-acting, non-disease-specific anti-inflammatory drugs. These compounds can attenuate autoimmune inflammation, but tend to impair normal immunity against infection and cancer, cannot restore normal immune homeostasis and are not curative. Nanoparticle (NP)- and microparticle (MP)-based delivery of immunotherapeutic agents affords a unique opportunity to not only increase the specificity and potency of broad-acting immunomodulators, but also to elicit the formation of organ-specific immunoregulatory cell networks capable of inducing bystander immunoregulation. Here, we review the various NP/MP-based strategies that have so far been tested in models of experimental and/or spontaneous autoimmunity, with a focus on mechanisms of action.
Topics: Autoantigens; Autoimmune Diseases; Autoimmunity; Humans; Immunologic Factors; Immunomodulation; Nanomedicine
PubMed: 34969600
DOI: 10.1016/j.smim.2021.101535 -
Nature Aging Oct 2022Immune system and blood-brain barrier dysfunction are implicated in the development of Alzheimer's and other dementia-causing diseases, but their causal role remains...
Immune system and blood-brain barrier dysfunction are implicated in the development of Alzheimer's and other dementia-causing diseases, but their causal role remains unknown. We performed Mendelian randomization for 1,827 immune system- and blood-brain barrier-related biomarkers and identified 127 potential causal risk factors for dementia-causing diseases. Pathway analyses linked these biomarkers to amyloid-β, tau and α-synuclein pathways and to autoimmunity-related processes. A phenome-wide analysis using Mendelian randomization-based polygenic risk score in the FinnGen study (n = 339,233) for the biomarkers indicated shared genetic background for dementias and autoimmune diseases. This association was further supported by human leukocyte antigen analyses. In inverse-probability-weighted analyses that simulate randomized controlled drug trials in observational data, anti-inflammatory methotrexate treatment reduced the incidence of Alzheimer's disease in high-risk individuals (hazard ratio compared with no treatment, 0.64, 95% confidence interval 0.49-0.88, P = 0.005). These converging results from different lines of human research suggest that autoimmunity is a modifiable component in dementia-causing diseases.
Topics: Humans; Autoimmunity; Mendelian Randomization Analysis; Alzheimer Disease; Biomarkers; Autoimmune Diseases; Immune System
PubMed: 37118290
DOI: 10.1038/s43587-022-00293-x -
Frontiers in Immunology 2022
Topics: Humans; Autoimmune Diseases; Autoimmunity
PubMed: 36591245
DOI: 10.3389/fimmu.2022.1092469 -
Frontiers in Immunology 2022
Topics: Humans; Antigen Presentation; Autoimmunity; Aminopeptidases; Immune System Diseases
PubMed: 36311705
DOI: 10.3389/fimmu.2022.1055152 -
Neurology(R) Neuroimmunology &... Nov 2019To describe the neurologic spectrum and treatment outcomes for neurochondrin-IgG positive cases identified serologically in the Mayo Clinic Neuroimmunology Laboratory.
OBJECTIVES
To describe the neurologic spectrum and treatment outcomes for neurochondrin-IgG positive cases identified serologically in the Mayo Clinic Neuroimmunology Laboratory.
METHODS
Archived serum and CSF specimens previously scored positive for IgGs that stained mouse hippocampal tissue in a nonuniform synaptic pattern by immunofluorescence assay (89 among 616,025 screened, 1993-2019) were reevaluated. Antibody characterization experiments revealed specificity for neurochondrin, confirmed by recombinant protein assays.
RESULTS
IgG in serum (9) or CSF (4) from 8 patients yielded identical neuron-restricted CNS patterns, most pronounced in hippocampus (stratum lucidum in particular), cerebellum (Purkinje cells and molecular layer), and amygdala. All were neurochondrin-IgG positive. Five were women; median symptom onset age was 43 years (range, 30-69). Of 7 with clinical data, 6 presented with rapidly progressive cerebellar ataxia, brainstem signs, or both; 1 had isolated unexplained psychosis 1 year prior. Five of 6 had cerebellar signs, 4 with additional brainstem symptoms or signs (eye movement abnormalities, 3; dysphagia, 2; nausea and vomiting, 1). One patient with brainstem signs (vocal cord paralysis and VII nerve palsy) had accompanying myelopathy (longitudinally extensive abnormality on MRI; aquaporin-4-IgG and myelin oligodendrocyte glycoprotein-IgG negative). The 7th patient had small fiber neuropathy only. Just 1 of 7 had contemporaneous cancer (uterine). Six patients with ataxia or brainstem signs received immunotherapy, but just 1 remained ambulatory. At last follow-up, 5 had MRI evidence of severe cerebellar atrophy.
CONCLUSION
In our series, neurochondrin autoimmunity was usually accompanied by a nonparaneoplastic rapidly progressive rhombencephalitis with poor neurologic outcomes. Other phenotypes and occasional paraneoplastic causes may occur.
Topics: Adult; Aged; Animals; Autoimmune Diseases of the Nervous System; Autoimmunity; Encephalitis; Female; Humans; Male; Mice; Middle Aged; Nerve Tissue Proteins
PubMed: 31511329
DOI: 10.1212/NXI.0000000000000612 -
Cell Research Feb 2023Autoimmunity and autoinflammation arise from aberrant immunological and inflammatory responses toward self-components, contributing to various autoimmune diseases and... (Review)
Review
Autoimmunity and autoinflammation arise from aberrant immunological and inflammatory responses toward self-components, contributing to various autoimmune diseases and autoinflammatory diseases. RNA-binding proteins (RBPs) are essential for immune cell development and function, mainly via exerting post-transcriptional regulation of RNA metabolism and function. Functional dysregulation of RBPs and abnormities in RNA metabolism are closely associated with multiple autoimmune or autoinflammatory disorders. Distinct RBPs play critical roles in aberrant autoreactive inflammatory responses via orchestrating a complex regulatory network consisting of DNAs, RNAs and proteins within immune cells. In-depth characterizations of RBP-RNA interactomes during autoimmunity and autoinflammation will lead to a better understanding of autoimmune pathogenesis and facilitate the development of effective therapeutic strategies. In this review, we summarize and discuss the functions of RBP-RNA interactions in controlling aberrant autoimmune inflammation and their potential as biomarkers and therapeutic targets.
Topics: Humans; Autoimmunity; RNA; Autoimmune Diseases; Gene Expression Regulation; Inflammation
PubMed: 36599968
DOI: 10.1038/s41422-022-00752-5 -
Autophagy Feb 2021IRGM is a genetic risk factor for several autoimmune diseases. However, the mechanism of IRGM-mediated protection in autoimmunity remains undetermined. The abnormal... (Review)
Review
IRGM is a genetic risk factor for several autoimmune diseases. However, the mechanism of IRGM-mediated protection in autoimmunity remains undetermined. The abnormal activation of type I interferon (IFN) response is one of the significant factors in the pathogenesis of several autoimmune diseases. In our recent study, we showed that IRGM is a master suppressor of the interferon response. We found that the depletion of IRGM results in constitutively activated CGAS-STING1, DDX58/RIG-I-MAVS, and TLR3-TICAM1/TRIF signaling pathways resulting in upregulation of almost all IFN-responsive genes. Mechanistically, IRGM utilizes a two-pronged mechanism to suppress the interferon response. First, it mediates SQSTM1/p62-dependent selective macroautophagy/autophagy of nucleic acid sensor proteins, including CGAS, DDX58/RIG-I, and TLR3. Second, it facilitates the removal of defective mitochondria by mitophagy and avoids a buildup of mito-ROS and mito-damage/danger-associated molecular patterns (DAMPs). Thus, IRGM deficiency results in increased nucleic acid sensors and DAMPs engaging a vicious cycle of aberrant activation of IFN response that is known to occur in systemic autoimmune-like conditions.
Topics: Autoimmune Diseases; Autoimmunity; Autophagy; GTP-Binding Proteins; Humans; Mitochondria; Signal Transduction
PubMed: 32813580
DOI: 10.1080/15548627.2020.1810920 -
Journal of Autoimmunity May 2023Immune aging is a complex process rendering the host susceptible to cancer, infection, and insufficient tissue repair. Many autoimmune diseases preferentially occur... (Review)
Review
Immune aging is a complex process rendering the host susceptible to cancer, infection, and insufficient tissue repair. Many autoimmune diseases preferentially occur during the second half of life, counterintuitive to the concept of excess adaptive immunity driving immune-mediated tissue damage. T cells are particularly susceptible to aging-imposed changes, as they are under extreme proliferative pressure to fulfill the demands of clonal expansion and of homeostatic T cell repopulation. T cells in older adults have a footprint of genetic and epigenetic changes, lack mitochondrial fitness, and fail to maintain proteostasis, diverging them from host protection to host injury. Here, we review recent progress in understanding how the human T-cell system ages and the evidence detailing how T cell aging contributes to autoimmune conditions. T cell aging is now recognized as a risk determinant in two prototypic autoimmune syndromes; rheumatoid arthritis and giant cell arteritis. The emerging concept adds susceptibility to autoimmune and autoinflammatory disease to the spectrum of aging-imposed adaptations and opens new opportunities for immunomodulatory therapy by restoring the functional intactness of aging T cells.
Topics: Humans; Aged; Autoimmunity; T-Lymphocytes; Autoimmune Diseases; Aging; Cellular Senescence; Risk Factors
PubMed: 36357240
DOI: 10.1016/j.jaut.2022.102947 -
The Journal of Investigative Dermatology Mar 2022T cells are key drivers of autoimmunity in numerous noncommunicable inflammatory skin diseases by directly harming host tissue or through helping B cells in producing... (Review)
Review
T cells are key drivers of autoimmunity in numerous noncommunicable inflammatory skin diseases by directly harming host tissue or through helping B cells in producing autoantibodies. Technological advances have contributed to identifying autoantigens, the Holy Grail of autoimmunity, in many inflammatory disorders of the skin. Novel therapeutic approaches such as chimeric (auto)antibody receptor T cells are a milestone on the way to finding individualized, well-tolerated, targeted therapies. This review summarizes the current knowledge on pathogenesis, immune response pattern‒related ontology, diagnostic approaches, and treatment options of autoimmune skin diseases.
Topics: Autoantibodies; Autoantigens; Autoimmune Diseases; Autoimmunity; Humans; T-Lymphocytes
PubMed: 34538423
DOI: 10.1016/j.jid.2021.04.032