-
Science (New York, N.Y.) Jan 2024Strategies that modulate antigen delivery are being tested to reverse autoimmunity.
Strategies that modulate antigen delivery are being tested to reverse autoimmunity.
Topics: Autoimmunity; Autoimmune Diseases; Autoantigens; Antigen-Presenting Cells; Antigen Presentation; Desensitization, Immunologic; Humans; Animals; Mice; Self Tolerance
PubMed: 38175899
DOI: 10.1126/science.adg7505 -
Immunologic Research Aug 2023Autoimmune diseases are caused by the break-down in self-tolerance mechanisms and can result in the generation of autoantibodies specific to human antigens. Human... (Review)
Review
Autoimmune diseases are caused by the break-down in self-tolerance mechanisms and can result in the generation of autoantibodies specific to human antigens. Human autoantigen profiling technologies such as solid surface arrays and display technologies are powerful high-throughput technologies utilised to discover and map novel autoantigens associated with disease. This review compares human autoantigen profiling technologies including the application of these approaches in chronic and post-infectious autoimmune disease. Each technology has advantages and limitations that should be considered when designing new projects to profile autoantibodies. Recent studies that have utilised these technologies across a range of diseases have highlighted marked heterogeneity in autoantibody specificity between individuals as a frequent feature. This individual heterogeneity suggests that epitope spreading maybe an important mechanism in the pathogenesis of autoimmune disease in general and likely contributes to inflammatory tissue damage and symptoms. Studies focused on identifying autoantibody biomarkers for diagnosis should use targeted data analysis to identify the rarer public epitopes and antigens, common between individuals. Thus, utilisation of human autoantigen profiling technology, combined with different analysis approaches, can illuminate both pathogenesis and biomarker discovery.
Topics: Humans; Autoimmune Diseases; Autoantibodies; Autoantigens; Epitopes
PubMed: 36690876
DOI: 10.1007/s12026-023-09362-8 -
Trends in Molecular Medicine May 2021Although autoimmunity and autoimmune disease (AID) are relatively common, the repertoire of autoantigens is paradoxically very limited. Highly enriched in this... (Review)
Review
Although autoimmunity and autoimmune disease (AID) are relatively common, the repertoire of autoantigens is paradoxically very limited. Highly enriched in this autoantigen repertoire are nucleic acids and their binding proteins, which together form large macromolecular structures. Most of these complexes are of ancient evolutionary origin, with homologs throughout multiple kingdoms of life. Why and if these nucleic acid-protein particles drive the development of autoimmunity remains unresolved. Recent advances in our understanding of the microbiome may provide clues about the origins of autoimmunity - and the particular puzzle of why the autoantigen repertoire is so particularly enriched in ribonucleoprotein particles (RNPs). We discuss the possibility that autoimmunity to some RNPs may arise from molecular mimicry to microbial orthologs.
Topics: Autoantigens; Autoimmune Diseases; Autoimmunity; Genes, Bacterial; Humans; Immunity; Microbiota; Molecular Mimicry; Ribonucleoproteins
PubMed: 33722441
DOI: 10.1016/j.molmed.2021.02.003 -
Acta Pharmacologica Sinica Apr 2024Autoimmune diseases (AIDs) arise from a breakdown in immunological self-tolerance, wherein the adaptive immune system mistakenly attacks healthy cells, tissues and... (Review)
Review
Autoimmune diseases (AIDs) arise from a breakdown in immunological self-tolerance, wherein the adaptive immune system mistakenly attacks healthy cells, tissues and organs. AIDs impose excessive treatment costs and currently rely on non-specific and universal immunosuppression, which only offer symptomatic relief without addressing the underlying causes. AIDs are driven by autoantigens, targeting the autoantigens holds great promise in transforming the treatment of these diseases. To achieve this goal, a comprehensive understanding of the pathogenic mechanisms underlying different AIDs and the identification of specific autoantigens are critical. In this review, we categorize AIDs based on their underlying causes and compile information on autoantigens implicated in each disease, providing a roadmap for the development of novel immunotherapy regimens. We will focus on type 1 diabetes (T1D), which is an autoimmune disease characterized by irreversible destruction of insulin-producing β cells in the Langerhans islets of the pancreas. We will discuss insulin as possible autoantigen of T1D and its role in T1D pathogenesis. Finally, we will review current treatments of TID and propose a potentially effective immunotherapy targeting autoantigens.
Topics: Humans; Autoantigens; Autoimmune Diseases; Diabetes Mellitus, Type 1; Drug Discovery; Insulin
PubMed: 38097717
DOI: 10.1038/s41401-023-01207-2 -
Frontiers in Immunology 2020Molecular or antigenic mimicry is a term for the similarity of different antigens, which can be confused by the immune system. Antigen recognition by antibodies and T... (Review)
Review
Molecular or antigenic mimicry is a term for the similarity of different antigens, which can be confused by the immune system. Antigen recognition by antibodies and T cell receptors is specific, but not restricted to a single antigen. Both types of receptors specifically recognize antigens and are expressed with a very high but still restricted variability compared to the number of different antigens they potentially could bind. T cell receptors only can bind to antigen peptides presented on certain self-MHC-molecules by screening only some amino acid side chains on both the presented peptides and the MHC molecule. The other amino acids of the peptide are not directly perceived by the T cell, offering the opportunity for a single T cell to recognize a variety of different antigens with the same receptor, which significantly increases the immune repertoire. The immune system is usually tolerant to autoantigens, especially to those of immune privileged sites, like the eye. Therefore, autoimmune diseases targeting these organs were hard to explain, unless a T cell is activated by an environmental peptide (e.g. pathogen) that is similar, but not necessarily identical with an autoantigen. Here we describe antigenic mimicry of retinal autoantigens with a variety of non-ocular antigens resulting in the induction of intraocular inflammation. T cells that are activated by mimotopes outside of the eye can pass the blood-retina barrier and enter ocular tissues. When reactivated in the eye by crossreaction with autoantigens they induce uveitis by recruiting inflammatory cells.
Topics: Animals; Autoantigens; Cross Reactions; Eye; Humans; Immune Privilege; Immune Tolerance; Molecular Mimicry; T-Lymphocytes; Uveitis
PubMed: 33193382
DOI: 10.3389/fimmu.2020.580636 -
Frontiers in Immunology 2022Autoimmune diseases are often associated with autoantibodies that abnormally target self-antigens (autoantigens). An intuitive therapeutic strategy for diseases caused... (Review)
Review
Autoimmune diseases are often associated with autoantibodies that abnormally target self-antigens (autoantigens). An intuitive therapeutic strategy for diseases caused by aAbs is to design decoys, or soluble molecules that target the antigen combining site of these aAbs, thereby blocking binding of aAb to self-antigen and subsequent tissue damage. Here, we review the known decoy molecules of these types, discuss newer technological opportunities afforded by monoclonal antibody and structural biology advances, and discuss the challenges to this approach. Recent opportunities relevant to this approach for cardiac phenotypes, specifically Ro-associated long QT syndrome, are discussed.
Topics: Antibodies, Monoclonal; Autoantibodies; Autoantigens; Autoimmune Diseases; Cardiomyopathies; Humans; Immunoassay; Phenotype
PubMed: 35154130
DOI: 10.3389/fimmu.2022.812649 -
Frontiers in Immunology 2023The development of new autoantigen discovery techniques, like programmable phage immunoprecipitation sequencing (PhIP-Seq), has accelerated the discovery of...
INTRODUCTION
The development of new autoantigen discovery techniques, like programmable phage immunoprecipitation sequencing (PhIP-Seq), has accelerated the discovery of neural-specific autoantibodies. Herein, we report the identification of a novel biomarker for paraneoplastic neurologic syndrome (PNS), Sloan-Kettering-Virus-Family-Transcriptional-Corepressor-2 (SKOR2)-IgG, utilizing PhIP-Seq. We have also performed a thorough clinical validation using normal, healthy, and disease/cancer control samples.
METHODS
Stored samples with unclassified staining at the junction of the Purkinje cell and the granule cell layers were analyzed by PhIP-Seq for putative autoantigen identification. The autoantigen was confirmed by recombinant antigen-expressing cell-based assay (CBA), Western blotting, and tissue immunofluorescence assay colocalization.
RESULTS
PhIP-Seq data revealed SKOR2 as the candidate autoantigen. The target antigen was confirmed by a recombinant SKOR-2-expressing, and cell lysate Western blot. Furthermore, IgG from both patient samples colocalized with a commercial SKOR2-specific IgG on cryosections of the mouse brain. Both SKOR2 IgG-positive patients had central nervous system involvement, one presenting with encephalitis and seizures (Patient 1) and the other with cognitive dysfunction, spastic ataxia, dysarthria, dysphagia, and pseudobulbar affect (Patient 2). They had a refractory progressive course and were diagnosed with adenocarcinoma (Patient 1: lung, Patient 2: gallbladder). Sera from adenocarcinoma patients without PNS (n=30) tested for SKOR2-IgG were negative.
DISCUSSION
SKOR2 IgG represents a novel biomarker for PNS associated with adenocarcinoma. Identification of additional SKOR2 IgG-positive cases will help categorize the associated neurological phenotype and the risk of underlying malignancy.
Topics: Mice; Animals; Humans; Paraneoplastic Syndromes, Nervous System; Biomarkers; Adenocarcinoma; Autoantigens; Immunoglobulin G
PubMed: 37795104
DOI: 10.3389/fimmu.2023.1243946 -
Immunological Reviews Sep 2016Neutrophil serine proteases (NSPs) exercise tissue-degrading and microbial-killing effects. The spectrum of NSP-mediated functions grows continuously, not least because... (Review)
Review
Neutrophil serine proteases (NSPs) exercise tissue-degrading and microbial-killing effects. The spectrum of NSP-mediated functions grows continuously, not least because of methodological progress. Sensitive and specific FRET substrates were developed to study the proteolytic activity of each NSP member. Advanced biochemical methods are beginning to characterize common and specific NSP substrates. The resulting novel information indicates that NSPs contribute not only to genuine inflammatory neutrophil functions but also to autoimmunity, metabolic conditions, and cancer. Tight regulatory mechanisms control the proteolytic potential of NSPs. However, not all NSP functions depend on their enzymatic activity. Proteinase-3 (PR3) is somewhat unique among the NSPs for PR3 functions as an autoantigen. Patients with small-vessel vasculitis develop autoantibodies to PR3 that bind their target antigens on the neutrophil surface and trigger neutrophil activation. These activated cells subsequently contribute to vascular necrosis with life-threatening multiorgan failure. This article discusses various aspects of NSP biology and highlights translational aspects with strong clinical implications.
Topics: Animals; Autoantigens; Autoimmunity; Humans; Inflammation; Myeloblastin; Neutrophil Activation; Neutrophils; Proteolysis; Serine Proteases; Vasculitis
PubMed: 27558338
DOI: 10.1111/imr.12441 -
Current Opinion in Immunology Dec 2018High-affinity antibodies to double-stranded DNA are a hallmark of systemic lupus erythematosus (SLE) and are thought to contribute to disease flares and tissue... (Review)
Review
High-affinity antibodies to double-stranded DNA are a hallmark of systemic lupus erythematosus (SLE) and are thought to contribute to disease flares and tissue inflammation such as nephritis. Notwithstanding their clinical importance, major questions remain about the development and regulation of these pathogenic anti-DNA responses. These include the mechanisms that prevent anti-DNA responses in healthy subjects, despite the constant generation of self-DNA and the abundance of DNA-reactive B cells; the nature and physical form of antigenic DNA in SLE; the regulation of DNA availability as an antigen; and potential therapeutic strategies targeting the pathogenic DNA in SLE. This review summarizes current progress in these directions, focusing on the role of secreted DNases in the regulation of antigenic extracellular DNA.
Topics: Autoantigens; DNA; Deoxyribonucleases; Humans; Lupus Erythematosus, Systemic
PubMed: 30261321
DOI: 10.1016/j.coi.2018.09.009 -
Current Opinion in Rheumatology Jul 2018The aim of this review is to summarize the recent studies regarding the relationship between anti-DFS70 antibodies and HIV-1 infection. Examining the interaction between... (Review)
Review
PURPOSE OF REVIEW
The aim of this review is to summarize the recent studies regarding the relationship between anti-DFS70 antibodies and HIV-1 infection. Examining the interaction between HIV-1 integrate (HIV-IN) and DFS70 and its role in the integration into the host's chromatin. Then, summarizing the importance of anti-DFS70 autoantibodies binding the DFS70 in the same region as the HIV-IN.
RECENT FINDINGS
The interaction between HIV-IN and DFS70 protein could be a proficient target in the treatment against HIV-1 infection. The blockade of DFS70 is more effective than the blockade of HIV-IN as anti-HIV-1 drug. The anti-DFS70 autoantibodies could be an interesting therapeutic target for anti-HIV-1 treatment. Currently, there are no studies that measured the levels of anti-DFS70 autoantibodies in HIV-1-infected individuals.
SUMMARY
The anti-DFS70 antibodies bind to the DFS70 autoantigen in the same region as the HIV-IN. This fact makes the autoantibodies a potential treatment for HIV-1-infected individuals. Blood levels of anti-DFS70 antibodies have not been measured in HIV-1-infected individuals. This issue opens new lines of research about the protective role of antibodies against HIV-1 infection.
Topics: Autoantibodies; Autoantigens; HIV Infections; HIV-1; Humans
PubMed: 29401119
DOI: 10.1097/BOR.0000000000000495