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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 -
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 -
Journal of Proteome Research Jun 2023Understanding autoimmunity to endogenous proteins is crucial in diagnosing and treating autoimmune diseases. In this work, we developed a user-friendly AAgAtlas portal...
Understanding autoimmunity to endogenous proteins is crucial in diagnosing and treating autoimmune diseases. In this work, we developed a user-friendly AAgAtlas portal (http://biokb.ncpsb.org.cn/aagatlas_portal/index.php#), which can be used to search for 8045 non-redundant autoantigens (AAgs) and 47 post-translationally modified AAgs against 1073 human diseases that are prioritized by a credential score developed by multisource evidence. Using AAgAtlas, the immunogenic properties of human AAgs was systematically elucidated according to their genetic, biophysical, cytological, expression profile, and evolutionary characteristics. The results indicated that human AAgs are evolutionally conserved in protein sequence and enriched in three hydrophilic and polar amino acid residues (K, D, and E) that are located at the protein surface. AAgs are enriched in proteins that are involved in nucleic acid binding, transferase, and the cytoskeleton. Genome, transcriptome, and proteome analyses further indicated that AAb production is associated with gene variance and abnormal protein expression related to the pathological activities of different tumors. Collectively, our data outlines the hallmarks of human AAgs that facilitate the understanding of humoral autoimmunity and the identification of biomarkers of human diseases.
Topics: Humans; Autoantigens; Autoantibodies; Autoimmune Diseases; Autoimmunity; Amino Acid Sequence
PubMed: 37183442
DOI: 10.1021/acs.jproteome.2c00799 -
Rheumatology (Oxford, England) Mar 2020Anti-transcription intermediary factor 1 (TIF1)-γ autoantibodies are robustly linked with cancer-associated DM in adults. This review aims to give an overview of the... (Review)
Review
Anti-transcription intermediary factor 1 (TIF1)-γ autoantibodies are robustly linked with cancer-associated DM in adults. This review aims to give an overview of the physiological context of TIF1-γ and to determine whether there is a pathophysiological link between anti-TIF1-γ autoantibodies and the occurrence of cancer. Detection of anti-TIF1-γ autoantibodies has a high sensitivity and specificity for cancer-associated DM in adults and is therefore useful for both diagnosis and cancer risk stratification. The function of the autoantigen, TIF1-γ, may provide insight into the mechanism behind this association. TIF1-γ is a ubiquitously present protein involved in various biological pathways, including TGF-β signalling. In cancer, it can act either as a tumour suppressor or promoter, depending on the cellular context and cancer stage. Evolving data provide pathophysiological insights, linking anti-TIF1-γ autoantibodies to both the anti-tumour response and to muscle and skin damage. TIF1-γ expression is increased in muscle and skin tissue of patients with DM. Mutations or loss-of-heterozygosity in TIF1-γ alleles in malignant tissue may result in the expression of tumour-specific neo-antigens stimulating autoantibody production. The newly formed autoantibodies are hypothesized to cross-react with antigens in muscle and skin, driving the development of DM. Based on the current evidence, anti-TIF1-γ autoantibodies should be considered warning lights of a potential tumour autoantigen and should alert the physician to the possibility of an underlying cancer.
Topics: Autoantibodies; Autoantigens; Dermatomyositis; Humans; Transcription Factors
PubMed: 31883334
DOI: 10.1093/rheumatology/kez572 -
Nature Reviews. Rheumatology Apr 2018The discovery of novel autoantigen systems related to idiopathic inflammatory myopathies (collectively referred to as myositis) in adults and children has had major... (Review)
Review
The discovery of novel autoantigen systems related to idiopathic inflammatory myopathies (collectively referred to as myositis) in adults and children has had major implications for the diagnosis and management of this group of diseases across a wide range of medical specialties. Traditionally, autoantibodies found in patients with myositis are described as being myositis-specific autoantibodies (MSAs) or myositis-associated autoantibodies (MAAs), depending on their prevalence in other, related conditions. However, certain MSAs are more closely associated with extramuscular manifestations, such as skin and lung disease, than with myositis itself. It is very rare for more than one MSA to coexist in the same individual, underpinning the potential to use MSAs to precisely define genetic and disease endotypes. Each MSA is associated with a distinctive pattern of disease or phenotype, which has implications for diagnosis and a more personalized approach to therapy. Knowledge of the function and localization of the autoantigenic targets for MSAs has provided key insights into the potential immunopathogenic mechanisms of myositis. In particular, evidence suggests that the alteration of expression of a myositis-related autoantigen by certain environmental influences or oncogenesis could be a pivotal event linking autoantibody generation to the development of disease.
Topics: Adult; Autoantibodies; Autoantigens; Child; Humans; Myositis; Phenotype; Precision Medicine
PubMed: 29674612
DOI: 10.1038/nrrheum.2018.56 -
International Journal of Molecular... Feb 2020Autoantigen treatment has been tried for the prevention of type 1 diabetes (T1D) and to preserve residual beta-cell function in patients with a recent onset of the... (Review)
Review
Autoantigen treatment has been tried for the prevention of type 1 diabetes (T1D) and to preserve residual beta-cell function in patients with a recent onset of the disease. In experimental animal models, efficacy was good, but was insufficient in human subjects. Besides the possible minor efficacy of peroral insulin in high-risk individuals to prevent T1D, autoantigen prevention trials have failed. Other studies on autoantigen prevention and intervention at diagnosis are ongoing. One problem is to select autoantigen/s; others are dose and route. Oral administration may be improved by using different vehicles. Proinsulin peptide therapy in patients with T1D has shown possible minor efficacy. In patients with newly diagnosed T1D, subcutaneous injection of glutamic acid decarboxylase (GAD) bound to alum hydroxide (GAD-alum) can likely preserve beta-cell function, but the therapeutic effect needs to be improved. Intra-lymphatic administration may be a better alternative than subcutaneous administration, and combination therapy might improve efficacy. This review elucidates some actual problems of autoantigen therapy in the prevention and/or early intervention of type 1 diabetes.
Topics: Administration, Oral; Animals; Autoantigens; Chemotherapy, Adjuvant; Diabetes Mellitus, Type 1; Drug Therapy, Combination; Glutamate Decarboxylase; Humans; Injections, Intralymphatic; Injections, Subcutaneous; Insulin; Proinsulin; Vitamin D
PubMed: 32111075
DOI: 10.3390/ijms21051598 -
Hormone and Metabolic Research =... Dec 2018Human thyroid peroxidase (TPO), is an important enzyme responsible for the biosynthesis of thyroid hormones and is a major autoantigen in autoimmune thyroid diseases... (Review)
Review
Human thyroid peroxidase (TPO), is an important enzyme responsible for the biosynthesis of thyroid hormones and is a major autoantigen in autoimmune thyroid diseases (AITDs) such as the destructive Hashimoto's thyroiditis. Although the structure of TPO has yet to be determined, its extracellular domain consists of three regions that exhibit a high degree of sequence similarity to domains of known three-dimensional structure: the myeloperoxidase (MPO)-like domain, complement control protein (CCP)-like domain, and epidermal growth factor (EGF)-like domain. Homology models of TPO can therefore be constructed, providing some structural context to its known function, as well as facilitating the mapping of regions that are responsible for its autoantigenicity. In this review, we highlight recent progress in this area, in particular how a molecular modelling approach has advanced the visualisation and interpretation of epitope mapping studies for TPO, facilitating the dissection of the interplay between TPO protein structure, function, and autoantigenticity.
Topics: Amino Acid Sequence; Animals; Autoantigens; Epitopes; Hashimoto Disease; Humans; Iodide Peroxidase; Protein Engineering; Structural Homology, Protein
PubMed: 30360003
DOI: 10.1055/a-0717-5514 -
Autoimmunity Reviews Feb 2020Autoimmune diseases are mostly characterized by autoantibodies in the patients' serum or cerebrospinal fluid, representing diagnostic or prognostic biomarkers. For... (Review)
Review
Autoimmune diseases are mostly characterized by autoantibodies in the patients' serum or cerebrospinal fluid, representing diagnostic or prognostic biomarkers. For decades, research has focused on single autoantigens or panels of single autoantigens. In this article, we advocate to broaden the focus by addressing the entire autoantigen repertoire in a systemic "omics-like" way. This approach aims to capture the enormous biodiversity in the sets of targeted antigens and pave the way toward a more holistic understanding of the concerted character of antibody-related humoral immune responses. Ongoing technological progress permits high-throughput screenings of thousands of autoantigens in parallel, e.g., via protein microarrays, phage display, or immunoprecipitation with mass spectrometry. We argue that the time is right for combining omics and autoantibody screening approaches into "autoantigenomics" as a novel omics subcategory. In this article, we introduce the concept of autoantigenomics, describe its roots and application options, and demarcate the method from related holistic approaches such as systems serology or immune-related transcriptomics and proteomics. We suggest the following extendable method set to be applied to autoantigen repertoires: (1) principal component analysis, (2) hierarchical cluster analysis, (3) partial least-square discriminant analysis or orthogonal projections to latent structures discriminant analysis, (4) analysis of the repertoire sizes in disease groups and clinical subgroups, (5) overrepresentation analyses using databases like those of Gene Ontology, Reactome Pathway, or DisGeNET, (6) analysis of pathways that are significantly targeted by specific repertoires, and (7) machine learning approaches. In an unsupervised way, these methods can identify clusters of autoantigens sharing certain functional or spatial properties, or clusters of patients comprising clinical subgroups potentially useful for patient stratification. In a supervised way, these methods can lead to prediction models that may eventually assist diagnosis and prognosis. The untargeted autoantigenomics approach allows for the systematic survey of antibody-related humoral immune responses. This may enhance our understanding of autoimmune diseases in a more comprehensive way compared to current single or panel autoantibodies approaches.
Topics: Autoantibodies; Autoantigens; Autoimmune Diseases; Humans; Proteomics
PubMed: 31838165
DOI: 10.1016/j.autrev.2019.102450 -
Biochemistry. Biokhimiia Apr 2023Demyelinating diseases of the central nervous system are caused by an autoimmune attack on the myelin sheath surrounding axons. Myelin structural proteins become... (Review)
Review
Demyelinating diseases of the central nervous system are caused by an autoimmune attack on the myelin sheath surrounding axons. Myelin structural proteins become antigenic, leading to the development of myelin lesions. The use of highly specialized laboratory diagnostic techniques for identification of specific antibodies directed against myelin components can significantly improve diagnostic approaches. Myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease (MOGAD) currently includes demyelinating syndromes with known antigens. Based on the demonstrated pathogenic role of human IgG against MOG, MOGAD was classified as a distinct nosological entity. However, generation of multiple MOG isoforms by alternative splicing hinders antigen detection even with the most advanced immunofluorescence techniques. On the other hand, MOG conformational changes ensure the structural integrity of other myelin proteins and maintain human-specific mechanisms of immune autotolerance.
Topics: Humans; Autoantibodies; Autoantigens; Central Nervous System; Demyelinating Diseases; Immunoglobulin G; Myelin-Oligodendrocyte Glycoprotein
PubMed: 37080940
DOI: 10.1134/S0006297923040107 -
Autoimmunity Reviews Jul 2016Autoantigen development is poorly understood at the atomic level. Heparin-induced thrombocytopenia (HIT) is an autoimmune thrombotic disorder caused by antibodies to an... (Review)
Review
Autoantigen development is poorly understood at the atomic level. Heparin-induced thrombocytopenia (HIT) is an autoimmune thrombotic disorder caused by antibodies to an antigen composed of platelet factor 4 (PF4) and heparin or cellular glycosaminoglycans (GAGs). In solution, PF4 exists as an equilibrium among monomers, dimers and tetramers. Structural studies of these interacting components helped delineate a multi-step process involved in the pathogenesis of HIT. First, heparin binds to the 'closed' end of the PF4 tetramer and stabilizes its conformation; exposing the 'open' end. Second, PF4 arrays along heparin/GAG chains, which approximate tetramers, form large antigenic complexes that enhance antibody avidity. Third, pathogenic HIT antibodies bind to the 'open' end of stabilized PF4 tetramers to form an IgG/PF4/heparin ternary immune complex and also to propagate the formation of 'ultralarge immune complexes' (ULCs) that contain multiple IgG antibodies. Fourth, ULCs signal through FcγRIIA receptors, activating platelets and monocytes directly and generating thrombin, which transactivates hematopoietic and endothelial cells. A non-pathogenic anti-PF4 antibody prevents tetramer formation, binding of pathogenic antibody, platelet activation and thrombosis, providing a new approach to manage HIT. An improved understanding of the pathogenesis of HIT may lead to novel diagnostics and therapeutics for this autoimmune disease.
Topics: Autoantigens; Heparin; Humans; Thrombocytopenia
PubMed: 26970483
DOI: 10.1016/j.autrev.2016.03.011