-
Current Opinion in Rheumatology Nov 2014The purpose of this review is to highlight recent progress in autoantibody detection technologies and describe how these methods are providing novel information and... (Review)
Review
PURPOSE OF REVIEW
The purpose of this review is to highlight recent progress in autoantibody detection technologies and describe how these methods are providing novel information and insights into autoimmune disorders.
RECENT FINDINGS
In recent years, alternative methods such as comprehensive phage display, fluid-phase immunoassays, and antigen microarrays have been developed for autoantigen discovery and profiling autoantibody responses. Compared with classic approaches such as Western blot and ELISA, these methods show improved diagnostic performance, the ability to measure antibody responses to multiple targets, and/or allow more quantitative analyses. Specific notable findings include uncovering previously unrecognized autoantigens, the improved classification of patient clinical phenotypes, and the discovery of pathogenic autoantibodies promoting disease.
SUMMARY
Advances in immunoassay technologies offer many opportunities for understanding the relationship between autoantibody detection and the myriad complex, clinical phenotypes characteristic of most autoimmune diseases. Further simplification and standardization of these technologies may allow routine integration into clinical practice with improved diagnostic and therapeutic outcomes.
Topics: Autoantibodies; Autoantigens; Autoimmune Diseases; Humans; Immunoassay
PubMed: 25203116
DOI: 10.1097/BOR.0000000000000107 -
Journal of Interferon & Cytokine... Jul 2022Immunoglobulin A (IgA) nephropathy is the most common primary glomerulonephritis worldwide, with no disease-specific treatment and up to 40% of patients progressing to... (Review)
Review
Immunoglobulin A (IgA) nephropathy is the most common primary glomerulonephritis worldwide, with no disease-specific treatment and up to 40% of patients progressing to kidney failure. IgA nephropathy (IgAN), characterized by IgA1-containing immunodeposits in the glomeruli, is considered to be an autoimmune disease in which the kidneys are injured as innocent bystanders. Glomerular immunodeposits are thought to originate from the circulating immune complexes that contain aberrantly -glycosylated IgA1, the main autoantigen in IgAN, bound by IgG autoantibodies. A common clinical manifestation associated with IgAN includes synpharyngitic hematuria at disease onset or during disease activity. This observation suggests a connection of disease pathogenesis with an activated mucosal immune system of the upper-respiratory and/or gastrointestinal tract and IgA1 glycosylation. In fact, some cytokines can enhance production of aberrantly -glycosylated IgA1. This process involves abnormal cytokine signaling in IgA1-producing cells from patients with IgAN. In this article, we present our view of pathogenesis of IgAN and review how some cytokines can contribute to the disease process by enhancing production of aberrantly glycosylated IgA1. We also review current clinical trials of IgAN based on cytokine-targeting therapeutic approaches.
Topics: Autoantigens; Cytokines; Glomerulonephritis, IGA; Glycosylation; Humans; Immunoglobulin A
PubMed: 35793525
DOI: 10.1089/jir.2022.0039 -
Autoimmunity Reviews Sep 2017Chronic immune-mediated disorders (IMDs) constitute a major health burden. Understanding IMD pathogenesis is facing two major constraints: Missing heritability... (Review)
Review
Chronic immune-mediated disorders (IMDs) constitute a major health burden. Understanding IMD pathogenesis is facing two major constraints: Missing heritability explaining familial clustering, and missing autoantigens. Pinpointing IMD risk genes and autoimmune targets, however, is of fundamental importance for developing novel causal therapies. The strongest association of all IMDs is seen with human leukocyte antigen (HLA) alleles. Using psoriasis as an IMD model this article reviews the pathogenic role HLA molecules may have within the polygenic predisposition of IMDs. It concludes that disease-associated HLA alleles account for both missing heritability and autoimmune mechanisms by facilitating tissue-specific autoimmune responses through autoantigen presentation.
Topics: Animals; Antigen Presentation; Autoantigens; Autoimmunity; Genetic Association Studies; Genetic Predisposition to Disease; Genotype; HLA Antigens; Humans; Psoriasis; Receptors, Antigen, T-Cell
PubMed: 28705779
DOI: 10.1016/j.autrev.2017.07.011 -
Molecular Metabolism Oct 2021Since its discovery 100 years ago, insulin, as the 'cure' for type 1 diabetes, has rescued the lives of countless individuals. As the century unfolded and the autoimmune... (Review)
Review
BACKGROUND
Since its discovery 100 years ago, insulin, as the 'cure' for type 1 diabetes, has rescued the lives of countless individuals. As the century unfolded and the autoimmune nature of type 1 diabetes was recognised, a darker side of insulin emerged. Autoimmunity to insulin was found to be an early marker of risk for type 1 diabetes in young children. In humans, it remains unclear if autoimmunity to insulin is primarily due to a defect in the beta cell itself or to dysregulated immune activation. Conversely, it may be secondary to beta-cell damage from an environmental agent (e.g., virus). Nevertheless, direct, interventional studies in non-obese diabetic (NOD) mouse models of type 1 diabetes point to a critical role for (pro)insulin as a primary autoantigen that drives beta cell pathology.
SCOPE OF REVIEW
Modelled on Koch's postulates for the pathogenicity of an infectious agent, evidence for a pathogenic role of (pro)insulin as an autoantigen in type 1 diabetes, particularly applicable to the NOD mouse model, is reviewed. Evidence in humans remains circumstantial. Additionally, as (pro)insulin is a target of autoimmunity in type 1 diabetes, its application as a therapeutic tool to elicit antigen-specific immune tolerance is assessed.
MAJOR CONCLUSIONS
Paradoxically, insulin is both a 'cure' and a potential 'cause' of type 1 diabetes, actively participating as an autoantigen to drive autoimmune destruction of beta cells - the instrument of its own destruction.
Topics: Animals; Autoantibodies; Autoantigens; Diabetes Mellitus, Type 1; Disease Models, Animal; Humans; Insulin; Insulin-Secreting Cells; Mice; Mice, Inbred NOD
PubMed: 34242821
DOI: 10.1016/j.molmet.2021.101288 -
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 -
Diabetes May 2019Type 1 diabetes (T1D) is an autoimmune disease that is caused, in part, by T cell-mediated destruction of insulin-producing β-cells. High risk for disease, in those...
Type 1 diabetes (T1D) is an autoimmune disease that is caused, in part, by T cell-mediated destruction of insulin-producing β-cells. High risk for disease, in those with genetic susceptibility, is predicted by the presence of two or more autoantibodies against insulin, the 65-kDa form of glutamic acid decarboxylase (GAD65), insulinoma-associated protein 2 (IA-2), and zinc transporter 8 (ZnT8). Despite this knowledge, we still do not know what leads to the breakdown of tolerance to these autoantigens, and we have an incomplete understanding of T1D etiology and pathophysiology. Several new autoantibodies have recently been discovered using innovative technologies, but neither their potential utility in monitoring disease development and treatment nor their role in the pathophysiology and etiology of T1D has been explored. Moreover, neoantigen generation (through posttranslational modification, the formation of hybrid peptides containing two distinct regions of an antigen or antigens, alternative open reading frame usage, and translation of RNA splicing variants) has been reported, and autoreactive T cells that target these neoantigens have been identified. Collectively, these new studies provide a conceptual framework to understand the breakdown of self-tolerance, if such modifications occur in a tissue- or disease-specific context. A recent workshop sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases brought together investigators who are using new methods and technologies to identify autoantigens and characterize immune responses toward these proteins. Researchers with diverse expertise shared ideas and identified resources to accelerate antigen discovery and the detection of autoimmune responses in T1D. The application of this knowledge will direct strategies for the identification of improved biomarkers for disease progression and treatment response monitoring and, ultimately, will form the foundation for novel antigen-specific therapeutics. This Perspective highlights the key issues that were addressed at the workshop and identifies areas for future investigation.
Topics: Animals; Autoantigens; Biomarkers; Diabetes Mellitus, Type 1; Humans
PubMed: 31010879
DOI: 10.2337/dbi18-0066 -
Kidney International Jan 1993Goodpasture syndrome is an autoimmune disease causing rapidly progressive glomerulonephritis and pulmonary hemorrhage. The clinical manifestations are caused by... (Review)
Review
Goodpasture syndrome is an autoimmune disease causing rapidly progressive glomerulonephritis and pulmonary hemorrhage. The clinical manifestations are caused by autoantibodies that bind to a constituent, termed the Goodpasture autoantigen, of alveolar and glomerular basement membranes. Searches for the identity of this constituent have recently culminated in the discovery of two new chains (alpha 3 and alpha 4) of type IV collagen and the identification of the alpha 3 chain as the Goodpasture autoantigen. The gene, COL4A3, encoding this autoantigen was recently cloned and localized to the q35-37 region of chromosome 2. The major protomeric form of the alpha 3 chain is a homotrimer. The alpha 3-protomers associate through NC1-to-NC1 interactions mainly with each other to form a suprastructure, although some associate with protomers containing the alpha 1(IV) and alpha 2(IV) chains. The alpha 3-protomers also form suprastructures involving triple helical interactions of three or more protomers. The Goodpasture epitope is localized to the carboxylterminal region of the alpha 3(IV) chain, encompassing the last 36 residues of the chain, as the primary interaction site, and its structure is discontinuous.
Topics: Amino Acid Sequence; Anti-Glomerular Basement Membrane Disease; Autoantigens; Collagen; Epitopes; Humans; Molecular Sequence Data; Molecular Structure
PubMed: 7679455
DOI: 10.1038/ki.1993.22 -
Clinical and Experimental Immunology May 2021In this second and final part of the collection of articles for the Immunology of Diabetes Society review series on insights into pathogenesis of type 1 diabetes, we...
In this second and final part of the collection of articles for the Immunology of Diabetes Society review series on insights into pathogenesis of type 1 diabetes, we present two articles. The first of these covers a debate that took place in the Immunology of Diabetes Society meeting in London 2018, in which five investigators presented a case for specific immune cells/targets to be the 'Achilles Heel of type 1 diabetes'. The second article presents further insights into the generation of post-translationally modified peptides. It focuses upon mechanisms and processes that lead to new potentially autoantigenic targets for CD8 T cells, and complements the review of new hybrid peptide targets for CD4 T cells in the first part of our series.
Topics: Autoantigens; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Diabetes Mellitus, Type 1; Humans
PubMed: 33890285
DOI: 10.1111/cei.13597 -
Medecine Sciences : M/S 2005Autoimmune response is diverse. This diversity is thought not to take place at the beginning of the autoimmune process but to occur as the disease evolves. It is mainly... (Review)
Review
Autoimmune response is diverse. This diversity is thought not to take place at the beginning of the autoimmune process but to occur as the disease evolves. It is mainly the consequence of the so-called epitope-spreading phenomenon and of the cross-reactivity of antibodies. Analysing autoantibody repertoire constitutes a powerful means to understand physiopathological processes at work in various diseases, mainly autoimmune diseases. In particular this analysis opens the way to precisely identify autoantigens and their changes in various pathological situations, and allows providing new biological markers in chronic inflammatory diseases. New methodologies have recently emerged for the analysis of the autoantibody repertoire in a given individual. They propose diagnostic approaches no more related upon few markers but founded upon analysis of global changes of the antibody repertoire. They belong to methodologies called target-oriented proteomics. Their common feature is to isolate autoantigens by means of affinity chromatography based upon antibody/antigen reactions. Autoantibodies to be studied interact with a protein substratum susceptible to include autoantibody targets. These interactions take place on solid macro- or microsurfaces, i.e. membrane filters or chips. Several strategies can be used for locating the specific autoantibody/autoantigen complexes and for identifying behind autoantigens. In this paper three approaches, namely, the recombinant protein chips, the SELDI techniques and the 2-D gel electrophoresis linked to mass spectrometry are described and compared.
Topics: Autoantibodies; Autoantigens; Humans; Models, Immunological; Proteomics
PubMed: 16115463
DOI: 10.1051/medsci/2005218-9759 -
Autoimmunity Reviews Jan 2010For the past twenty years the type 1 diabetes autoantigen glutamic acid decarboxylase (65 kDa isoform; GAD65) has become a prototypic autoantigen, yielding a wealth of... (Review)
Review
For the past twenty years the type 1 diabetes autoantigen glutamic acid decarboxylase (65 kDa isoform; GAD65) has become a prototypic autoantigen, yielding a wealth of immunological and clinical insights. However for most of that period, much of the data could not be placed in a structural context, and relied upon modelling 'guess-work'. The high-resolution crystal structure of GAD65, as well as that of its isoform GAD67, was determined in 2007, providing many insights into the molecular determinants of antigenicity, as well as an atomic positioning of the epitope-mapping data. Despite the two isoforms having the same fold and high sequence identity, it is intriguing that only the 65 kDa isoform functions as an autoantigen. The structures shed much light on this question, revealing striking differences in structure and mobility at the C-terminal domain of the isoforms, which agreed with remarkable accuracy with epitope-mapping data. Furthermore the structures provided an explanation of why two enzymes are required to catalyse the same reaction in mammals, and how this might be linked to their contrasting antigenicities. This review thus focuses on how the GAD system represents a unique testbed for understanding the relationships between molecular structure, function and antigenicity.
Topics: Animals; Autoantigens; Epitopes; Glutamate Decarboxylase; Humans; Isoenzymes; Structural Homology, Protein
PubMed: 19465164
DOI: 10.1016/j.autrev.2009.05.003