-
Clinical and Experimental Immunology Dec 2019In recent years, there have been exciting new insights into pathogenesis of type 1 diabetes in a number of areas of immunology. In this edition, a collection of four...
In recent years, there have been exciting new insights into pathogenesis of type 1 diabetes in a number of areas of immunology. In this edition, a collection of four review articles are presented, which encompass new findings presented at the Immunology of Diabetes Society meeting in London 2018. The articles are focused particularly in 4 related areas of investigation, which include autoantibodies in type 1 diabetes, new autoantigenic targets for CD4 T cells, trafficking of immune cells to the pancreas and islet-immune interactions in the pancreas.
Topics: Autoantibodies; Autoantigens; CD4-Positive T-Lymphocytes; Diabetes Mellitus, Type 1; Humans; Islets of Langerhans; Pancreas
PubMed: 31729755
DOI: 10.1111/cei.13396 -
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 -
Nature Communications Feb 2023Cryptic peptides, hidden from the immune system under physiologic conditions, are revealed by changes to MHC class II processing and hypothesized to drive the loss of...
Cryptic peptides, hidden from the immune system under physiologic conditions, are revealed by changes to MHC class II processing and hypothesized to drive the loss of immune tolerance to self-antigens in autoimmunity. Rheumatoid arthritis (RA) is an autoimmune disease characterized by immune responses to citrullinated self-antigens, in which arginine residues are converted to citrullines. Here, we investigate the hypothesis that citrullination exposes cryptic peptides by modifying protein structure and proteolytic cleavage. We show that citrullination alters processing and presentation of autoantigens, resulting in the generation of a unique citrullination-dependent repertoire composed primarily of native sequences. This repertoire stimulates T cells from RA patients with anti-citrullinated protein antibodies more robustly than controls. The generation of this unique repertoire is achieved through altered protease cleavage and protein destabilization, rather than direct presentation of citrulline-containing epitopes, suggesting a novel paradigm for the role of protein citrullination in the breach of immune tolerance in RA.
Topics: Humans; Epitopes; Citrullination; Antigen Presentation; Arthritis, Rheumatoid; Autoantigens; Peptides; Citrulline
PubMed: 36828807
DOI: 10.1038/s41467-023-36620-y -
Clinical and Experimental Immunology Apr 2023Anti-centromere (ACA) and antimitochondrial antibodies (AMA) are specific for limited-cutaneous systemic sclerosis (lcSSc) and primary biliary cholangitis (PBC),...
Anti-centromere (ACA) and antimitochondrial antibodies (AMA) are specific for limited-cutaneous systemic sclerosis (lcSSc) and primary biliary cholangitis (PBC), respectively, and can coexist in up to 25 and 30% of SSc and PBC patients. Here, we evaluated whether anti-centromeric protein A (CENP-A) antibodies cross-react with mitochondrial antigens. To this end, sera from two lcSSc patients (pt1 and pt4), one of them (pt4) also affected by PBC, were used as the source of ACA, previously shown to recognize different groups of amino acids (motifs) in the CENP-A region spanning amino acids 1-17 (Ap1-17). Pt1 and pt4 Ap1-17-specific IgG were purified by affinity-chromatography on insolubilized Ap1-17-peptide column and tested by western blotting with nuclear and cytoplasmic protein extract from HeLa cells. Immunoreactive proteins were identified by mass spectrometry and validated by immunodot. The results showed that affinity-purified SSc/PBC pt4 anti-Ap1-17 and not SSc pt1 anti-Ap1-17 Ab, specifically cross-reacted with the E2 component of the mitochondrial pyruvate dehydrogenase complex (PDC-E2), the major mitochondrial autoantigen in PBC. Sequence homology analysis indicated that the motif A-x-x-P-x-A-P recognized by pt4 anti-Ap1-17 IgG and shared by CENP-A and PDC-E2, is also expressed by some members of the Human Herpesvirus family, suggesting that they may trigger the production of these cross-reacting antibodies.
Topics: Humans; Autoantibodies; Centromere Protein A; Pyruvate Dehydrogenase Complex; Liver Cirrhosis, Biliary; HeLa Cells; Scleroderma, Systemic; Autoantigens; Immunoglobulin G; Amino Acids; Antibody Specificity
PubMed: 36715304
DOI: 10.1093/cei/uxad012 -
Cell Research Apr 2024Autoreactive B cells are silenced through receptor editing, clonal deletion and anergy induction. Additional autoreactive B cells are ignorant because of physical...
Autoreactive B cells are silenced through receptor editing, clonal deletion and anergy induction. Additional autoreactive B cells are ignorant because of physical segregation from their cognate autoantigen. Unexpectedly, we find that follicular B cell-derived autoantigen, including cell surface molecules such as FcγRIIB, is a class of homeostatic autoantigen that can induce spontaneous germinal centers (GCs) and B cell-reactive autoantibodies in non-autoimmune animals with intact T and B cell repertoires. These B cell-reactive B cells form GCs in a manner dependent on spontaneous follicular helper T (T) cells, which preferentially recognize B cell-derived autoantigen, and in a manner constrained by spontaneous follicular regulatory T (T) cells, which also carry specificities for B cell-derived autoantigen. B cell-reactive GC cells are continuously generated and, following immunization or infection, become intermixed with foreign antigen-induced GCs. Production of plasma cells and antibodies derived from B cell-reactive GC cells are markedly enhanced by viral infection, potentially increasing the chance for autoimmunity. Consequently, immune homeostasis in healthy animals not only involves classical tolerance of silencing and ignoring autoreactive B cells but also entails a reactive equilibrium attained by a spontaneous B cell-reactive triad of B cells, T cells and T cells.
Topics: Animals; T-Lymphocytes, Regulatory; T-Lymphocytes, Helper-Inducer; B-Lymphocytes; Germinal Center; Autoantigens
PubMed: 38326478
DOI: 10.1038/s41422-024-00929-0 -
Frontiers in Immunology 2021Detecting autoantibodies provides foundational information for the diagnosis of most autoimmune diseases. An important pathophysiological distinction is whether... (Review)
Review
Detecting autoantibodies provides foundational information for the diagnosis of most autoimmune diseases. An important pathophysiological distinction is whether autoantibodies are directed against extracellular or intracellular proteins. Autoantibodies targeting extracellular domains of proteins, such as membrane receptors, channels or secreted molecules are often directly pathogenic, whereby autoantibody binding to the autoantigen disrupts the normal function of a critical protein or pathway, and/or triggers antibody-dependent cell surface complement killing. By comparison, autoantibodies directed against intracellular proteins are recognized as useful diagnostic biomarkers of abnormal autoimmune activity, but the link between antigenicity and pathogenicity is less straightforward. Because intracellular autoantigens are generally inaccessible to autoantibody binding, for the most part, they do not directly contribute to pathogenesis. In a few diseases, autoantibodies to intracellular targets cause damage indirectly by immune complex formation, immune activation, and other processes. In this review, the general features of and differences between autoimmune diseases segregated on the basis of intracellular or extracellular autoantigens are explored using over twenty examples. Expression profiles of autoantigens in relation to the tissues targeted by autoimmune disease and the temporal appearance of autoantibodies before clinical diagnosis often correlate with whether the respective autoantibodies mostly recognize either intracellular or extracellular autoantigens. In addition, current therapeutic strategies are discussed from this vantage point. One drug, rituximab, depletes CD20+ B-cells and is highly effective for autoimmune disorders associated with autoantibodies against extracellular autoantigens. In contrast, diseases associated with autoantibodies directed predominately against intracellular autoantigens show much more complex immune cell involvement, such as T-cell mediated tissue damage, and require different strategies for optimal therapeutic benefit. Understanding the clinical ramifications of autoimmunity derived by autoantibodies against either intracellular or extracellular autoantigens, or a spectrum of both, has practical implications for guiding drug development, generating monitoring tools, stratification of patient interventions, and designing trials based on predictive autoantibody profiles for autoimmune diseases.
Topics: Autoantibodies; Autoantigens; Autoimmune Diseases; Autoimmunity; B-Lymphocytes; Extracellular Space; Humans; Intracellular Space; Proteins; T-Lymphocytes
PubMed: 33763057
DOI: 10.3389/fimmu.2021.548469 -
Seminars in Cell & Developmental Biology Feb 2023Centromeres are highly specialised chromosome domains defined by the presence of an epigenetic mark, the specific histone H3 variant called CENP-A (centromere protein... (Review)
Review
Centromeres are highly specialised chromosome domains defined by the presence of an epigenetic mark, the specific histone H3 variant called CENP-A (centromere protein A). They constitute the genomic regions on which kinetochores form and when defective cause segregation defects that can lead to aneuploidy and cancer. Here, we discuss how CENP-A is established and maintained to propagate centromere identity while subjected to dynamic chromatin remodelling during essential cellular processes like DNA repair, replication, and transcription. We highlight parallels and identify conserved mechanisms between different model organism with a particular focus on 1) the establishment of CENP-A at centromeres, 2) CENP-A maintenance during transcription and replication, and 3) the mechanisms that help preventing CENP-A localization at non-centromeric sites. We then give examples of how timely loading of new CENP-A to the centromere, maintenance of old CENP-A during S-phase and transcription, and removal of CENP-A at non-centromeric sites are coordinated and controlled by an intricate network of factors whose identity is slowly being unravelled.
Topics: Histones; Chromatin; Centromere Protein A; Chromosomal Proteins, Non-Histone; Centromere; Cell Cycle Proteins; Autoantigens
PubMed: 35422390
DOI: 10.1016/j.semcdb.2022.04.003 -
The EMBO Journal Sep 2023Eukaryotic chromosome segregation requires the kinetochore, a megadalton-sized machine that forms on specialized centromeric chromatin containing CENP-A, a histone H3...
Eukaryotic chromosome segregation requires the kinetochore, a megadalton-sized machine that forms on specialized centromeric chromatin containing CENP-A, a histone H3 variant. CENP-A deposition requires a chaperone protein HJURP that targets it to the centromere, but it has remained unclear whether HJURP has additional functions beyond CENP-A targeting and why high AT DNA content, which disfavors nucleosome assembly, is widely conserved at centromeres. To overcome the difficulties of studying nucleosome formation in vivo, we developed a microscopy assay that enables direct observation of de novo centromeric nucleosome recruitment and maintenance with single molecule resolution. Using this assay, we discover that CENP-A can arrive at centromeres without its dedicated centromere-specific chaperone HJURP, but stable incorporation depends on HJURP and additional DNA-binding proteins of the inner kinetochore. We also show that homopolymer AT runs in the yeast centromeres are essential for efficient CENP-A deposition. Together, our findings reveal requirements for stable nucleosome formation and provide a foundation for further studies of the assembly and dynamics of native kinetochore complexes.
Topics: Nucleosomes; Centromere Protein A; Chromosomal Proteins, Non-Histone; Autoantigens; Centromere; Saccharomyces cerevisiae
PubMed: 37469281
DOI: 10.15252/embj.2023114534 -
Frontiers in Immunology 2019Autoimmune blistering diseases (AIBDs) of the skin are characterized by autoantibodies against different intra-/extracellular structures within the epidermis and at the... (Review)
Review
Autoimmune blistering diseases (AIBDs) of the skin are characterized by autoantibodies against different intra-/extracellular structures within the epidermis and at the basement membrane zone (BMZ). Binding of the antibodies to their target antigen leads to inflammation at the respective binding site and degradation of these structures, resulting in the separation of the affected skin layers. Clinically, blistering, erythema and lesions of the skin and/or mucous membranes can be observed. Based on the localization of the autoantigen, AIBDs can be divided into pemphigus (intra-epidermal blistering diseases) and pemphigoid diseases (sub-epidermal blistering diseases), respectively. Although autoantigens have been extensively characterized, the underlying causes that trigger the diseases are still poorly understood. Besides the environment, genetic factors seem to play an important role in a predisposition to AIBDs. Here, we review currently known genetic and immunological mechanisms that contribute to the pathogenesis of AIBDs. Among the most commonly encountered genetic predispositions for AIBDs are the HLA gene region, and deleterious mutations of key genes for the immune system. Particularly, HLA class II genes such as the and alleles have been shown to be prevalent in patients. This has prompted further epidemiological studies as well as unbiased Omics approaches on the transcriptome, microbiome, and proteome level to elucidate common and individual genetic risk factors as well as the molecular pathways that lead to the pathogenesis of AIBDs.
Topics: Alleles; Autoantigens; Autoimmune Diseases; Genetic Predisposition to Disease; Genomics; HLA-DQ Antigens; HLA-DR Antigens; Humans; Risk Factors; Skin Diseases, Vesiculobullous
PubMed: 31749790
DOI: 10.3389/fimmu.2019.02327 -
Frontiers in Immunology 2022Rheumatoid arthritis is an autoimmune disease characterized by joint inflammation due to autoantibodies targeting multiple self-proteins. Most patients with poor...
Rheumatoid arthritis is an autoimmune disease characterized by joint inflammation due to autoantibodies targeting multiple self-proteins. Most patients with poor prognosis show elevated titers of IgM antibodies specifically binding to IgG. Such autoreactive antibodies are referred to as rheumatoid factor (RF). However, their biological function and contribution to disease progression remains elusive. We have recently shown that autoreactive antibodies are present in healthy individuals and play an important role in regulating physiological processes. This regulatory mechanism is determined by the class and affinity of the autoreactive antibody, as low-affinity autoreactive IgM neutralizes the recognized autoantigen while high-affinity IgM protects its autoantigen from degradation. Here, we show that RFs possessing a high affinity and mono-specificity to IgG have a stabilizing effect on IgG, whereas low-affinity polyreactive RFs neutralize IgG . These results suggest that autoreactive IgM antibodies recognizing IgG play a crucial role in regulating IgG homeostasis and that a disbalance between IgM-mediated IgG degradation and stabilization might affect the onset and progression of autoimmune diseases. Consequently, restoring this balance using low-affinity anti-IgG IgM might be a promising therapeutic approach for autoimmune diseases involving autoreactive IgG.
Topics: Humans; Rheumatoid Factor; Autoantibodies; Immunoglobulin M; Arthritis, Rheumatoid; Autoantigens; Homeostasis
PubMed: 36341420
DOI: 10.3389/fimmu.2022.1016263