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Molecular Diagnosis & Therapy Oct 2016The measurement of autoantibodies in the clinical care of autoimmune patients allows for diagnosis, monitoring, and even disease prediction. Despite their clinical... (Review)
Review
The measurement of autoantibodies in the clinical care of autoimmune patients allows for diagnosis, monitoring, and even disease prediction. Despite their clinical utility, the functional significance of autoantibody target proteins in many autoimmune diseases remains unclear. Here we present a comprehensive review of 52 autoantigens commonly employed for the serological diagnosis of 24 autoimmune diseases. We discuss their function, whether they have extracellular-exposed epitopes, and whether antibodies to these proteins are known to be pathogenic. Transcriptomics (RNA-Seq) datasets were mined to display messenger RNA (mRNA) expression of the autoantigens across 32 tissues and organs. This analysis revealed that autoantigens cluster into one of three groups: expression in the tissue most strongly affected in the disease (Group I), ubiquitous expression with enrichment in immune tissues (Group II), or expression in other tissues not typically associated with the clinical presentation (Group III). Clustering demonstrated that the autoantigens within Group I were often proteins containing extracellular epitopes, many of which are targets of pathogenic autoantibodies. Group II autoantigens were targets for several rheumatological diseases, including Sjögren syndrome, systemic lupus erythematosus, myositis, and systemic sclerosis, and were ubiquitously expressed with enrichment in immune-rich tissues. This raises the possibility that immune cells in Group II disorders may be the source of autoimmunization and/or targets of immune cell responses. Since tissues showing enriched autoantigen gene expression may contribute to the development of autoantibodies and subsequent autoimmunity, the emergent patterns arising from the autoantigen transcriptomic profiles may provide a new heuristic framework to deconvolute these complex disorders.
Topics: Autoantigens; Autoimmune Diseases; Biomarkers; Gene Expression Profiling; Humans; Transcriptome
PubMed: 27259330
DOI: 10.1007/s40291-016-0211-6 -
The Journal of Dermatology Feb 2023Pemphigus is a life-threatening autoimmune bullous disease mediated by anti-desmoglein IgG autoantibodies. Pemphigus is mainly classified into three subtypes: pemphigus... (Review)
Review
Pemphigus is a life-threatening autoimmune bullous disease mediated by anti-desmoglein IgG autoantibodies. Pemphigus is mainly classified into three subtypes: pemphigus vulgaris, pemphigus foliaceus, and paraneoplastic pemphigus. The pathogenicity of autoantibodies has been extensively studied. Anti-human CD20 antibody therapy targeting B cells emerged as a more effective treatment option compared to conventional therapy for patients with an intractable disease. On the other hand, autoreactive T cells are considered to be involved in the pathogenesis based on the test results of human leukocyte antigen association, autoreactive T cell detection, and cytokine profile analysis. Research on the role of T cells in pemphigus has continued to progress, including that on T follicular helper cells, which initiate molecular mechanisms involved in antibody production in B cells. Autoreactive T cell research in mice has highlighted the crucial roles of cellular autoimmunity and improved the understanding of its pathogenesis, especially in paraneoplastic pemphigus. The mouse research has helped elucidate novel regulatory mechanisms of autoreactive T cells, such as thymic tolerance to desmoglein 3 and the essential roles of regulatory T cells, Langerhans cells, and other molecules in peripheral tissues. This review focuses on the immunological aspects of autoreactive T cells in pemphigus by providing detailed information on various related topics.
Topics: Animals; Humans; Mice; Autoantibodies; Autoantigens; Autoimmunity; Desmoglein 1; Desmoglein 3; Pemphigus; T-Lymphocytes
PubMed: 36539957
DOI: 10.1111/1346-8138.16663 -
FEBS Letters Aug 2016Although RNA are synthesized as single-stranded molecules, most of them are characterized by extensive secondary structures. Two RNA that require distinct folding for... (Review)
Review
Although RNA are synthesized as single-stranded molecules, most of them are characterized by extensive secondary structures. Two RNA that require distinct folding for biogenesis and function are miRNA and tRNA. While miRNA are processed from hairpin-containing precursors, tRNA are folded into characteristic L-shaped structures. In addition, tRNA and their precursors are a rich source of RNA fragments. Recent findings suggest that their production might be determined by structural characteristics of the tRNA substrates. Importantly, correct folding of pre-tRNA is assisted by the Lupus autoantigen La, an RNA chaperone. In this context, La interacts with pre-tRNA to prevent alternative foldings leading to mis-channeling into the miRNA pathway. Thus, RNA chaperones also function as gatekeepers for correct RNA pathway selection.
Topics: Autoantigens; MicroRNAs; Nucleic Acid Conformation; Protein Structure, Secondary; RNA, Transfer; RNA, Untranslated; Ribonucleoproteins
PubMed: 27397696
DOI: 10.1002/1873-3468.12294 -
Journal of the American Society of... May 2016
Topics: Autoantibodies; Autoantigens; Glomerulonephritis, Membranous; Prognosis; Receptors, Phospholipase A2
PubMed: 26657866
DOI: 10.1681/ASN.2015101170 -
Frontiers in Immunology 2021Acute rheumatic fever (ARF) is a serious sequela of Group A (GAS) infection associated with significant global mortality. Pathogenesis remains poorly understood, with... (Clinical Trial)
Clinical Trial
BACKGROUND
Acute rheumatic fever (ARF) is a serious sequela of Group A (GAS) infection associated with significant global mortality. Pathogenesis remains poorly understood, with the current prevailing hypothesis based on molecular mimicry and the notion that antibodies generated in response to GAS infection cross-react with cardiac proteins such as myosin. Contemporary investigations of the broader autoantibody response in ARF are needed to both inform pathogenesis models and identify new biomarkers for the disease.
METHODS
This study has utilised a multi-platform approach to profile circulating autoantibodies in ARF. Sera from patients with ARF, matched healthy controls and patients with uncomplicated GAS pharyngitis were initially analysed for autoreactivity using high content protein arrays (Protoarray, 9000 autoantigens), and further explored using a second protein array platform (HuProt Array, 16,000 autoantigens) and 2-D gel electrophoresis of heart tissue combined with mass spectrometry. Selected autoantigens were orthogonally validated using conventional immunoassays with sera from an ARF case-control study (n=79 cases and n=89 matched healthy controls) and a related study of GAS pharyngitis (n=39) conducted in New Zealand.
RESULTS
Global analysis of the protein array data showed an increase in total autoantigen reactivity in ARF patients compared with controls, as well as marked heterogeneity in the autoantibody profiles between ARF patients. Autoantigens previously implicated in ARF pathogenesis, such as myosin and collagens were detected, as were novel candidates. Disease pathway analysis revealed several autoantigens within pathways linked to arthritic and myocardial disease. Orthogonal validation of three novel autoantigens (PTPN2, DMD and ANXA6) showed significant elevation of serum antibodies in ARF (p < 0.05), and further highlighted heterogeneity with patients reactive to different combinations of the three antigens.
CONCLUSIONS
The broad yet heterogenous elevation of autoantibodies observed suggests epitope spreading, and an expansion of the autoantibody repertoire, likely plays a key role in ARF pathogenesis and disease progression. Multiple autoantigens may be needed as diagnostic biomarkers to capture this heterogeneity.
Topics: Autoantibodies; Autoantigens; Child; Humans; New Zealand; Protein Array Analysis; Rheumatic Fever; Streptococcus pyogenes
PubMed: 34335616
DOI: 10.3389/fimmu.2021.702877 -
Frontiers in Immunology 2023LL-37 is the only member of the cathelicidin family of antimicrobial peptides in humans and is an autoantigen in several autoimmune diseases and in acute coronary...
BACKGROUND
LL-37 is the only member of the cathelicidin family of antimicrobial peptides in humans and is an autoantigen in several autoimmune diseases and in acute coronary syndrome (ACS). In this report, we profiled the specific T cell response to the autoimmune self-antigen LL-37 and investigated the factors modulating the response in peripheral blood mononuclear cells (PBMCs) of healthy subjects and ACS patients.
METHODS AND RESULTS
The activation induced marker (AIM) assay demonstrated differential T cell profiles characterized by the persistence of CD134 and CD137, markers that impair tolerance and promote immune effector and memory response, in ACS compared to Controls. Specifically, CD8+CD69+CD137+ T cells were significantly increased by LL-37 stimulation in ACS PBMCs. T effector cell response to LL-37 were either HLA dependent or independent as determined by blocking with monoclonal antibody to either Class-I HLA or Class-II HLA. Blocking of immune checkpoints PD-1 and CTLA-4 demonstrated the control of self-reactive T cell response to LL-37 was modulated predominantly by CTLA-4. Platelets from healthy controls down-modulated CD8+CD69+CD137+ T cell response to LL-37 in autologous PBMCs. CD8+CD69+CD137+ T cell AIM profile negatively correlated with platelet count in ACS patients.
CONCLUSIONS
Our report demonstrates that the immune response to the autoantigen LL-37 in ACS patients is characterized specifically by CD8+CD69+CD137+ T cell AIM profile with persistent T cell activation and the generation of immunologic memory. The results provide potentially novel insight into mechanistic pathways of antigen-specific immune signaling in ACS.
Topics: Humans; Acute Coronary Syndrome; Autoantigens; CD8-Positive T-Lymphocytes; CTLA-4 Antigen; Leukocytes, Mononuclear
PubMed: 37051254
DOI: 10.3389/fimmu.2023.1113904 -
Current Diabetes Reports Oct 2013Autoantibodies are currently the most robust biomarkers of type 1 diabetes and are frequently used to establish entry criteria for the participation of genetically... (Review)
Review
Autoantibodies are currently the most robust biomarkers of type 1 diabetes and are frequently used to establish entry criteria for the participation of genetically at-risk individuals in secondary prevention/intervention clinical trials. Since their original description almost 40 years ago, considerable efforts have been devoted toward identifying the precise molecular targets that are recognized. Such information can have significant benefit for developing improved metrics for identifying/stratifying of at-risk subjects, developing potential therapeutic targets, and advancing understanding of the pathophysiology of the disease. Currently, four major molecular targets ([pro]insulin, GAD65, IA-2, and ZnT8) have been confirmed, with approximately 94% of all subjects with a clinical diagnosis of type 1 diabetes expressing autoantibodies to at least one of these molecules at clinical onset. In this review, we summarize some of the salient properties of these targets that might contribute to their autoantigenicity and methods that have been used in attempts to identify new components of the humoral autoresponse.
Topics: Autoantibodies; Autoantigens; Cation Transport Proteins; Diabetes Mellitus, Type 1; Humans; Radioimmunoassay
PubMed: 23900975
DOI: 10.1007/s11892-013-0405-9 -
Frontiers in Immunology 2022NETosis is a form of neutrophil cell death during which extracellular fibrillary structures composed of cytosolic and granule proteins assembled on scaffolds of...
NETosis is a form of neutrophil cell death during which extracellular fibrillary structures composed of cytosolic and granule proteins assembled on scaffolds of decondensed chromatin, called neutrophil extracellular traps (NETs), are released. NETs normally contribute to host immune defense. Accumulating evidence implicates aberrant NET production and/or reduced NET clearance, along with alterations of molecules involved in NETosis pathway, in humans and animals with lupus. The extruded nuclear antigens released by NET are a source of autoantigens, which can contribute to the breakdown of self-tolerance in lupus. Excessive NET can also promote the production of pro-inflammatory cytokine interferon-α, elicit direct cytotoxic effect on various renal cells, and cause capillary necrosis and podocyte loss. Additionally, NET can induce endothelial-to-mesenchymal transdifferentiation, which can promote activated myofibroblasts leading to extracellular matrix production. Thus, aberrant NETosis can play diverse roles, including autoantibody production, inflammation, and tissue damage, at different stages of lupus pathogenesis. Evidence suggests that treatments currently used in lupus may reduce NETosis, suggesting a potential utility of targeting NETosis to treat lupus. In fact, several approaches are being experimented to therapeutically target pathways of NETosis. Future studies should precisely delineate distinct roles of NETosis at different stages of lupus pathogenesis in humans, which would offer a rational basis for NETosis-targeting treatments in the clinic.
Topics: Animals; Autoantigens; Cell Death; Extracellular Traps; Inflammation; Neutrophils
PubMed: 35686129
DOI: 10.3389/fimmu.2022.895216 -
Frontiers in Immunology 2022COVID-19 is accompanied by a myriad of both transient and long-lasting autoimmune responses. Dermatan sulfate (DS), a glycosaminoglycan crucial for wound healing, has...
UNLABELLED
COVID-19 is accompanied by a myriad of both transient and long-lasting autoimmune responses. Dermatan sulfate (DS), a glycosaminoglycan crucial for wound healing, has unique affinity for autoantigens (autoAgs) from apoptotic cells. DS-autoAg complexes are capable of stimulating autoreactive B cells and autoantibody production. We used DS-affinity proteomics to define the autoantigen-ome of lung fibroblasts and bioinformatics analyses to study the relationship between autoantigenic proteins and COVID-induced alterations. Using DS-affinity, we identified an autoantigen-ome of 408 proteins from human HFL1 cells, at least 231 of which are known autoAgs. Comparing with available COVID data, 352 proteins of the autoantigen-ome have thus far been found to be altered at protein or RNA levels in SARS-CoV-2 infection, 210 of which are known autoAgs. The COVID-altered proteins are significantly associated with RNA metabolism, translation, vesicles and vesicle transport, cell death, supramolecular fibrils, cytoskeleton, extracellular matrix, and interleukin signaling. They offer clues to neurological problems, fibrosis, smooth muscle dysfunction, and thrombosis. In particular, 150 altered proteins are related to the nervous system, including axon, myelin sheath, neuron projection, neuronal cell body, and olfactory bulb. An association with the melanosome is also identified. The findings from our study illustrate a connection between COVID infection and autoimmunity. The vast number of COVID-altered proteins with high intrinsic propensity to become autoAgs offers an explanation for the diverse autoimmune complications in COVID patients. The variety of autoAgs related to mRNA metabolism, translation, and vesicles suggests a need for long-term monitoring of autoimmunity in COVID. The COVID autoantigen atlas we are establishing provides a detailed molecular map for further investigation of autoimmune sequelae of the pandemic, such as "long COVID" syndrome.
SUMMARY SENTENCE
An autoantigen-ome by dermatan sulfate affinity from human lung HFL1 cells may explain neurological and autoimmune manifestations of COVID-19.
Topics: Autoantigens; COVID-19; Dermatan Sulfate; Humans; Lung; Proteins; RNA; SARS-CoV-2
PubMed: 35401574
DOI: 10.3389/fimmu.2022.831849 -
Molecular Cell Jan 2006A recent issue of Molecular Cell reported that the typical nucleic acid binding surfaces of the RRM and winged-helix motifs, although present in the RNA binding protein... (Review)
Review
A recent issue of Molecular Cell reported that the typical nucleic acid binding surfaces of the RRM and winged-helix motifs, although present in the RNA binding protein La, are not used to engage its best-characterized ligand, 3' UUU-OH. Instead, La uses edgewise and backsides of these motifs for UUU-OH recognition, leaving open their typical surfaces for other potential interactions. These observations provide a framework for appreciating the various activities attributed to this ubiquitous nuclear phosphoprotein, which include its principal function, snRNA 3' end protection, in addition to mRNA-related and RNA chaperone-like activities, as well as DNA and chromatin-associated activity.
Topics: Amino Acid Motifs; Autoantigens; Binding Sites; Humans; Macromolecular Substances; Models, Molecular; Protein Binding; Protein Conformation; RNA; Ribonucleoproteins; SS-B Antigen
PubMed: 16427005
DOI: 10.1016/j.molcel.2006.01.004