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The Journal of Allergy and Clinical... Nov 2022The presence of autoreactive antibodies is a hallmark of many autoimmune diseases. The effector functions of (auto)antibodies are determined by their constant domain,... (Review)
Review
The presence of autoreactive antibodies is a hallmark of many autoimmune diseases. The effector functions of (auto)antibodies are determined by their constant domain, which defines the antibody isotype and subclass. The most prevalent isotype in serum is IgG, which is often the only isotype used in diagnostic testing. Nevertheless, autoantibody responses can have their own unique isotype/subclass profile. Because comparing autoantibody isotype profiles may yield new insights into disease pathophysiology, here we summarize the isotype/subclass profiles of the most prominent autoantibodies. Despite substantial variation between (and within) autoantibody responses, this unprecedented comparison shows that autoantibodies share distinctive isotype patterns across different diseases. Although most autoantibody responses are dominated by IgG (and mainly IgG1), several specific diseases are characterized by a predominance of IgG4. In other diseases, IgE plays a key role. Importantly, shared features of autoantibody isotype/subclass profiles are seen in clinically unrelated diseases, suggesting potentially common trajectories in response evolution, disease pathogenesis, and treatment response. Isotypes beyond IgG are scarcely investigated in many autoantibody responses, leaving substantial gaps in our understanding of the pathophysiology of autoimmune diseases. Future research should address isotype/subclass profiling in more detail and incorporate autoantibody measurements beyond total IgG in disease models and clinical studies.
Topics: Humans; Autoantibodies; Immunoglobulin G; Autoimmune Diseases
PubMed: 36336400
DOI: 10.1016/j.jaci.2022.05.023 -
The New England Journal of Medicine Oct 2003Although much is known about the natural history of systemic lupus erythematosus (SLE), the development of SLE autoantibodies before the diagnosis of the disease has not...
BACKGROUND
Although much is known about the natural history of systemic lupus erythematosus (SLE), the development of SLE autoantibodies before the diagnosis of the disease has not been extensively explored. We investigated the onset and progression of autoantibody development before the clinical diagnosis.
METHODS
The Department of Defense Serum Repository contains approximately 30 million specimens prospectively collected from more than 5 million U.S. Armed Forces personnel. We evaluated serum samples obtained from 130 persons before they received a diagnosis of SLE, along with samples from matched controls.
RESULTS
In 115 of the 130 patients with SLE (88 percent), at least one SLE autoantibody tested was present before the diagnosis (up to 9.4 years earlier; mean, 3.3 years). Antinuclear antibodies were present in 78 percent (at a dilution of 1:120 or more), anti-double-stranded DNA antibodies in 55 percent, anti-Ro antibodies in 47 percent, anti-La antibodies in 34 percent, anti-Sm antibodies in 32 percent, anti-nuclear ribonucleoprotein antibodies in 26 percent, and antiphospholipid antibodies in 18 percent. Antinuclear, antiphospholipid antibodies, anti-Ro, and anti-La antibodies were present earlier than anti-Sm and anti-nuclear ribonucleoprotein antibodies (a mean of 3.4 years before the diagnosis vs. 1.2 years, P=0.005). Anti-double-stranded DNA antibodies, with a mean onset 2.2 years before the diagnosis, were found later than antinuclear antibodies (P=0.06) and earlier than anti-nuclear ribonucleoprotein antibodies (P=0.005). For many patients, the earliest available serum sample was positive; therefore, these measures of the average time from the first positive antibody test to the diagnosis are underestimates of the time from the development of antibodies to the diagnosis. Of the 130 initial matched controls, 3.8 percent were positive for one or more autoantibodies.
CONCLUSIONS
Autoantibodies are typically present many years before the diagnosis of SLE. Furthermore, the appearance of autoantibodies in patients with SLE tends to follow a predictable course, with a progressive accumulation of specific autoantibodies before the onset of SLE, while patients are still asymptomatic.
Topics: Antibodies, Antinuclear; Autoantibodies; Autoantigens; DNA; Humans; Lupus Erythematosus, Systemic; Military Personnel; Prospective Studies; Ribonucleoproteins; Ribonucleoproteins, Small Nuclear; Time Factors; snRNP Core Proteins; SS-B Antigen
PubMed: 14561795
DOI: 10.1056/NEJMoa021933 -
Frontiers in Immunology 2023Mutations in the recombination activating gene 1 () and in humans are associated with a broad spectrum of clinical phenotypes, from severe combined immunodeficiency to... (Review)
Review
Mutations in the recombination activating gene 1 () and in humans are associated with a broad spectrum of clinical phenotypes, from severe combined immunodeficiency to immune dysregulation. Partial (hypomorphic) RAG deficiency (pRD) in particular, frequently leads to hyperinflammation and autoimmunity, with several underlying intrinsic and extrinsic mechanisms causing a break in tolerance centrally and peripherally during T and B cell development. However, the relative contributions of these processes to immune dysregulation remain unclear. In this review, we specifically focus on the recently described tolerance break and B cell abnormalities, as well as consequent molecular and cellular mechanisms of autoantibody production in patients with pRD.
Topics: Humans; Homeodomain Proteins; Severe Combined Immunodeficiency; Autoimmunity; Phenotype; Autoantibodies
PubMed: 37475856
DOI: 10.3389/fimmu.2023.1155380 -
Frontiers in Immunology 2019Skin autoimmune conditions belong to a larger group of connective tissue diseases and primarily affect the skin, but might also involve underlying tissues, such as fat... (Review)
Review
Skin autoimmune conditions belong to a larger group of connective tissue diseases and primarily affect the skin, but might also involve underlying tissues, such as fat tissue, muscle, and bone. Autoimmune antibodies (autoantibodies) play a role in autoimmune skin diseases, such as localized scleroderma also termed morphea, and systemic scleroderma, also called systemic sclerosis (SSc). The detailed studies on the biological role of autoantibodies in autoimmune skin diseases are limited. This results in a few available tools for effective diagnosis and management of autoimmune skin diseases. This review aims to provide an update on the detection and most recent research on autoantibodies in morphea. Several recent studies have indicated the association of autoantibody profiles with disease subtypes, damage extent, and relapse potential, opening up exciting new possibilities for personalized disease management. We discuss the role of existing autoantibody tests in morphea management and the most recent studies on morphea pathogenesis. We also provide an update on novel autoantibody biomarkers for the diagnosis and study of morphea.
Topics: Autoantibodies; Biomarkers; Humans; Lupus Erythematosus, Systemic; Scleroderma, Localized; Skin
PubMed: 31354701
DOI: 10.3389/fimmu.2019.01487 -
Frontiers in Immunology 2021Dating to the discovery of the Lupus Erythematosus (LE) cell in 1948, there has been a dramatic growth in the discovery of unique autoantibodies and their cognate... (Review)
Review
Dating to the discovery of the Lupus Erythematosus (LE) cell in 1948, there has been a dramatic growth in the discovery of unique autoantibodies and their cognate targets, all of which has led to the availability and use of autoantibody testing for a broad spectrum of autoimmune diseases. Most studies of the sensitivity, specificity, commutability, and harmonization of autoantibody testing have focused on widely available, commercially developed and agency-certified autoantibody kits. However, this is only a small part of the spectrum of autoantibody tests that are provided through laboratories world-wide. This manuscript will review the wider spectrum of testing by exploring the innovation pathway that begins with autoantibody discovery followed by assessment of clinical relevance, accuracy, validation, and then consideration of regulatory requirements as an approved diagnostic test. Some tests are offered as "Research Use Only (RUO)", some as "Laboratory Developed Tests (LDT)", some enter Health Technology Assessment (HTA) pathways, while others are relegated to a "death valley" of autoantibody discovery and become "orphan" autoantibodies. Those that achieve regulatory approval are further threatened by the business world's "Darwinian Sea of Survival". As one example of the trappings of autoantibody progression or failure, it is reported that more than 200 different autoantibodies have been described in systemic lupus erythematosus (SLE), a small handful (~10%) of these have achieved regulatory approval and are widely available as commercial diagnostic kits, while a few others may be available as RUO or LDT assays. However, the vast majority (90%) are orphaned and languish in an autoantibody 'death valley'. This review proposes that it is important to keep an inventory of these "orphan autoantibodies" in 'death valley' because, with the increasing availability of multi-analyte arrays and artificial intelligence (MAAI), some can be rescued to achieve a useful role in clinical diagnostic especially in light of patient stratification and precision medicine.
Topics: Autoantibodies; Autoimmune Diseases; Biomarkers; Diagnostic Test Approval; Diagnostic Tests, Routine; Humans; Immunoassay; Translational Research, Biomedical
PubMed: 34122443
DOI: 10.3389/fimmu.2021.679613 -
International Journal of Molecular... Feb 2020Autoantibodies encountered in patients with systemic rheumatic diseases bear clinical significance as a biomarker to help or predict diagnosis, clinical phenotypes,... (Review)
Review
Autoantibodies encountered in patients with systemic rheumatic diseases bear clinical significance as a biomarker to help or predict diagnosis, clinical phenotypes, prognosis, and treatment decision-making. Furthermore, evidence has accumulated regarding the active involvement of disease-specific or disease-associated autoantibodies in the pathogenic process beyond simple association with the disease, and such knowledge has become essential for us to better understand the clinical value of autoantibodies as a biomarker. This review will focus on the current update on the autoantibodies of four rheumatic diseases (rheumatoid arthritis, myositis, systemic sclerosis, and anti-neutrophil cytoplasmic antibody associated vasculitis) where there has been a tremendous progress in our understanding on their biological effects and clinical use.
Topics: Antibodies, Antineutrophil Cytoplasmic; Autoantibodies; Biomarkers; Humans; Rheumatic Diseases
PubMed: 32085664
DOI: 10.3390/ijms21041382 -
Frontiers in Immunology 2023The Danger Model predicts that there are some molecules that no immune system can ever be fully tolerant of, namely proteins that are only transiently expressed during...
The Danger Model predicts that there are some molecules that no immune system can ever be fully tolerant of, namely proteins that are only transiently expressed during times of stress, infection, or injury. Among these are the danger/alarm signals themselves. Accordingly, a fleeting autoantibody response to danger signals is expected during times when they are released. Depending on context, these autoantibodies may serve beneficial "housekeeping" functions by removing surplus danger signals from the circulation or, conversely, create an immunodeficiency. Here, we will focus on the Type 1 Interferons as examples of foreseeable targets for a transient autoantibody response, but the principles outlined should hold for other danger-associated molecules as well.
Topics: Immune System; Autoantibodies; Interferon Type I
PubMed: 36742299
DOI: 10.3389/fimmu.2023.1046300 -
Current Cardiology Reports Nov 2020The role of autoantibodies in arrhythmogenesis has been the subject of research in recent times. This review focuses on the rapidly expanding field of... (Review)
Review
PURPOSE OF REVIEW
The role of autoantibodies in arrhythmogenesis has been the subject of research in recent times. This review focuses on the rapidly expanding field of autoantibody-mediated cardiac arrhythmias.
RECENT FINDINGS
Since the discovery of cardiac autoantibodies more than three decades ago, a great deal of effort has been devoted to understanding their contribution to arrhythmias. Different cardiac receptors and ion channels were identified as targets for autoantibodies, the binding of which either initiates a signaling cascade or serves as a biomarker of underlying remodeling process. Consequently, the wide spectrum of heart rhythm disturbances may emerge, ranging from atrial to ventricular arrhythmias as well as conduction diseases, irrespective of concomitant structural heart disease or manifest autoimmune disorder. The time has come to acknowledge autoimmune cardiac arrhythmias as a distinct disease entity. Establishing the autoantibody profile of patients will help to develop novel treatment approaches for patients.
Topics: Arrhythmias, Cardiac; Autoantibodies; Autoimmune Diseases; Heart Conduction System; Humans; Ion Channels
PubMed: 33241446
DOI: 10.1007/s11886-020-01430-x -
Current Opinion in Organ Transplantation Aug 2016The review analyzes the current biomarkers used in monitoring pancreas transplant, from the simple and time-tested, to more sophisticated, including markers of allo- and... (Review)
Review
PURPOSE OF REVIEW
The review analyzes the current biomarkers used in monitoring pancreas transplant, from the simple and time-tested, to more sophisticated, including markers of allo- and autoimmunity, that are likely to play a larger role in future studies.
RECENT FINDINGS
Evaluation of alloimmunity includes serum levels of donor-specific antibody, and, ultimately, pancreas transplant biopsies with C4d staining. Our center has focused on markers of autoimmunity, including assessment of autoantibodies and autoreactive T cells. We have found that conversion of autoantibodies (including GAD65, IA-2, and ZnT8), or the development of a new positive autoantibody, particularly ZnT8, are associated with type 1 diabetes (T1D) recurrence in the pancreas transplant. Autoreactive T cells have also been identified in the peripheral blood, pancreas transplant and peripancreas transplant-lymph nodes, that have the potential to mediate human β/islet cell destruction in vivo.
SUMMARY
The monitoring of pancreas transplant biomarkers, particularly those associated with autoimmunity, has led to new insights into the pathogenesis of T1D. Progress in the elucidation of mechanisms of autoimmunity may lead to novel therapeutic approaches to both T1D recurrence of the pancreas transplant and perhaps also new onset T1D.
Topics: Autoantibodies; Biomarkers, Tumor; Humans; Pancreas Transplantation
PubMed: 27348473
DOI: 10.1097/MOT.0000000000000333 -
Journal of Internal Medicine Jul 2016The aim of this review was to summarize recent advances in the understanding of the clinical and autoantibody phenotypes, their associated outcomes and the pathogenesis... (Review)
Review
The aim of this review was to summarize recent advances in the understanding of the clinical and autoantibody phenotypes, their associated outcomes and the pathogenesis of the juvenile idiopathic inflammatory myopathies (JIIMs). The major clinical and autoantibody phenotypes in children have many features similar to those in adults, and each has distinct demographic and clinical features and associated outcomes. The most common myositis autoantibodies in JIIM patients are anti-p155/140, anti-MJ and anti-MDA5. Higher mortality has been associated with overlap myositis as well as with the presence of anti-synthetase and anti-MDA5 autoantibodies; a chronic illness course and lipodystrophy have been associated with anti-p155/140 autoantibodies; and calcinosis has been associated with anti-MJ autoantibodies. Histologic abnormalities of JIIMs detectable on muscle biopsy have also been correlated with myositis-specific autoantibodies; for example, patients with anti-MDA5 show low levels of inflammatory infiltrate and muscle damage on biopsy. The first genome-wide association study of adult and juvenile dermatomyositis revealed three novel genetic associations, BLK, PLCL1 and CCL21 and confirmed that the human leucocyte antigen region is the primary risk region for juvenile dermatomyositis. Here, we review the well-established pathogenic processes in JIIMs, including the type 1 interferon and endoplasmic reticulum stress pathways. Several novel JIIM-associated inflammatory mediators, such as the innate immune system proteins, myeloid-related peptide 8/14, galectin 9 and eotaxin, have emerged as promising biomarkers of disease. Advances in our understanding of the phenotypes and pathophysiology of the JIIMs are leading to better tools to help clinicians stratify and treat these heterogeneous disorders.
Topics: Autoantibodies; Child; Humans; Muscle, Skeletal; Myositis; Phenotype; Prognosis
PubMed: 27028907
DOI: 10.1111/joim.12444