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Current Opinion in Rheumatology Nov 2020To provide an overview of recent discoveries related to myositis-specific autoantibodies (MSAs) and assays used for their measurement. (Review)
Review
PURPOSE OF REVIEW
To provide an overview of recent discoveries related to myositis-specific autoantibodies (MSAs) and assays used for their measurement.
RECENT FINDINGS
New autoantibody specificities have been reported including a MSA directed against eukaryotic initiation factor 3 and a myositis-associated autoantibody directed against heat shock factor 1. The association of anti-TIF1γ with cancer-associated dermatomyositis dependent on age has been confirmed in several large cohorts. Despite MSAs being almost entirely mutually exclusive, several myositis autoantigens are overexpressed in regenerating muscle and do not correlate with the corresponding MSA in any one patient. Further mechanisms may determine the final MSA specificity and are likely to include the need for autoantigen processing and presentation with adaptive T-cell help. The presence of CD4-positive T cells specific for histidyl tRNA synthetase protein in bronchial lavage fluid from antisynthetase patients lends support to this view. Finally, it is widely held that MSA do play an important role in clinical practice among some evidence and concern about commercial assay reliability.
SUMMARY
MSAs continue to provide important tools for clinical diagnosis and management as well as insights into disease mechanisms. Further improvement in the standardization and reliability of routine detection of MSAs is a high priority.
Topics: Autoantibodies; Autoantigens; Humans; Myositis; Reproducibility of Results
PubMed: 32890028
DOI: 10.1097/BOR.0000000000000742 -
The Journal of Applied Laboratory... Jan 2022Dermatologic diseases with autoantibodies were recognized early as autoimmunity became accepted as a pathogenic immunologic concept. Laboratory testing to identify... (Review)
Review
BACKGROUND
Dermatologic diseases with autoantibodies were recognized early as autoimmunity became accepted as a pathogenic immunologic concept. Laboratory testing to identify disease-defining autoantibodies and investigate their role in pathophysiology has evolved since.
CONTENT
Blistering dermatologic diseases, profiled by autoantibody production, target epithelial components critical in cell-cell and cell-matrix adhesion, resulting in epithelial separation and other characteristic features of the disorders. This review covers the clinical indications for dermatologic disease-related autoantibody testing, the specifics of procuring specimens to test, the available diagnostic tests, and information provided by the testing. Atypical, uncharacteristic, and less well-known clinical and autoantibody profiles as well as several of the many future prospects for expansion of the testing applications are elaborated on in the online Data Supplement.
SUMMARY
Autoantibody-associated dermatologic diseases are acquired immunologic disorders that have considerable clinical implications affecting essential barrier functions of skin and mucous membranes and causing discomfort, including pain and pruritus. Certain of the diseases can have life-threatening manifestations, and treatments can have significant side-effects. The skin diseases may presage other clinical associations that are important to recognize and treat. Laboratory testing aids in the diagnosis of these diseases through identification of the autoantibodies and is essential for prompt and precise knowledge of the disease type for prognosis, further clinical evaluations, and treatment decisions.
Topics: Autoantibodies; Humans; Pemphigoid, Bullous; Skin
PubMed: 34996089
DOI: 10.1093/jalm/jfab147 -
Frontiers in Immunology 2020
Topics: Autoantibodies; Autoimmune Diseases; Autoimmunity; Disease Management; Disease Susceptibility; Humans; Kidney Diseases
PubMed: 33042166
DOI: 10.3389/fimmu.2020.591338 -
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 -
Frontiers in Immunology 2022Autoantibodies are well known as potentially highly harmful antibodies which attack the host binding to self-antigens, thus causing severe associated diseases and... (Review)
Review
Autoantibodies are well known as potentially highly harmful antibodies which attack the host binding to self-antigens, thus causing severe associated diseases and symptoms (e.g. autoimmune diseases). However, detection of autoantibodies to a range of disease-associated antigens has enabled their successful usage as important tools in disease diagnosis, prognosis and treatment. There are several advantages of using such autoantibodies. These include the capacity to measure their presence very early in disease development, their stability, which is often much better than their related antigen, and the capacity to use an array of such autoantibodies for enhanced diagnostics and to better predict prognosis. They may also possess capacity for utilization in therapy, . In this review both the positive and negative aspects of autoantibodies are critically assessed, including their role in autoimmune diseases, cancers and the global pandemic caused by COVID-19. Important issues related to their detection are also highlighted.
Topics: Humans; Autoantibodies; COVID-19; Autoimmune Diseases; Autoantigens; Prognosis
PubMed: 36341384
DOI: 10.3389/fimmu.2022.953726 -
Brain and Nerve = Shinkei Kenkyu No... May 2024Autoimmune nodopathy (AN), a newly established category of autoimmune disease, refers to an immune-mediated neuropathy associated with development of autoantibodies...
Autoimmune nodopathy (AN), a newly established category of autoimmune disease, refers to an immune-mediated neuropathy associated with development of autoantibodies against membrane proteins, including neurofascin 186, neurofascin 155, contactin-1, and contactin-associated protein 1 located in the nodes of Ranvier or paranodes. Subclass analysis of these autoantibodies reveals predominant elevation of immunoglobulin (G4. Patients with AN show clinical and laboratory characteristics such as distal-predominant sensorimotor disturbance, sensory ataxia, poor response to intravenous immunoglobulin, and highly elevated cerebrospinal fluid protein levels. B cell-depletion therapy using an anti-CD20 monoclonal antibody is effective for patients with AN. Autoantibody measurement is beneficial not only for diagnosis but also for deciding treatment strategies for AN.
Topics: Humans; Autoantibodies; Autoimmune Diseases; Autoimmune Diseases of the Nervous System
PubMed: 38741493
DOI: 10.11477/mf.1416202640 -
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 -
Journal of Autoimmunity Dec 2021Delirium in hospitalized and intensive care unit patients is an emerging condition due to its rapid-onset requiring fast action to mitigate a worse clinical outcome.... (Review)
Review
BACKGROUND
Delirium in hospitalized and intensive care unit patients is an emerging condition due to its rapid-onset requiring fast action to mitigate a worse clinical outcome. Although several causes and conditions are known, the association between delirium and neural autoantibodies has often been neglected in cohort studies and reviews as causing delirium. The aim of our review is to delineate the occurrence and type of neural autoantibodies and to depict other biological markers of autoimmunity in relationship to delirium.
METHODS
For this narrative review Pubmed research was done to select articles about delirium and neural autoantibodies.
RESULTS
We can report on several cell-surface autoantibodies such as anti-α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors, anti-contactin associated protein 2, anti-Leucin rich glioma inactivated protein 1, anti-dipeptidyl-peptidase-like 6 protein, anti-glycine receptor and anti-myelin autoantibodies, as well as intracellular autoantibodies such as anti-glutamic acid decarboxylase 65 (GAD65), anti-CV2 and anti-Hu associated with delirium in patients. Our case reports and case series screening revealed that 20 of 63 patients with delirium presented neural autoantibodies, thus revealing a 32% frequency of autoantibody-associated delirium in delirium patients. Our main finding is that delirium's hyperactive form is associated with neural autoantibodies. Diagnosing delirium differentially is difficult, as in patients with delirium and GAD65 autoantibodies, as it must be distinguished from other psychopathological excitation states such as mania. We also describe autoimmune delirium's potential pathophysiologic pathways.
CONCLUSIONS
The existence of neural autoantibodies in delirious patients is scientifically and clinically highly relevant in its diagnosis, therapy, and pathogenesis. More large-scale studies should be conducted to evaluate their significance and prevalence in delirium.
Topics: Autoantibodies; Autoimmunity; Delirium; Glutamate Decarboxylase; Humans
PubMed: 34757245
DOI: 10.1016/j.jaut.2021.102740 -
The Lancet. Rheumatology Dec 2023Increased research over the past 30 years has greatly improved the understanding of the pathophysiological mechanisms and clinical aspects of autoantibody-positive... (Review)
Review
Increased research over the past 30 years has greatly improved the understanding of the pathophysiological mechanisms and clinical aspects of autoantibody-positive rheumatoid arthritis, resulting in improved management and outcomes. In contrast, the subset of rheumatoid arthritis that does not have autoantibodies (such as rheumatoid factor and anti-citrullinated protein autoantibodies) remains less well defined in its pathogenic mechanisms. Autoantibody-negative rheumatoid arthritis continues to pose diagnostic challenges, might respond differently to therapies, and appears to be burdened with different comorbidities and outcomes. The clear separation of rheumatoid arthritis according to serotypes is still a subject of uncertainty and controversy, and studies specifically focused on comparing rheumatoid arthritis and rheumatoid arthritis-like arthritides that do not have autoantibodies remain scarce. The purpose of this Review is to summarise the peculiarities that make autoantibody-negative rheumatoid arthritis different from its autoantibody-positive counterpart, with the aim of generating debate and stimulating further research on this challenging condition.
Topics: Humans; Autoantibodies; Rheumatologists; Arthritis, Rheumatoid; Rheumatoid Factor; Anti-Citrullinated Protein Antibodies
PubMed: 38251565
DOI: 10.1016/S2665-9913(23)00242-4 -
Neurology(R) Neuroimmunology &... Jul 2022Autoantibodies targeting the acetylcholine receptor (AChR), found in patients with myasthenia gravis (MG), mediate pathology through 3 mechanisms: complement-directed...
BACKGROUND AND OBJECTIVES
Autoantibodies targeting the acetylcholine receptor (AChR), found in patients with myasthenia gravis (MG), mediate pathology through 3 mechanisms: complement-directed tissue damage, blocking of the acetylcholine binding site, and internalization of the AChR. Clinical assays, used to diagnose and monitor patients, measure only autoantibody binding. Consequently, they are limited in providing association with disease burden, understanding of mechanistic heterogeneity, and monitoring therapeutic response. The objective of this study was to develop a cell-based assay that measures AChR autoantibody-mediated complement membrane attack complex (MAC) formation.
METHODS
An HEK293T cell line-modified using CRISPR/Cas9 genome editing to disrupt expression of the complement regulator genes (CD46, CD55, and CD59)-was used to measure AChR autoantibody-mediated MAC formation through flow cytometry.
RESULTS
Serum samples (n = 155) from 96 clinically confirmed AChR MG patients, representing a wide range of disease burden and autoantibody titer, were tested along with 32 healthy donor (HD) samples. AChR autoantibodies were detected in 139 of the 155 (89.7%) MG samples through a cell-based assay. Of the 139 AChR-positive samples, autoantibody-mediated MAC formation was detected in 83 (59.7%), whereas MAC formation was undetectable in the HD group or AChR-positive samples with low autoantibody levels. MAC formation was positively associated with autoantibody binding in most patient samples; ratios (mean fluorescence intensity) of MAC formation to AChR autoantibody binding ranged between 0.27 and 48, with a median of 0.79 and an interquartile range of 0.43 (0.58-1.1). However, the distribution of ratios was asymmetric and included extreme values; 16 samples were beyond the 10-90 percentile, with high MAC to low AChR autoantibody binding ratio or the reverse. Correlation between MAC formation and clinical disease scores suggested a modest positive association (rho = 0.34, = 0.0023), which included a subset of outliers that did not follow this pattern. MAC formation did not associate with exposure to immunotherapy, thymectomy, or MG subtypes defined by age-of-onset.
DISCUSSION
A novel assay for evaluating AChR autoantibody-mediated complement activity was developed. A subset of patients that lacks association between MAC formation and autoantibody binding or disease burden was identified. The assay may provide a better understanding of the heterogeneous autoantibody molecular pathology and identify patients expected to benefit from complement inhibitor therapy.
Topics: Autoantibodies; Complement Activation; HEK293 Cells; Humans; Myasthenia Gravis; Receptors, Cholinergic
PubMed: 35473886
DOI: 10.1212/NXI.0000000000001169