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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 -
Cells Dec 2023The heterogeneity of autoantibody targets in autoimmune encephalitides presents a challenge for understanding cellular and humoral pathophysiology, and the development... (Review)
Review
The heterogeneity of autoantibody targets in autoimmune encephalitides presents a challenge for understanding cellular and humoral pathophysiology, and the development of new treatment strategies. Thus, current treatment aims at autoantibody removal and immunosuppression, and is primarily based on data generated from other autoimmune neurological diseases and expert consensus. There are many subtypes of autoimmune encephalitides, which now entails both diseases with autoantibodies targeting extracellular antigens and classical paraneoplastic syndromes with autoantibodies targeting intracellular antigens. Here, we review the current knowledge of molecular and cellular effects of autoantibodies associated with autoimmune encephalitis, and evaluate the evidence behind the proposed pathophysiological mechanisms of autoantibodies in autoimmune encephalitis.
Topics: Humans; Autoantibodies; Consensus; Encephalitis; Hashimoto Disease; Autoimmune Diseases of the Nervous System
PubMed: 38201219
DOI: 10.3390/cells13010015 -
Hamostaseologie Apr 2024
Review
Topics: Humans; Purpura, Thrombocytopenic, Idiopathic; Autoantibodies
PubMed: 38688267
DOI: 10.1055/a-2280-1083 -
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 2022Bullous pemphigoid (BP) is the most common autoimmune subepidermal blistering disease. Although the pathomechanism of BP onset has yet to be elucidated in detail, BP... (Review)
Review
Bullous pemphigoid (BP) is the most common autoimmune subepidermal blistering disease. Although the pathomechanism of BP onset has yet to be elucidated in detail, BP autoantibodies targeting two hemidesmosomal components, BP180 and BP230, are known to play a pivotal role in BP pathogenesis. Thus, the detection and measurement of BP autoantibodies are necessary for diagnosing BP and monitoring the disease activity. Immune assays such as immunofluorescence microscopy, immunoblotting, and ELISAs using BP180 and BP230 detect BP autoantibodies in most BP cases with high specificity; however, BP autoantibodies are sometimes detected in BP patients before the onset of this disease. BP autoantibodies that are detected in patients without typical tense blisters are defined as "preclinical BP autoantibodies". These preclinical BP autoantibodies are detected even in a low percentage of normal healthy individuals. Although the importance of preclinical BP autoantibodies remains elusive, these autoantibodies might be a potential risk factor for subsequent BP development. Therefore, previous comparative epidemiological studies have focused on the prevalence of preclinical BP autoantibodies in populations susceptible to BP (e.g., the elderly) or in diseases with a higher risk of comorbid BP. This mini-review summarizes the literature on the prevalence of preclinical BP autoantibodies in patients with various conditions and diseases, and we discuss the significance of preclinical BP autoantibody detection.
Topics: Aged; Autoantibodies; Autoantigens; Humans; Immunoblotting; Non-Fibrillar Collagens; Pemphigoid, Bullous
PubMed: 36003369
DOI: 10.3389/fimmu.2022.963401 -
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 -
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 -
Virology Journal Oct 2023Interest in complications and sequelae following Coronavirus disease 2019 (COVID-19) is increasing. Several articles have reported COVID-19-associated autoimmune...
BACKGROUND
Interest in complications and sequelae following Coronavirus disease 2019 (COVID-19) is increasing. Several articles have reported COVID-19-associated autoimmune diseases and the association between autoantibodies and the severity of COVID-19. Thromboembolic complications are frequent in patients with COVID-19, and the anti-phospholipid antibodies (aPL) is frequently detected. We conducted this study to investigate the prevalence, clinical significance, and persistence of anti-nuclear antibodies (ANA) and aPLs in COVID-19.
METHODS
We enrolled patients diagnosed with COVID-19 with oxygen demand and admitted to a tertiary hospital in South Korea between July 2020 and March 2022. ANA and aPLs levels were assessed using an immunoassay kit.
RESULTS
A total of 248 patients were enrolled in the study. Among them, five patients were ANA-positive, and 41 were aPL-positive (IgM anti-cardiolipin (aCL) antibody in seven patients, IgG aCL in seven patients, IgM anti-β2Glycoprotein1 antibody (aβ2-GPI) in 32 patients, and IgG aβ2-GPI in one patient). Two of five ANA-positive patients, 13 of 32 IgM aβ2-GPI-positive patients, 5 of 7 IgM aCL-positive patients, and 2 of 7 IgG aCL-positive patients were eligible for follow-up analysis, and 100%, 69.2%, 40%, and 50% of the patients remained autoantibody-positive, respectively. There were no differences in clinical outcomes between the autoantibody-positive and autoantibody-negative groups, except for the IgG aCL group showing a tendency for worse outcomes.
CONCLUSION
A significant proportion of COVID-19 patients with oxygen demand were autoantibody-positive, and autoantibodies persisted for several months after symptom onset. Whether these autoantibodies are related to long-term sequelae in COVID-19 patients requires further investigation.
Topics: Humans; Autoantibodies; Prevalence; Clinical Relevance; beta 2-Glycoprotein I; Immunoglobulin G; COVID-19; Antibodies, Anticardiolipin; Immunoglobulin M; Oxygen
PubMed: 37845706
DOI: 10.1186/s12985-023-02191-z