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Clinical Immunology (Orlando, Fla.) Nov 2023Anti-phospholipid autoantibodies are a group of antibodies that can specifically bind to anionic phospholipids and phospholipid protein complexes. Recent studies have... (Review)
Review
Anti-phospholipid autoantibodies are a group of antibodies that can specifically bind to anionic phospholipids and phospholipid protein complexes. Recent studies have reported elevated serum anti-phospholipid autoantibody levels in patients with antiphospholipid syndrome, systemic lupus erythematosus, rheumatoid arthritis, metabolic disorders, malaria, SARS-CoV-2 infection, obstetric diseases and cardiovascular diseases. However, the underlying mechanisms of anti-phospholipid autoantibodies in disease pathogenesis remain largely unclear. Emerging evidence indicate that anti-phospholipid autoantibodies modulate NETs formation, monocyte activation, blockade of apoptotic cell phagocytosis in macrophages, complement activation, dendritic cell activation and vascular endothelial cell activation. Herein, we provide an update on recent advances in elucidating the effector mechanisms of anti-phospholipid autoantibodies in the pathogenesis of various diseases, which may facilitate the development of potential therapeutic targets for the treatment of anti-phospholipid autoantibody-related disorders.
Topics: Humans; Autoantibodies; Antibodies, Antiphospholipid; Antiphospholipid Syndrome; Lupus Erythematosus, Systemic; Macrophages
PubMed: 37821073
DOI: 10.1016/j.clim.2023.109803 -
Journal of Lipid Research Nov 2020Some cases of chylomicronemia are caused by autoantibodies against glycosylphosphatidylinositol-anchored HDL binding protein 1 (GPIHBP1), an endothelial cell protein... (Review)
Review
Some cases of chylomicronemia are caused by autoantibodies against glycosylphosphatidylinositol-anchored HDL binding protein 1 (GPIHBP1), an endothelial cell protein that shuttles LPL to the capillary lumen. GPIHBP1 autoantibodies prevent binding and transport of LPL by GPIHBP1, thereby disrupting the lipolytic processing of triglyceride-rich lipoproteins. Here, we review the "GPIHBP1 autoantibody syndrome" and summarize clinical and laboratory findings in 22 patients. All patients had GPIHBP1 autoantibodies and chylomicronemia, but we did not find a correlation between triglyceride levels and autoantibody levels. Many of the patients had a history of pancreatitis, and most had clinical and/or serological evidence of autoimmune disease. IgA autoantibodies were present in all patients, and IgG4 autoantibodies were present in 19 of 22 patients. Patients with GPIHBP1 autoantibodies had low plasma LPL levels, consistent with impaired delivery of LPL into capillaries. Plasma levels of GPIHBP1, measured with a monoclonal antibody-based ELISA, were very low in 17 patients, reflecting the inability of the ELISA to detect GPIHBP1 in the presence of autoantibodies (immunoassay interference). However, GPIHBP1 levels were very high in five patients, indicating little capacity of their autoantibodies to interfere with the ELISA. Recently, several GPIHBP1 autoantibody syndrome patients were treated successfully with rituximab, resulting in the disappearance of GPIHBP1 autoantibodies and normalization of both plasma triglyceride and LPL levels. The GPIHBP1 autoantibody syndrome should be considered in any patient with newly acquired and unexplained chylomicronemia.
Topics: Autoantibodies; Humans; Hypertriglyceridemia; Receptors, Lipoprotein
PubMed: 32948662
DOI: 10.1194/jlr.R120001116 -
Autoimmunity Reviews Jun 2016As autoantibodies bind to target tissues, Fc-region dependent inflammation can induce pain via mediators exciting nociceptors. But recently another possibility has... (Review)
Review
As autoantibodies bind to target tissues, Fc-region dependent inflammation can induce pain via mediators exciting nociceptors. But recently another possibility has emerged, where autoantibody binding to nociceptors can directly cause pain, without inflammation. This is thought to occur as a result of Fab-region mediated modification of nerve transduction, transmission, or neuropeptide release. In three conditions, complex regional pain syndrome, anti-voltage gated potassium channel complex autoimmunity, and chronic fatigue syndrome, all associated with no or only little inflammation, initial laboratory-, and clinical trial-results have suggested a potential role for autoantibody-mediated mechanisms. More research assessing the pathogenic roles of autoantibodies in these and other chronic pain conditions is required. The concept of autoantibody-mediated pain offers hope for the development of novel therapies for currently intractable pains.
Topics: Autoantibodies; Chronic Disease; Humans; Inflammation; Neuralgia
PubMed: 26883460
DOI: 10.1016/j.autrev.2016.02.011 -
Immunology and Cell Biology Jul 2020Preventing self-reactive lymphocytes from participating in effector responses is fundamental to maintaining immunological self-tolerance and circumventing autoimmunity.... (Review)
Review
Preventing self-reactive lymphocytes from participating in effector responses is fundamental to maintaining immunological self-tolerance and circumventing autoimmunity. A range of complementary mechanisms are known to act upon the primary B- and T-cell repertoires to this effect, eliminating or silencing lymphocytes expressing self-reactive antigen receptors generated through V(D)J recombination in early lymphoid precursors. In the case of B cells, secondary diversification of antigen receptor repertoire by somatic hypermutation (SHM) provides an additional challenge, especially because this occurs in germinal center (GC) B cells that are actively responding to antigen and primed for differentiation into antibody-producing plasma cells. While it is clear that self-tolerance mechanisms do act to prevent antibody production by self-reactive GC B cells, it is also apparent that most pathogenic autoantibodies carry somatic mutations and so have derived from a GC response. Recent advances in the analysis of autoantibody-producing cells associated with human autoimmune diseases together with insights gained from animal models have increased our understanding of the relationships between GCs, SHM and autoantibody production. Here we discuss these developments and focus in particular on how they have illuminated the genesis and pathogenesis of one archetypal autoantibody, rheumatoid factor.
Topics: Animals; Autoantibodies; Autoimmunity; B-Lymphocytes; Germinal Center; Humans; Rheumatoid Factor; Self Tolerance
PubMed: 32080878
DOI: 10.1111/imcb.12321 -
Annals of the Rheumatic Diseases Jul 2023A novel longitudinal clustering technique was applied to comprehensive autoantibody data from a large, well-characterised, multinational inception systemic lupus...
OBJECTIVES
A novel longitudinal clustering technique was applied to comprehensive autoantibody data from a large, well-characterised, multinational inception systemic lupus erythematosus (SLE) cohort to determine profiles predictive of clinical outcomes.
METHODS
Demographic, clinical and serological data from 805 patients with SLE obtained within 15 months of diagnosis and at 3-year and 5-year follow-up were included. For each visit, sera were assessed for 29 antinuclear antibodies (ANA) immunofluorescence patterns and 20 autoantibodies. K-means clustering on principal component analysis-transformed longitudinal autoantibody profiles identified discrete phenotypic clusters. One-way analysis of variance compared cluster enrolment demographics and clinical outcomes at 10-year follow-up. Cox proportional hazards model estimated the HR for survival adjusting for age of disease onset.
RESULTS
Cluster 1 (n=137, high frequency of anti-Smith, anti-U1RNP, AC-5 (large nuclear speckled pattern) and high ANA titres) had the highest cumulative disease activity and immunosuppressants/biologics use at year 10. Cluster 2 (n=376, low anti-double stranded DNA (dsDNA) and ANA titres) had the lowest disease activity, frequency of lupus nephritis and immunosuppressants/biologics use. Cluster 3 (n=80, highest frequency of all five antiphospholipid antibodies) had the highest frequency of seizures and hypocomplementaemia. Cluster 4 (n=212) also had high disease activity and was characterised by multiple autoantibody reactivity including to antihistone, anti-dsDNA, antiribosomal P, anti-Sjögren syndrome antigen A or Ro60, anti-Sjögren syndrome antigen B or La, anti-Ro52/Tripartite Motif Protein 21, antiproliferating cell nuclear antigen and anticentromere B). Clusters 1 (adjusted HR 2.60 (95% CI 1.12 to 6.05), p=0.03) and 3 (adjusted HR 2.87 (95% CI 1.22 to 6.74), p=0.02) had lower survival compared with cluster 2.
CONCLUSION
Four discrete SLE patient longitudinal autoantibody clusters were predictive of long-term disease activity, organ involvement, treatment requirements and mortality risk.
Topics: Humans; Autoantibodies; Lupus Erythematosus, Systemic; Antibodies, Antinuclear; DNA; Immunosuppressive Agents; Machine Learning
PubMed: 37085289
DOI: 10.1136/ard-2022-223808 -
Continuum (Minneapolis, Minn.) Oct 2023This article reviews autoimmune axonal neuropathies, their characteristic clinical features, disease and antibody associations, appropriate ancillary testing, treatment,... (Review)
Review
OBJECTIVE
This article reviews autoimmune axonal neuropathies, their characteristic clinical features, disease and antibody associations, appropriate ancillary testing, treatment, and prognosis.
LATEST DEVELOPMENTS
In 2021, the American College of Rheumatology and the Vasculitis Foundation released new summary guidelines for the treatment of antineutrophil cytoplasmic autoantibody-associated vasculitides. In addition, novel autoantibodies have been recently identified; they are often paraneoplastic and associated with axonal neuropathies.
ESSENTIAL POINTS
Recognition of autoimmune axonal neuropathies is important because of the potential for effective treatment to either reverse deficits or slow the progression of disease. It is necessary to properly assess for associations with other systemic disorders (eg, systemic vasculitis, connective tissue disease, neoplasm) so that adequate treatment for both neurologic and non-neurologic aspects of the disease can be initiated.
Topics: Humans; Autoantibodies; Antibodies, Antineutrophil Cytoplasmic; Vasculitis; Treatment Outcome; Peripheral Nervous System Diseases
PubMed: 37851035
DOI: 10.1212/CON.0000000000001344 -
Deutsches Arzteblatt International Nov 2018Acute and subacute disturbances of wakefulness and cognitive function are common neurological manifestations in the hospital and in outpatient care. An important element...
BACKGROUND
Acute and subacute disturbances of wakefulness and cognitive function are common neurological manifestations in the hospital and in outpatient care. An important element of the differential diagnosis was described only a few years ago: autoimmune encephalitis, a condition whose diagnosis and treatment pose an interdisciplinary challenge.
METHODS
This review is based on pertinent publications from the years 2005-2017 that were retrieved by a selective search in PubMed, and on the authors' personal experience and case reports.
RESULTS
The incidence of autoimmune encephalitis in Germany is estimated at 8-15 cases per million persons per year. In some patients with psychotic manifestations or impaired consciousness of acute or subacute onset, an autoimmune patho - genesis can be demonstrated by the laboratory detection of autoantibodies against neuronal target antigens (e.g., glutamate receptors). Testing of this type should be performed in patients with inflammatory changes in the cerebrospinal fluid or on magnetic resonance imaging (MRI), or those who have had an otherwise unexplained first epileptic seizure or status epilepticus. The cumulative sensitivity of testing for all potentially causative antineuronal antibodies in patients with clinically defined autoimmune encephalitis is estimated at 60-80 %. Figures on cumulative specificity are currently unavailable.
CONCLUSION
The detection of antineuronal antibodies in patients with the corresponding appropriate symptoms implies the diagnosis of autoimmune encephalitis. Observational studies have shown that rapidly initiated immunosuppressive treatment improves these patients' outcomes. Further studies are needed to determine the positive predictive value of antineuronal antibody detection and to develop further treatment options under randomized and controlled conditions.
Topics: Aged; Autoantibodies; Encephalitis; Female; Germany; Humans; Magnetic Resonance Imaging; Male; Prognosis; Young Adult
PubMed: 30381132
DOI: 10.3238/arztebl.2018.0666 -
Annals of the Rheumatic Diseases Sep 2023Identify autoantibodies in anti-Ro/SS-A negative primary Sjögren's syndrome (SS).
OBJECTIVE
Identify autoantibodies in anti-Ro/SS-A negative primary Sjögren's syndrome (SS).
METHODS
This is a proof-of-concept, case-control study of SS, healthy (HC) and other disease (OD) controls. A discovery dataset of plasma samples (n=30 SS, n=15 HC) was tested on human proteome arrays containing 19 500 proteins. A validation dataset of plasma and stimulated parotid saliva from additional SS cases (n=46 anti-Ro, n=50 anti-Ro), HC (n=42) and OD (n=54) was tested on custom arrays containing 74 proteins. For each protein, the mean+3 SD of the HC value defined the positivity threshold. Differences from HC were determined by Fisher's exact test and random forest machine learning using 2/3 of the validation dataset for training and 1/3 for testing. Applicability of the results was explored in an independent rheumatology practice cohort (n=38 Ro, n=36 Ro, n=10 HC). Relationships among antigens were explored using Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) interactome analysis.
RESULTS
Ro SS parotid saliva contained autoantibodies binding to Ro60, Ro52, La/SS-B and muscarinic receptor 5. SS plasma contained 12 novel autoantibody specificities, 11 of which were detected in both the discovery and validation datasets. Binding to ≥1 of the novel antigens identified 54% of Ro SS and 37% of Ro SS cases, with 100% specificity in both groups. Machine learning identified 30 novel specificities showing receiver operating characteristic area under the curve of 0.79 (95% CI 0.64 to 0.93) for identifying Ro SS. Sera from Ro cases of an independent cohort bound 17 of the non-canonical antigens. Antigenic targets in both Ro and Ro SS were part of leukaemia cell, ubiquitin conjugation and antiviral defence pathways.
CONCLUSION
We identified antigenic targets of the autoantibody response in SS that may be useful for identifying up to half of Ro seronegative SS cases.
Topics: Humans; Autoantibodies; Sjogren's Syndrome; Case-Control Studies; Autoantigens; ROC Curve; Immunoglobulin G; Antibodies, Antinuclear
PubMed: 37147113
DOI: 10.1136/ard-2022-223105 -
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 -
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