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Nature Medicine May 2024Although B cells are implicated in multiple sclerosis (MS) pathophysiology, a predictive or diagnostic autoantibody remains elusive. In this study, the Department of...
Although B cells are implicated in multiple sclerosis (MS) pathophysiology, a predictive or diagnostic autoantibody remains elusive. In this study, the Department of Defense Serum Repository (DoDSR), a cohort of over 10 million individuals, was used to generate whole-proteome autoantibody profiles of hundreds of patients with MS (PwMS) years before and subsequently after MS onset. This analysis defines a unique cluster in approximately 10% of PwMS who share an autoantibody signature against a common motif that has similarity with many human pathogens. These patients exhibit antibody reactivity years before developing MS symptoms and have higher levels of serum neurofilament light (sNfL) compared to other PwMS. Furthermore, this profile is preserved over time, providing molecular evidence for an immunologically active preclinical period years before clinical onset. This autoantibody reactivity was validated in samples from a separate incident MS cohort in both cerebrospinal fluid and serum, where it is highly specific for patients eventually diagnosed with MS. This signature is a starting point for further immunological characterization of this MS patient subset and may be clinically useful as an antigen-specific biomarker for high-risk patients with clinically or radiologically isolated neuroinflammatory syndromes.
Topics: Humans; Multiple Sclerosis; Autoantibodies; Neurofilament Proteins; Biomarkers; Cohort Studies; Female; Male; Adult; Middle Aged
PubMed: 38641750
DOI: 10.1038/s41591-024-02938-3 -
Annals of the Rheumatic Diseases Dec 2023The severity of skin involvement in diffuse cutaneous systemic sclerosis (dcSSc) depends on stage of disease and differs between anti-RNA-polymerase III (ARA) and...
OBJECTIVES
The severity of skin involvement in diffuse cutaneous systemic sclerosis (dcSSc) depends on stage of disease and differs between anti-RNA-polymerase III (ARA) and anti-topoisomerase antibody (ATA) subsets. We have investigated cellular differences in well-characterised dcSSc patients compared with healthy controls (HCs).
METHODS
We performed single-cell RNA sequencing on 4 mm skin biopsy samples from 12 patients with dcSSc and HCs (n=3) using droplet-based sequencing (10× genomics). Patients were well characterised by stage (>5 or <5 years disease duration) and autoantibody (ATA+ or ARA+). Analysis of whole skin cell subsets and fibroblast subpopulations across stage and ANA subgroup were used to interpret potential cellular differences anchored by these subgroups.
RESULTS
Fifteen forearm skin biopsies were analysed. There was a clear separation of SSc samples, by disease, stage and antibody, for all cells and fibroblast subclusters. Further analysis revealed differing cell cluster gene expression profiles between ATA+ and ARA+ patients. Cell-to-cell interaction suggest differing interactions between early and late stages of disease and autoantibody. TGFβ response was mainly seen in fibroblasts and smooth muscle cells in early ATA+dcSSc skin samples, whereas in early ARA+dcSSc patient skin samples, the responding cells were endothelial, reflect broader differences between clinical phenotypes and distinct skin score trajectories across autoantibody subgroups of dcSSc.
CONCLUSIONS
We have identified cellular differences between the two main autoantibody subsets in dcSSc (ARA+ and ATA+). These differences reinforce the importance of considering autoantibody and stage of disease in management and trial design in SSc.
Topics: Humans; Autoantibodies; Scleroderma, Systemic; Scleroderma, Diffuse; Skin; Single-Cell Analysis
PubMed: 37580109
DOI: 10.1136/ard-2023-224184 -
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 -
Acta Neuropathologica Aug 2023Serum autoantibodies targeting the nicotinic acetylcholine receptor (AChR) in patients with autoimmune myasthenia gravis (MG) can mediate pathology via three distinct...
Serum autoantibodies targeting the nicotinic acetylcholine receptor (AChR) in patients with autoimmune myasthenia gravis (MG) can mediate pathology via three distinct molecular mechanisms: complement activation, receptor blockade, and antigenic modulation. However, it is unclear whether multi-pathogenicity is mediated by individual or multiple autoantibody clones. Using an unbiased B cell culture screening approach, we generated a library of 11 human-derived AChR-specific recombinant monoclonal autoantibodies (mAb) and assessed their binding properties and pathogenic profiles using specialized cell-based assays. Five mAbs activated complement, three blocked α-bungarotoxin binding to the receptor, and seven induced antigenic modulation. Furthermore, two clonally related mAbs derived from one patient were each highly efficient at more than one of these mechanisms, demonstrating that pathogenic mechanisms are not mutually exclusive at the monoclonal level. Using novel Jurkat cell lines that individually express each monomeric AChR subunit (αβδε), these two mAbs with multi-pathogenic capacity were determined to exclusively bind the α-subunit of AChR, demonstrating an association between mAb specificity and pathogenic capacity. These findings provide new insight into the immunopathology of MG, demonstrating that single autoreactive clones can efficiently mediate multiple modes of pathology. Current therapeutic approaches targeting only one autoantibody-mediated pathogenic mechanism may be evaded by autoantibodies with multifaceted capacity.
Topics: Humans; Autoantibodies; Myasthenia Gravis; Receptors, Cholinergic; Clone Cells; B-Lymphocytes
PubMed: 37344701
DOI: 10.1007/s00401-023-02603-y -
Trends in Endocrinology and Metabolism:... Oct 2023Anti-glutamic acid decarboxylase (GAD) autoantibodies are a hallmark of stiff-person syndrome (SPS) and insulin-dependent diabetes mellitus (IDDM). However, patients... (Review)
Review
Anti-glutamic acid decarboxylase (GAD) autoantibodies are a hallmark of stiff-person syndrome (SPS) and insulin-dependent diabetes mellitus (IDDM). However, patients with concurrent IDDM and SPS often manifest insulin resistance, and SPS-associated IDDM probably has heterogeneous causes. Some patients manifest IDDM associated only with high titers of anti-GAD65 caused by SPS. By contrast, other patients develop IDDM only after being treated with high-dose corticosteroids or they progress to insulin dependency following their treatment with high-dose corticosteroids. The profile of autoantibodies differs markedly between type 1 diabetes mellitus (T1DM), late-onset diabetes mellitus, and SPS-associated IDDM. Therefore, as with new-onset diabetes after transplantation (NODAT), SPS-associated IDDM should be classified as a specific diabetes entity, the pathophysiology of which requires increased attention.
Topics: Humans; Diabetes Mellitus, Type 1; Stiff-Person Syndrome; Diabetes Mellitus, Type 2; Insulin; Autoantibodies
PubMed: 37586963
DOI: 10.1016/j.tem.2023.07.005 -
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 -
Hematology. American Society of... Dec 2023Acquired hemophilia A (AHA) is an autoimmune disorder characterized by the formation of autoantibodies that neutralize the function of coagulation factor VIII....
Acquired hemophilia A (AHA) is an autoimmune disorder characterized by the formation of autoantibodies that neutralize the function of coagulation factor VIII. Immunosuppressive therapy (IST) with glucocorticoids, cyclophosphamide, rituximab, or combinations thereof is the standard of care to suppress autoantibody formation and induce remission of AHA. About 80% of patients achieve remission over the course of a few weeks to several months. However, patients with AHA are often elderly and frail and have adverse events from IST. Therefore, guidelines suggest an individualized approach using caution in elderly and frail patients. Prophylaxis with emicizumab may reduce the need for early and aggressive IST in the future.
Topics: Humans; Aged; Hemophilia A; Factor VIII; Cyclophosphamide; Rituximab; Autoantibodies; Immunotherapy
PubMed: 38066859
DOI: 10.1182/hematology.2023000461 -
Current Neurology and Neuroscience... May 2024Immune-mediated necrotizing myopathy (IMNM), characterized by acute or subacute onset, severe weakness, and elevated creatine kinase levels, poses diagnostic and... (Review)
Review
PURPOSE OF REVIEW
Immune-mediated necrotizing myopathy (IMNM), characterized by acute or subacute onset, severe weakness, and elevated creatine kinase levels, poses diagnostic and therapeutic challenges. This article provides a succinct overview of IMNM, including clinical features, diagnostic strategies, and treatment approaches.
RECENT FINDINGS
Recent insights highlight the different clinical presentations and therapeutic options of IMNM stratified by autoantibody positivity and type. Additionally, recent findings call into question the reported link between statin use and IMNM. This review synthesizes current knowledge on IMNM, emphasizing its distinct clinical features and challenging management. The evolving understanding of IMNM underscores the need for a comprehensive diagnostic approach that utilizes a growing range of modalities. Early and aggressive immunomodulatory therapy remains pivotal. Ongoing research aims to refine diagnostic tools and therapeutic interventions for this challenging muscle disorder, underscoring the importance of advancing our understanding to enhance patient outcomes.
Topics: Humans; Muscle, Skeletal; Necrosis; Myositis; Autoimmune Diseases; Muscular Diseases; Autoantibodies
PubMed: 38589696
DOI: 10.1007/s11910-024-01337-y -
Neurology(R) Neuroimmunology &... Sep 2023The therapeutic success and widespread approval of genetically engineered T cells for a variety of hematologic malignancies spurred the development of synthetic... (Review)
Review
The therapeutic success and widespread approval of genetically engineered T cells for a variety of hematologic malignancies spurred the development of synthetic cell-based immunotherapies for CNS lymphoma, primary brain tumors, and a growing spectrum of nononcologic disease conditions of the nervous system. Chimeric antigen receptor effector T cells bear the potential to deplete target cells with higher efficacy, better tissue penetration, and greater depth than antibody-based cell depletion therapies. In multiple sclerosis and other autoimmune disorders, engineered T-cell therapies are being designed and currently tested in clinical trials for their safety and efficacy to eliminate pathogenic B-lineage cells. Chimeric autoantibody receptor T cells expressing a disease-relevant autoantigen as cell surface domains are designed to selectively deplete autoreactive B cells. Alternative to cell depletion, synthetic antigen-specific regulatory T cells can be engineered to locally restrain inflammation, support immune tolerance, or efficiently deliver neuroprotective factors in brain diseases in which current therapeutic options are very limited. In this article, we illustrate prospects and bottlenecks for the clinical development and implementation of engineered cellular immunotherapies in neurologic diseases.
Topics: Humans; Artificial Cells; Nervous System Diseases; Immunotherapy; Brain Diseases; Autoantibodies
PubMed: 37385738
DOI: 10.1212/NXI.0000000000200139