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Annals of the Rheumatic Diseases Aug 2023Research elucidating the pathogenesis of systemic lupus erythematosus (SLE) has defined two critical families of mediators, type I interferon (IFN-I) and autoantibodies... (Review)
Review
Research elucidating the pathogenesis of systemic lupus erythematosus (SLE) has defined two critical families of mediators, type I interferon (IFN-I) and autoantibodies targeting nucleic acids and nucleic acid-binding proteins, as fundamental contributors to the disease. On the fertile background of significant genetic risk, a triggering stimulus, perhaps microbial, induces IFN-I, autoantibody production or most likely both. When innate and adaptive immune system cells are engaged and collaborate in the autoimmune response, clinical SLE can develop. This review describes recent data from genetic analyses of patients with SLE, along with current studies of innate and adaptive immune function that contribute to sustained IFN-I pathway activation, immune activation and autoantibody production, generation of inflammatory mediators and tissue damage. The goal of these studies is to understand disease mechanisms, identify therapeutic targets and stimulate development of therapeutics that can achieve improved outcomes for patients.
Topics: Humans; Lupus Erythematosus, Systemic; Autoantibodies; Interferon Type I
PubMed: 36792346
DOI: 10.1136/ard-2022-223741 -
Nature Reviews. Nephrology Aug 2023Autoimmune diseases are a diverse group of conditions characterized by aberrant B cell and T cell reactivity to normal constituents of the host. These diseases occur... (Review)
Review
Autoimmune diseases are a diverse group of conditions characterized by aberrant B cell and T cell reactivity to normal constituents of the host. These diseases occur widely and affect individuals of all ages, especially women. Among these diseases, the most prominent immunological manifestation is the production of autoantibodies, which provide valuable biomarkers for diagnosis, classification and disease activity. Although T cells have a key role in pathogenesis, they are technically more difficult to assay. In general, autoimmune disease results from an interplay between a genetic predisposition and environmental factors. Genetic predisposition to autoimmunity is complex and can involve multiple genes that regulate the function of immune cell populations. Less frequently, autoimmunity can result from single-gene mutations that affect key regulatory pathways. Infection seems to be a common trigger for autoimmune disease, although the microbiota can also influence pathogenesis. As shown in seminal studies, patients may express autoantibodies many years before the appearance of clinical or laboratory signs of disease - a period called pre-clinical autoimmunity. Monitoring autoantibody expression in at-risk populations may therefore enable early detection and the initiation of therapy to prevent or attenuate tissue damage. Autoimmunity may not be static, however, and remission can be achieved by some patients treated with current agents.
Topics: Humans; Female; Genetic Predisposition to Disease; Autoimmune Diseases; Autoimmunity; Autoantibodies; T-Lymphocytes
PubMed: 37165096
DOI: 10.1038/s41581-023-00720-1 -
Current Opinion in Pulmonary Medicine Sep 2023In idiopathic inflammatory myopathies (IIMs), interstitial lung disease (ILD) is common and the autoantibody profile, made up of myositis-specific and... (Review)
Review
PURPOSE OF REVIEW
In idiopathic inflammatory myopathies (IIMs), interstitial lung disease (ILD) is common and the autoantibody profile, made up of myositis-specific and myositis-associated (MSA and MAA) antibodies, can predict the clinical phenotype and progression over time. This review will focus on the characteristics and management of antisynthetase syndrome related ILD and anti-MDA5 positive ILD, which are the most clinically relevant subtypes.
RECENT FINDINGS
The prevalence of ILD in IIM has been estimated in Asia, North America and Europe at 50, 23 and 26%, respectively, and is increasing. In antisynthetase syndrome related ILD, the clinical presentation, progression and prognosis varies among anti-ARS antibodies. ILD is more common and severe in patients with anti-PL-7/anti-PL-12 antibodies when compared with anti Jo-1 patients. The prevalence of anti-MDA5 antibodies is higher in Asians (11-60%) than in whites (7-16%). Sixty-six percent of antisynthetase syndrome patients had 'chronic ILD' compared with the more rapidly progressive ILD (RP-ILD) seen in 69% of patients with anti-MDA5 antibodies.
SUMMARY
ILD is most common in the antisynthetase subtype of IIM and can be a chronic indolent or RP- ILD. The MSA and MAAs are associated with different clinical phenotypes of ILD. Treatments typically involve combinations of corticosteroids and other immunosuppressants.
Topics: Humans; Myositis; Autoantibodies; Lung Diseases, Interstitial; Immunosuppressive Agents
PubMed: 37435671
DOI: 10.1097/MCP.0000000000001000 -
Cell Feb 2024Autoimmune diseases disproportionately affect females more than males. The XX sex chromosome complement is strongly associated with susceptibility to autoimmunity. Xist...
Autoimmune diseases disproportionately affect females more than males. The XX sex chromosome complement is strongly associated with susceptibility to autoimmunity. Xist long non-coding RNA (lncRNA) is expressed only in females to randomly inactivate one of the two X chromosomes to achieve gene dosage compensation. Here, we show that the Xist ribonucleoprotein (RNP) complex comprising numerous autoantigenic components is an important driver of sex-biased autoimmunity. Inducible transgenic expression of a non-silencing form of Xist in male mice introduced Xist RNP complexes and sufficed to produce autoantibodies. Male SJL/J mice expressing transgenic Xist developed more severe multi-organ pathology in a pristane-induced lupus model than wild-type males. Xist expression in males reprogrammed T and B cell populations and chromatin states to more resemble wild-type females. Human patients with autoimmune diseases displayed significant autoantibodies to multiple components of XIST RNP. Thus, a sex-specific lncRNA scaffolds ubiquitous RNP components to drive sex-biased immunity.
Topics: Animals; Female; Humans; Male; Mice; Autoantibodies; Autoimmune Diseases; Autoimmunity; Ribonucleoproteins; RNA, Long Noncoding; X Chromosome; X Chromosome Inactivation; Sex Characteristics
PubMed: 38306984
DOI: 10.1016/j.cell.2023.12.037 -
Cell Nov 2023Anti-NMDA receptor (NMDAR) autoantibodies cause NMDAR encephalitis, the most common autoimmune encephalitis, leading to psychosis, seizures, and autonomic dysfunction....
Anti-NMDA receptor (NMDAR) autoantibodies cause NMDAR encephalitis, the most common autoimmune encephalitis, leading to psychosis, seizures, and autonomic dysfunction. Current treatments comprise broad immunosuppression or non-selective antibody removal. We developed NMDAR-specific chimeric autoantibody receptor (NMDAR-CAAR) T cells to selectively eliminate anti-NMDAR B cells and disease-causing autoantibodies. NMDAR-CAARs consist of an extracellular multi-subunit NMDAR autoantigen fused to intracellular 4-1BB/CD3ζ domains. NMDAR-CAAR T cells recognize a large panel of human patient-derived autoantibodies, release effector molecules, proliferate, and selectively kill antigen-specific target cell lines even in the presence of high autoantibody concentrations. In a passive transfer mouse model, NMDAR-CAAR T cells led to depletion of an anti-NMDAR B cell line and sustained reduction of autoantibody levels without notable off-target toxicity. Treatment of patients may reduce side effects, prevent relapses, and improve long-term prognosis. Our preclinical work paves the way for CAAR T cell phase I/II trials in NMDAR encephalitis and further autoantibody-mediated diseases.
Topics: Animals; Humans; Mice; Autoantibodies; Encephalitis; Receptors, N-Methyl-D-Aspartate; T-Lymphocytes; Autoimmune Diseases; Disease Models, Animal
PubMed: 37918394
DOI: 10.1016/j.cell.2023.10.001 -
Lancet (London, England) May 2024Systemic lupus erythematosus (SLE) is a multisystemic autoimmune disease characterised by the presence of autoantibodies towards nuclear antigens, immune complex... (Review)
Review
Systemic lupus erythematosus (SLE) is a multisystemic autoimmune disease characterised by the presence of autoantibodies towards nuclear antigens, immune complex deposition, and chronic inflammation at classic target organs such as skin, joints, and kidneys. Despite substantial advances in the diagnosis and management of SLE, the burden of disease remains high. It is important to appreciate the typical presentations and the diagnostic process to facilitate early referral and diagnosis for patients. In most patients, constitutional, mucocutaneous, and musculoskeletal symptoms represent the earliest complaints; these symptoms can include fatigue, lupus-specific rash, mouth ulcers, alopecia, joint pain, and myalgia. In this Seminar we will discuss a diagnostic approach to symptoms in light of the latest classification criteria, which include a systematic evaluation of clinical manifestations (weighted within each domain) and autoantibody profiles (such as anti-double-stranded DNA, anti-Sm, hypocomplementaemia, or antiphospholipid antibodies). Non-pharmacotherapy management is tailored to the individual, with specific lifestyle interventions and patient education to improve quality of life and medication (such as hydroxychloroquine or immunosuppressant) adherence. In the last decade, there have been a few major breakthroughs in approved treatments for SLE and lupus nephritis, such as belimumab, anifrolumab, and voclosporin. However the disease course remains variable and mortality unacceptably high. Access to these expensive medications has also been restricted across different regions of the world. Nonetheless, understanding of treatment goals and strategies has improved. We recognise that the main goal of treatment is the achievement of remission or low disease activity. Comorbidities due to both disease activity and treatment adverse effects, especially infections, osteoporosis, and cardiovascular disease, necessitate vigilant prevention and management strategies. Tailoring treatment options to achieve remission, while balancing treatment-related comorbidities, are priority areas of SLE management.
Topics: Humans; Lupus Erythematosus, Systemic; Immunosuppressive Agents; Autoantibodies
PubMed: 38642569
DOI: 10.1016/S0140-6736(24)00398-2 -
Journal of Neurology Aug 2023In 2015, we wrote a review in The Journal of Neurology summarizing the field of autoantibody-associated neurological diseases. Now, in 2023, we present an update of the...
In 2015, we wrote a review in The Journal of Neurology summarizing the field of autoantibody-associated neurological diseases. Now, in 2023, we present an update of the subject which reflects the rapid expansion and refinement of associated clinical phenotypes, further autoantibody discoveries, and a more detailed understanding of immunological and neurobiological pathophysiological pathways which mediate these diseases. Increasing awareness around distinctive aspects of their clinical phenotypes has been a key driver in providing clinicians with a better understanding as to how these diseases are best recognized. In clinical practice, this recognition supports the administration of often effective immunotherapies, making these diseases 'not to miss' conditions. In parallel, there is a need to accurately assess patient responses to these drugs, another area of growing interest. Feeding into clinical care are the basic biological underpinnings of the diseases, which offer clear pathways to improved therapies toward enhanced patient outcomes. In this update, we aim to integrate the clinical diagnostic pathway with advances in patient management and biology to provide a cohesive view on how to care for these patients in 2023, and the future.
Topics: Humans; Encephalitis; Autoantibodies; Hashimoto Disease; Autoimmune Diseases of the Nervous System
PubMed: 37115360
DOI: 10.1007/s00415-023-11685-3 -
Frontiers in Immunology 2023Muscle-specific kinase (MuSK) Myasthenia Gravis (MG) represents a prototypical antibody-mediated disease characterized by predominantly focal muscle weakness (neck,... (Review)
Review
Muscle-specific kinase (MuSK) Myasthenia Gravis (MG) represents a prototypical antibody-mediated disease characterized by predominantly focal muscle weakness (neck, facial, and bulbar muscles) and fatigability. The pathogenic antibodies mostly belong to the immunoglobulin subclass (Ig)G4, a feature which attributes them their specific properties and pathogenic profile. On the other hand, acetylcholine receptor (AChR) MG, the most prevalent form of MG, is characterized by immunoglobulin (Ig)G1 and IgG3 antibodies to the AChR. IgG4 class autoantibodies are impotent to fix complement and only weakly bind Fc-receptors expressed on immune cells and exert their pathogenicity interfering with the interaction between their targets and binding partners (e.g. between MuSK and LRP4). Cardinal differences between AChR and MuSK-MG are the thymus involvement (not prominent in MuSK-MG), the distinct HLA alleles, and core immunopathological patterns of pathology in neuromuscular junction, structure, and function. In MuSK-MG, classical treatment options are usually less effective (e.g. IVIG) with the need for prolonged and high doses of steroids difficult to be tapered to control symptoms. Exceptional clinical response to plasmapheresis and rituximab has been particularly observed in these patients. Reduction of antibody titers follows the clinical efficacy of anti-CD20 therapies, a feature implying the role of short-lived plasma cells (SLPB) in autoantibody production. Novel therapeutic monoclonal against B cells at different stages of their maturation (like plasmablasts), or against molecules involved in B cell activation, represent promising therapeutic targets. A revolution in autoantibody-mediated diseases is pharmacological interference with the neonatal Fc receptor, leading to a rapid reduction of circulating IgGs (including autoantibodies), an approach already suitable for AChR-MG and promising for MuSK-MG. New precision medicine approaches involve Chimeric autoantibody receptor T (CAAR-T) cells that are engineered to target antigen-specific B cells in MuSK-MG and represent a milestone in the development of targeted immunotherapies. This review aims to provide a detailed update on the pathomechanisms involved in MuSK-MG (cellular and humoral aberrations), fostering the understanding of the latest indications regarding the efficacy of different treatment strategies.
Topics: Humans; Autoantibodies; Immunoglobulin G; Immunotherapy; Myasthenia Gravis; Receptor Protein-Tyrosine Kinases; Receptors, Cholinergic
PubMed: 37564637
DOI: 10.3389/fimmu.2023.1212757 -
Arthritis & Rheumatology (Hoboken, N.J.) Apr 2024B cell generation of autoantibodies is a crucial step in the pathogenesis of systemic lupus erythematosus (SLE). After their differentiation in the bone marrow, B cells... (Review)
Review
B cell generation of autoantibodies is a crucial step in the pathogenesis of systemic lupus erythematosus (SLE). After their differentiation in the bone marrow, B cells populate the secondary lymphatic organs, where they undergo further maturation leading to the development of memory B cells as well as antibody-producing plasmablasts and plasma cells. Targeting B cells is an important strategy to treat autoimmune diseases such as SLE, in which B cell tolerance is disturbed and autoimmune B cells and autoantibodies emerge. This review discusses the functional aspects of antibody- and cell-based B cell-depleting therapy in SLE. It thereby particularly focuses on lessons learned from chimeric antigen receptor (CAR) T cell treatment on the role of B cells in SLE for understanding B cell pathology in SLE. CAR T cells model a deep B cell depletion and thereby allow understanding the role of aberrant B cell activation in the pathogenesis of SLE. Furthermore, the effects of B cell depletion on autoantibody production can be better described, ie, explaining the concept of different cellular sources of (auto-) antibodies in the form of short-lived plasmablasts and long-lived plasma cells, which differ in their susceptibility to B cell depletion and require different targeted therapeutic approaches. Finally, the safety of deep B cell depletion in autoimmune disease is discussed.
Topics: Humans; Receptors, Chimeric Antigen; B-Lymphocytes; Lupus Erythematosus, Systemic; Antigens, CD19; Autoantibodies; T-Lymphocytes
PubMed: 38114423
DOI: 10.1002/art.42784 -
Circulation Aug 2023Atrial fibrillation (AF) is by far the most common cardiac arrhythmia. In about 3% of individuals, AF develops as a primary disorder without any identifiable trigger...
BACKGROUND
Atrial fibrillation (AF) is by far the most common cardiac arrhythmia. In about 3% of individuals, AF develops as a primary disorder without any identifiable trigger (idiopathic or historically termed lone AF). In line with the emerging field of autoantibody-related cardiac arrhythmias, the objective of this study was to explore whether autoantibodies targeting cardiac ion channels can underlie unexplained AF.
METHODS
Peptide microarray was used to screen patient samples for autoantibodies. We compared patients with unexplained AF (n=37 pre-existent AF; n=14 incident AF on follow-up) to age- and sex-matched controls (n=37). Electrophysiological properties of the identified autoantibody were then tested in vitro with the patch clamp technique and in vivo with an experimental mouse model of immunization.
RESULTS
A common autoantibody response against K3.4 protein was detected in patients with AF and even before the development of clinically apparent AF. K3.4 protein forms a heterotetramer that underlies the cardiac acetylcholine-activated inwardly rectifying K current, . Functional studies on human induced pluripotent stem cell-derived atrial cardiomyocytes showed that anti-K3.4 IgG purified from patients with AF shortened action potentials and enhanced the constitutive form of , both key mediators of AF. To establish a causal relationship, we developed a mouse model of K3.4 autoimmunity. Electrophysiological study in K3.4-immunized mice showed that K3.4 autoantibodies significantly reduced atrial effective refractory period and predisposed animals to a 2.8-fold increased susceptibility to AF.
CONCLUSIONS
To our knowledge, this is the first report of an autoimmune pathogenesis of AF with direct evidence of K3.4 autoantibody-mediated AF.
Topics: Humans; Animals; Mice; Atrial Fibrillation; G Protein-Coupled Inwardly-Rectifying Potassium Channels; Induced Pluripotent Stem Cells; Heart Atria; Autoantibodies
PubMed: 37401487
DOI: 10.1161/CIRCULATIONAHA.122.062776