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Psoriasis is a chronic skin disease evolving to psoriatic arthritis (PsA) in 30% of cases. LL37 is a psoriasis T-cell autoantigen and, in complex with self-DNA/RNA, a trigger of type I interferon (IFN-I) and pro-inflammatory factors in dendritic cells. LL37 can undergo irreversible post-translational modifications (PTMs), namely, citrullination and carbamylation, which are linked to a neutrophil-dominated inflammation. Notably, in PsA, carbamylated and citrullinated LL37 (carb-LL37 and cit-LL37) become antibody targets. Here, we analyze the presence of, and the T-cell and antibody reactivity to, cit-LL37 and carb-LL37, to address the occurrence and significance of these PTMs in psoriasis. The presence of modified LL37 in skin biopsies was assessed by laser scanner confocal microscopy (LSCM); T-cell responses to modified LL37 were assessed by Ki67 assay and intracellular cytokine staining using flow cytometry; serum autoantibodies to the same antigens were tested by enzyme-linked immunosorbent assay (ELISA). The results show that native and modified LL37 (both carb-LL37 and cit-LL37) are detectable in psoriatic skin, but not in healthy donors’ (HD) skin, where they colocalize with neutrophil infiltrates and neutrophil extracellular trap formation (NETosis). Psoriatic T cells and antibodies recognize native LL37, cit-LL37, and carb-LL37, but only CD4-T-cell responses to native LL37 and carb-LL37 correlate with psoriasis area severity index (PASI), whereas CD8-T-cell responses to the same peptides correlate with PASI in the HLA-Cw6*02-positive subgroup. CD4-T cells specific for modified LL37 express heterogeneous T-helper (Th) phenotypes: native/carb-LL37-specific T cells mainly manifest a Th1/Th17-like phenotype, whereas cit-LL37-specific T cells resemble Th-follicular (Thf)-like cells. In vitro T-cell polarization experiments suggest that distinct pro-inflammatory effects of LL37 and modified LL37, in complex with self-nucleic acids, may concur to these phenomena. This is the first evidence in psoriasis that PTMs of an autoantigen with innate immune cell stimulatory ability dictate autoreactive Th-cell polarization. These data, obtained using LL37 as a model autoantigen, indicate that citrullination and carbamylation pathways may play a role in the psoriasis course, generating epitopes to which immunological tolerance does not exist and potentially concur to PsA development.

Cladribine tablet therapy is an efficacious treatment for multiple sclerosis (MS). Recently, we showed that one year after the initiation of cladribine treatment, T and B cell crosstalk was impaired, reducing potentially pathogenic effector functions along with a specific reduction of autoreactivity to RAS guanyl releasing protein 2 (RASGRP2). In the present study we conducted a longitudinal analysis of the effect of cladribine treatment in patients with RRMS, focusing on the extent to which the effects observed on T and B cell subsets and autoreactivity after one year of treatment are maintained, modulated, or amplified during the second year of treatment. In this case-control exploratory study, frequencies and absolute counts of peripheral T and B cell subsets and B cell cytokine production from untreated patients with relapsing-remitting MS (RRMS) and patients treated with cladribine for 52 (W52), 60 (W60), 72 (W72) and 96 (W96) weeks, were measured using flow cytometry. Autoreactivity was assessed using a FluoroSpot assay. We found a substantial reduction in circulating memory B cells and proinflammatory B cell responses. Furthermore, we observed reduced T cell responses to autoantigens possibly presented by B cells (RASGRP2 and a-B crystallin (CRYAB)) at W52 and W96 and a further reduction in responses to the myelin antigens myelin basic protein (MBP) and myelin oligodendrocyte glycoprotein (MOG) after 96 weeks. We conclude that the effects of cladribine observed after year one are maintained and, for some effects, even increased two years after the initiation of a full course of treatment with cladribine tablets.

The gut microbiota plays a major role in the developmental biology and homeostasis of cells belonging to the adaptive and innate arms of the immune system. Alterations in its composition, which are known to be regulated by both genetic and environmental factors, can either promote or suppress the pathogenic processes underlying the development of various autoimmune diseases, including inflammatory bowel disease, multiple sclerosis, systemic lupus erythematosus, type 1 diabetes and rheumatoid arthritis, to just name a few. Cross-recognition of gut microbial antigens by autoreactive T cells as well as gut microbe-driven alterations in the activation and homeostasis of effector and regulatory T cells have been implicated in this process. Here, we summarize our current understanding of the positive and negative associations between alterations in the composition of the gut microbiota and the development of various autoimmune disorders, with a special emphasis on antigenic mimicry.

BackgroundStudies have shown that autoimmune response contributes to chronic hepatitis B (CHB) development.AimThis study aimed to identify autoantibodies in the sera of patients with CHB and to investigate the association of autoimmune response with disease severity in CHB.MethodsProteins from human liver carcinoma cell line HepG2 were separated by two-dimensional electrophoresis. The candidate autoantigens were recognized by serum autoantibodies from Chinese CHB patients. Immunohistochemical staining was performed to determine the hepatic expression of the autoantigen in CHB patients with different inflammatory grades. Enzyme-linked immunosorbent assay (ELISA) was conducted to measure the prevalence and the levels of serum autoantibody in CHB patients with different disease severity. Flow cytometry analysis was carried out to assess the autoreactive T cell response in the peripheral circulation of CHB patients.ResultsErbB-3-binding protein-1 (EBP-1) was identified as an autoantigen of serum autoantibodies in CBP patients. EBP-1 protein expression was upregulated in the liver of CHB patients with high-grade hepatic inflammation. The prevalence and levels of serum anti-EBP1 IgG were significantly increased in CHB patients with severe diseases compared with those with mild or moderate diseases, but none was detectable in the healthy controls. EBP-1 peptides induced proinflammatory cytokine expression in CD4+ T cells from CHB patients.ConclusionOur results demonstrate the presence of an autoantibody against EBP-1 in the sera as well as EBP-1-reactive T cells in the peripheral blood of CHB patient. EBP-1-induced autoimmune response is positively associated with the disease severity, suggesting that EBP-1-induced autoimmune response possibly contributes to progressive liver failure.

Graves’ disease (GD) is a thyroid-specific autoimmune disease with a high prevalence worldwide. The disease is primarily mediated by B cells, which produce autoantibodies against the thyroid-stimulating hormone receptor (TSHR), chronically stimulating it and leading to high levels of thyroid hormones in the body. Interest in characterizing the immune response in GD has motivated many phenotyping studies. The immunophenotype of the cells involved and the interplay between them and their secreted factors are crucial to understanding disease progression and future treatment options. T cell populations are markedly distinct, including increased levels of Th17 and follicular helper T cells (Tfh), while Treg cells appear to be impaired. Some B cells subsets are autoreactive, and anti-TSHR antibodies are the key disease-causing outcome of this interplay. Though some consensus across phenotyping studies will be discussed here, there are also complexities that are yet to be resolved. A better understanding of the immunophenotype of Graves’ disease can lead to improved treatment strategies and novel drug targets.

Aims/hypothesisNumerous clinical studies have investigated the anti-CD3ɛ monoclonal antibody otelixizumab in individuals with type 1 diabetes, but limited progress has been made in identifying the optimal clinical dose with acceptable tolerability and safety. The aim of this study was to evaluate the association between dose–response, safety and tolerability, beta cell function preservation and the immunological effects of otelixizumab in new-onset type 1 diabetes.MethodsIn this randomised, single-blind, placebo-controlled, 24 month study, conducted in five centres in Belgium via the Belgian Diabetes Registry, participants (16–27 years old, <32 days from diagnosis of type 1 diabetes) were scheduled to receive placebo or otelixizumab in one of four dose cohorts (cumulative i.v. dose 9, 18, 27 or 36 mg over 6 days; planned n = 40). Randomisation to treatment was by a central computer system; only participants and bedside study personnel were blinded to study treatment. The co-primary endpoints were the incidence of adverse events, the rate of Epstein–Barr virus (EBV) reactivation, and laboratory measures and vital signs. A mixed-meal tolerance test was used to assess beta cell function; exploratory biomarkers were used to measure T cell responses.ResultsThirty participants were randomised/28 were analysed (placebo, n = 6/5; otelixizumab 9 mg, n = 9/8; otelixizumab 18 mg, n = 8/8; otelixizumab 27 mg, n = 7/7; otelixizumab 36 mg, n = 0). Dosing was stopped at otelixizumab 27 mg as the predefined EBV reactivation stopping criteria were met. Adverse event frequency and severity were dose dependent; all participants on otelixizumab experienced at least one adverse event related to cytokine release syndrome during the dosing period. EBV reactivation (otelixizumab 9 mg, n = 2/9; 18 mg, n = 4/8: 27 mg, n = 5/7) and clinical manifestations (otelixizumab 9 mg, n = 0/9; 18 mg, n = 1/8; 27 mg, n = 3/7) were rapid, dose dependent and transient, and were associated with increased productive T cell clonality that diminished over time. Change from baseline mixed-meal tolerance test C-peptide weighted mean AUC0–120 min following otelixizumab 9 mg was above baseline for up to 18 months (difference from placebo 0.39 [95% CI 0.06, 0.72]; p = 0.023); no beta cell function preservation was observed at otelixizumab 18 and 27 mg.Conclusions/interpretationA metabolic response was observed with otelixizumab 9 mg, while doses higher than 18 mg increased the risk of unwanted clinical EBV reactivation. Although otelixizumab can temporarily compromise immunocompetence, allowing EBV to reactivate, the effect is dose dependent and transient, as evidenced by a rapid emergence of EBV-specific T cells preceding long-term control over EBV reactivation.Trial registrationClinicalTrials.gov NCT02000817.FundingThe study was funded by GlaxoSmithKline.

Ischemic Stroke is a major cause of morbidity and mortality worldwide. Sterile inflammation occurs after both stroke subtypes and contributes to neuronal injury and damage to the blood-brain barrier with release of brain antigens and a potential induction of autoimmune responses that escape central and peripheral tolerance mechanisms. In stroke patients, the detection of T cells and antibodies specific to neuronal antigens suggests a role of humoral adaptive immunity. In experimental models stroke leads to a significant increase of autoreactive T and B cells to CNS antigens. Lesion volume and functional outcome in stroke patients and murine stroke models are connected to antigen-specific responses to brain proteins. In patients with traumatic brain injury (TBI) a range of antibodies against brain proteins can be detected in serum samples. In this review, we will summarize the role of autoimmunity in post-lesional conditions and discuss the role of B and T cells and their potential neuroprotective or detrimental effects.

Antibodies are a vital part of the armamentarium of the adaptive immune system for the fine-tuning of the recognition and response to foreign threats. However, in health there are some types of antibodies that instead recognize self-antigens and these contribute to the enhancement of primitive innate functions. This repertoire of natural IgM antibodies is postulated to have been selected during immune evolution for their contributions to critical immunoregulatory and housekeeping properties. The clearance of dying cells is one of the most essential responsibilities of the immune system, which is required to prevent uncontrolled inflammation and autoimmunity. In the murine immune system, natural IgM antibodies that recognize apoptotic cells have been shown to enhance the phagocytic clearance of dead and dying cells and to suppress innate immune signaling pathways. In the mouse, natural IgM are often the products of B-1 cell clones that arise during immune development without an absolute requirement for exogenous antigenic stimulation. In patients with systemic lupus erythematosus, IgM autoantibodies, which bind to neo-epitopes on apoptotic cells, have been demonstrated to be present at significantly higher levels in patients with lower disease activity and with less severe organ damage. While certain specificities of IgM autoantibodies correlate with protection from lupus renal disease, others may convey protective properties from lupus-associated atherosclerotic cardiovascular disease. New and unexpected insights into the functional roles of IgM antibodies are still emerging, especially regarding the functions of natural antibodies. Herein, we review recent progress in our understanding of the potential roles of natural IgM autoantibodies in the regulation of immune homeostasis and for protection from autoimmune and inflammatory diseases.

Aim: To investigate the types of immune response regulation and immunological tolerance disorders in autoimmune diseases. Methods: Bibliometric indicators` analysis of scientific articles and analytical materials from databases such as Scopus, Web of Science, DOAJ, and PubMed were used. Results. The most important types of regulation of the immune response, which are disturbed in autoimmune diseases, are the withdrawal of immunological tolerance to self-antigens (in which cellular and cytokine types of regulation become unbalanced) and genetic type. It analyzed the consequences of dysregulation of cellular, cytokine, genetic, idiotypic-anti-idiotypic, and immune-neuroendocrine types, which cause a breakage of immunological tolerance and the start of autoaggression. Conclusions. The consequences of dysregulation of the immune response, which causes the reversal of immunological tolerance, create the ground on which numerous autoimmune reactions quickly form into an autoimmune syndrome and become autoimmune diseases.

Although current treatments for autoimmune diseases can effectively control symptoms, they rarely lead to cures and often require lifelong use, accompanied by considerable adverse effects. This emphasizes the urgent need for more targeted therapies that offer long-term efficacy and curative potential. Chimeric antigen receptor (CAR) T-cell therapy presents a promising option by specifically targeting and eliminating autoreactive B cells, with the potential to reset the patient’s immune system and promote long-term immune balance. Originally developed for treating hematologic malignancies, where it has achieved remarkable success, recent studies have demonstrated substantial promise of CAR T-cell therapy, such as systemic lupus erythematosus (SLE) and myasthenia gravis. This article provides an overview of the current progress in CAR T-cell therapy for autoimmune diseases, focusing on five key approaches: CD19-targeted CAR T cells, CAR T cells targeting long-lived plasma cells, CAR T cells targeting specific autoantibodies, organ-specific CAR regulatory T cells (Treg cells), and mRNA-engineered CAR T cells. Additionally, this article discusses strategies for optimizing CAR T-cell therapy, including “off-the-shelf” allogeneic CAR T-cell therapy, combined CAR T-cell therapy, establishing timely consensus guidelines for their application in autoimmune diseases, and risk stratification strategies aimed at enhancing the personalization of treatments and minimizing adverse effects. While current research results are promising, further large-scale clinical trials and long-term follow-up are essential to thoroughly evaluate the safety and efficacy of CAR T-cell therapy in autoimmune diseases.