COVID-19 shares the feature of autoantibody production with systemic autoimmune diseases. In order to understand the role of these immune globulins in the pathogenesis of the disease, it is important to explore the autoantibody spectra. Here we show, by a cross-sectional study of 246 individuals, that autoantibodies targeting G protein-coupled receptors (GPCR) and RAS-related molecules associate with the clinical severity of COVID-19. Patients with moderate and severe disease are characterized by higher autoantibody levels than healthy controls and those with mild COVID-19 disease. Among the anti-GPCR autoantibodies, machine learning classification identifies the chemokine receptor CXCR3 and the RAS-related molecule AGTR1 as targets for antibodies with the strongest association to disease severity. Besides antibody levels, autoantibody network signatures are also changing in patients with intermediate or high disease severity. Although our current and previous studies identify anti-GPCR antibodies as natural components of human biology, their production is deregulated in COVID-19 and their level and pattern alterations might predict COVID-19 disease severity.

Regulatory T cells (Treg) are crucial for the maintenance of peripheral tolerance and for the control of ongoing inflammation and autoimmunity. The cytokine interleukin-2 (IL-2) is essentially required for the growth and survival of Treg in the peripheral lymphatic tissues and thus plays a vital role in the biology of Treg. Most autoimmune and rheumatic diseases exhibit disturbances in Treg biology either at a numerical or functional level resulting in an imbalance between protective and pathogenic immune cells. In addition, in some autoimmune diseases, a relative deficiency of IL-2 develops during disease pathogenesis leading to a disturbance of Treg homeostasis, which further amplifies the vicious cycle of tolerance breach and chronic inflammation. Low-dose IL-2 therapy aims either to compensate for this IL-2 deficiency to restore a physiological state or to strengthen the Treg population in order to be more effective in counter-regulating inflammation while avoiding global immunosuppression. Here we highlight key findings and summarize recent advances in the clinical translation of low-dose IL-2 therapy for the treatment of autoimmune and rheumatic diseases.

Systemic sclerosis (SSc) is a rare connective tissue disorder characterized by immune dysregulation evoking the pathophysiological triad of inflammation, fibrosis and vasculopathy. In SSc, several alterations in the B-cell compartment have been described, leading to polyclonal B-cell hyperreactivity, hypergammaglobulinemia and autoantibody production. Autoreactive B cells and autoantibodies promote and maintain pathologic mechanisms. In addition, autoantibodies in SSc are important biomarkers for predicting clinical phenotype and disease progression. Autoreactive B cells and autoantibodies represent potentially promising targets for therapeutic approaches including B-cell-targeting therapies, as well as strategies for unselective and selective removal of autoantibodies. In this review, we present mechanisms of the innate immune system leading to the generation of autoantibodies, alterations of the B-cell compartment in SSc, autoantibodies as biomarkers and autoantibody-mediated pathologies in SSc as well as potential therapeutic approaches to target these.

An estimated 20–25% of the population is affected by chronic, non-communicable inflammatory skin diseases. Chronic skin inflammation has many causes. Among the most frequent chronic inflammatory skin diseases are atopic dermatitis, psoriasis, urticaria, lichen planus, and hidradenitis suppurativa, driven by a complex interplay of genetics and environmental factors. Autoimmunity is another important cause of chronic skin inflammation. The autoimmune response may be mainly T cell driven, such as in alopecia areata or vitiligo, or B cell driven in chronic spontaneous urticaria, pemphigus and pemphigoid diseases. Rare causes of chronic skin inflammation are autoinflammatory diseases, or rheumatic diseases, such as cutaneous lupus erythematosus or dermatomyositis. Whilst we have seen a significant improvement in diagnosis and treatment, several challenges remain. Especially for rarer causes of chronic skin inflammation, early diagnosis is often missed because of low awareness and lack of diagnostics. Systemic immunosuppression is the treatment of choice for almost all of these diseases. Adverse events due to immunosuppression, insufficient therapeutic responses and relapses remain a challenge. For atopic dermatitis and psoriasis, a broad spectrum of innovative treatments has been developed. However, treatment responses cannot be predicted so far. Hence, development of (bio)markers allowing selection of specific medications for individual patients is needed. Given the encouraging developments during the past years, we envision that many of these challenges in the diagnosis and treatment of chronic inflammatory skin diseases will be thoroughly addressed in the future.

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The coronavirus disease 2019 (COVID-19) can evolve to clinical manifestations resembling systemic autoimmune diseases, with the presence of autoantibodies that are still poorly characterized. To address this issue, we performed a cross-sectional study of 246 individuals to determine whether autoantibodies targeting G protein-coupled receptors (GPCRs) and renin-angiotensin system (RAS)-related molecules were associated with COVID-19-related clinical outcomes. Moderate and severe patients exhibited the highest autoantibody levels, relative to both healthy controls and patients with mild COVID-19 symptoms. Random Forest, a machine learning model, ranked anti-GPCR autoantibodies targeting downstream molecules in the RAS signaling pathway such as the angiotensin II type 1 and Mas receptor, and the chemokine receptor CXCR3 as the three strongest predictors of severe disease. Moreover, while the autoantibody network signatures were relatively conserved in patients with mild COVID-19 compared to healthy controls, they were disrupted in moderate and most perturbed in severe patients. Our data indicate that the relationship between autoantibodies targeting GPCRs and RAS-related molecules associates with the clinical severity of COVID-19, suggesting novel molecular pathways for therapeutic interventions.

ObjectiveTo determine contributions and functions of autoantibodies (Abs) directed to the angiotensin receptor type 1 (AT1R), which are suggested to be involved in the pathogenesis of AT1R Abs-related diseases such as systemic sclerosis (SSc).MethodsC57BL/6J mice were immunised with membrane-embedded human AT1R or empty membrane as control. Mice deficient for CD4+ or CD8+ T cells and B cells were immunised with membrane-embedded AT1R or an AT1R peptide proposed to be a dominant T cell epitope. A monoclonal (m)AT1R Ab was generated by hybridoma technique and transferred into C57BL/6J and AT1Ra/b knockout mice. The induced phenotype was examined by histology, immunohistochemistry, immunofluorescence, apoptosis assay and ELISA. In vitro, Abs responses towards AT1R were measured in cells of different origins and species.ResultsAT1R-immunised mice developed perivascular skin and lung inflammation, lymphocytic alveolitis, weak lung endothelial apoptosis and skin fibrosis accompanied by Smad2/3 signalling, not present in controls or mice deficient for CD4+ T and B cells. The AT1R peptide 149–172 provoked lung inflammation. Application of the mAT1R Ab induced skin and lung inflammation, not observed in AT1Ra/b knockout mice. In vitro, AT1R Abs activated rat cardiomyocytes and human monocytes, enhanced angiotensin II-mediated AT1R activation in AT1R-transfected HEK293 cells via AT1R binding and mAT1R Ab-activated monocytes mediated the induction of profibrotic markers in dermal fibroblasts.ConclusionOur immunisation strategy successfully induced AT1R Abs, contributing to inflammation and, possibly, to fibrosis via activation of AT1R. Therefore, AT1R Abs are valuable targets for future therapies of SSc and other AT1R Ab-related diseases.

Immune perturbation is a hallmark of Coronavirus Disease 2019 (COVID-19) with ambiguous roles of various immune cell compartments. Plasma cells, responsible for antibody production, have a two-pronged response while mounting an immune defence with 1) physiological immune response producing neutralizing antibodies against protein structures of SARS-CoV-2 and 2) potentially deleterious autoantibody generation. Growing evidence hints towards broad activation of plasma cells and the presence of pathologic autoantibodies (abs) that mediate immune perturbation in acute COVID-19 [1]. Recently, a systematic screening for abs confirmed induction of diverse functional abs in SARS-CoV-2 infection, targeting several immunomodulatory proteins, including cytokines/chemokines and their respective G-protein coupled receptors (GPCR) [1]. Abs against GPCR act as agonistic and allosteric receptor modulators and are linked to chronic inflammatory diseases [2] and, as we recently demonstrated, disease severity in acute COVID-19 [3].