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Psoriasis is a chronic inflammatory skin disease, which affects 2–4% of the population worldwide. T-cell derived factors such as Th17 and Th1 cytokines or cytokines such as IL-23, which favors Th17-expansion/differentiation, dominate in the disease. Therapies targeting these factors have been developed over the years. An autoimmune component is present, as autoreactive T-cells specific for keratins, the antimicrobial peptide LL37 and ADAMTSL5 have been described. Both autoreactive CD4 and CD8 T-cells exist, produce pathogenic cytokines, and correlate with disease activity. Along with the assumption that psoriasis is a T-cell-driven disease, Tregs have been studied extensively over the years, both in the skin and in circulation. This narrative review resumes the main findings about Tregs in psoriasis. We discuss how Tregs increase in psoriasis but are impaired in their regulatory/suppressive function. We debate the possibility that Tregs convert into T-effector cells under inflammatory conditions; for instance, they may turn into Th17-cells. We put particular emphasis on therapies that seem to counteract this conversion. We have enriched this review with an experimental section analyzing T-cells specific for the autoantigen LL37 in a healthy subject, suggesting that a shared specificity may exist between Tregs and autoreactive responder T-cells. This suggests that successful psoriasis treatments may, among other effects, restore Tregs numbers and functions.

The pathogenesis of chronic spontaneous urticaria (CSU) is still insufficiently understood. Recent findings suggest that immunoglobulins, in particular IgE but also IgA, play a role in the development of CSU. Our aim was to assess differences in clinical and laboratory markers between CSU patients with and without lower levels of serum IgA and IgE. We analyzed the data of 606 patients with CSU by dividing them into four groups based on their IgA and IgE levels. The groups were compared for their spectrum of symptoms, disease activity, concomitant autoimmunity and routine laboratory markers. Autoreactivity was assessed by basophil activation test (BAT). Moreover, IgE-anti-thyroid peroxidase (TPO) was measured. Of the patients with lower IgE levels, 66.5% also had lower IgA levels (r=0.316, p<0.001). Patients with lower IgA and lower IgE levels showed a higher prevalence of recurrent angioedema (p=0.03, p=0.04) and concomitant autoimmunity (p=0.006, p<0.001). Autoreactivity was also found more frequently in patients with lower IgA and lower IgE levels (p=0.003, p<0.001). Reduced basophil counts were linked to both, lower IgA and lower IgE levels (p<0.001), whereas low eosinophil counts were primarily present in patients with lower IgE levels (p=0.04, p<0.001). Patients with elevated IgE-anti-TPO levels had lower IgA (p=0.007) and IgE levels (p=0.001). Lower IgA levels in CSU are linked to lower IgE levels and features of autoimmune urticaria. Our findings encourage to screen CSU patients for serum IgA and IgE levels and to further assess their role as disease biomarkers.

Antibodies are theoretically limitless in their diversity and specificity to foreign antigens; however they are constrained by the need to avoid binding to self. Germinal centers (GC) allow diversification and maturation of the antibody response towards the foreign antigen. While self-tolerance mechanisms controlling self-reactivity during B cell maturation are well recognized, the mechanisms by which GCs balance self-tolerance and foreign binding especially in the face of cross-reactivity between self and foreign, remain much less well defined. In this review we explore the extent to which GC self-tolerance restricts affinity maturation. We present studies suggesting that the outcome is situationally dependent, affected by affinity and avidity to self-antigen, and the extent to which self-binding and foreign-binding are interdependent. While auto-reactive GC B cells can mutate away from self while maturing towards the foreign antigen, if no mutational trajectories allow for self-reactive redemption, self-tolerance prevails and GC responses to the foreign pathogen are restricted, except when self-tolerance checkpoints are relaxed. Finally, we consider whether polyreactivity is subject to the same level of restriction in GC responses, especially if polyreactivity is linked to an increase in foreign protection, as occurs in certain broadly neutralizing antibodies. Overall, the outcomes for GC B cells that bind self-antigen can range from redemption, transient relaxation in self-tolerance or restriction of the antibody response to the foreign pathogen.

Atopic dermatitis (AD), one of the most frequent inflammatory skin diseases worldwide, is believed to result from a disturbed skin barrier as well as aberrant immune reactions against harmless allergens. Starting mostly during childhood with a chronic, remitting relapsing course, the disease can persist into adulthood in about one fifth of patients. Immune reactions to self-proteins have been observed in AD patients already in the beginning of the Twentieth century, when human cellular extracts were shown to provoke skin lesions. However, the term \"autoimmunity\" has never been claimed, since AD is first and foremost an atopic disease. In contrast, this IgE-hallmarked autoreactivity was termed \"autoallergy\" and is ongoing discussed regarding its impact on the disease. Since severely affected patients tend to develop IgE-hypersensitivity reactions to numerous environmental allergens, the impact of immune responses to self-proteins is difficult to determine. On the other hand: any autoreactivity, irrespective of the magnitude, implicates the potential of driving the chronification of the disease while shaping the immune response. This review article revisits the observations made on autoallergy from an actual point of view and tries to approach the question whether these still point to a contribution to the disease.

Autologous hematopoietic stem cell transplantation (AHSCT) increases C-peptide levels and induces insulin independence in patients with type 1 diabetes. This study aimed to investigate how clinical outcomes may associate with the immunological status, especially concerning the balance between immunoregulation and autoreactivity. Twenty-one type 1 diabetes patients were monitored after AHSCT and assessed every 6 months for duration of insulin independence, C-peptide levels, frequencies of islet-specific autoreactive CD8 T cells (CTL), regulatory lymphocyte subsets, thymic function, and T-cell repertoire diversity. In median follow-up of 78 (range 15-106) months, all patients became insulin-independent, resuming insulin after median of 43 (range 6-100) months. Patients were retrospectively divided into short- or prolonged-remission groups, according to duration of insulin independence. For the entire follow-up, CD3 CD4 T-cell numbers remained lower than baseline in both groups, whereas CD3 CD8 T-cell levels did not change, resulting in a CD4/CD8 ratio inversion. Memory CTL comprehended most of T cells detected on long-term follow-up of patients after AHSCT. B cells reconstituted to baseline levels at 2-3 months post-AHSCT in both patient groups. In the prolonged-remission-group, baseline islet-specific T-cell autoreactivity persisted after transplantation, but regulatory T cell counts increased. Patients with lower frequencies of autoreactive islet-specific T cells remained insulin-free longer and presented greater C-peptide levels than those with lower frequencies of these cells. Therefore, immune monitoring identified a subgroup of patients with superior clinical outcome of AHSCT. Our study shows that improved immunoregulation may balance autoreactivity endorsing better metabolic outcomes in patients with lower frequencies of islet-specific T cells. Development of new strategies of AHSCT is necessary to increase frequency and function of T and B regulatory cells and decrease efficiently autoreactive islet-specific T and B memory cells in type 1 diabetes patients undergoing transplantation.

The interaction of some human antibodies with heme results in posttranslational acquisition of binding to various self- and pathogen-derived antigens. The previous studies on this phenomenon were performed with oxidized heme (Fe3+). In the present study, we elucidated the effect of other pathologically relevant species of heme, i.e., species that were formed after contact of heme with oxidizing agents such as hydrogen peroxide, situations in which heme’s iron could acquire higher oxidation states. Our data reveal that hyperoxidized species of heme have a superior capacity to heme (Fe3+) in triggering the autoreactivity of human IgG. Mechanistic studies demonstrated that oxidation status of iron was of critical importance for the heme’s effect on antibodies. We also demonstrated that hyperoxidized heme species interacted at higher affinities with IgG and that this binding occurred through a different mechanism as compared to heme (Fe3+). Regardless of their profound functional impact on the antigen-binding properties of antibodies, hyperoxidized species of heme did not affect Fc-mediated functions of IgG, such as binding to the neonatal Fc receptor. The obtained data contribute to a better understanding of the pathophysiological mechanism of hemolytic diseases and of the origin of elevated antibody autoreactivity in patients with some hemolytic disorders.

This study investigated the role of molecular mimicry in the context of autoimmunity associated with viral infection, using SARS-CoV-2 as a model system. A bioinformatic analysis was performed to identify sequence homologies between the SARS-CoV-2 Spike (S) protein and the human proteome, with a specific focus on immunogenic regions to assess potential cross-reactivity. The analysis revealed homologous regions between the viral S protein and several human proteins, including DAAM2, CHL1, HAVR2/TIM3, FSTL1, FHOD3, MYO18A, EMILIN3, LAMP1, and αENaC, which are predicted to be recognizable by B-cell receptors. Such recognition could potentially lead to the production of autoreactive antibodies, which can contribute to the development of autoimmune diseases. Furthermore, the study examined potential autoreactive CD4+ T-cell responses to human protein autoepitopes that could be presented by HLA class II molecules. Several HLA class II genetic variants were computationally associated with a higher likelihood of cross-reactive immune reactions following COVID-19, including HLA-DPA1*01:03/DPB1*02:01, HLA-DPA1*02:01/DPB1*01:01, HLA-DPA1*02:01/DPB1*05:01, HLA-DPA1*02:01/DPB1*14:01, HLA-DQA1*01:02/DQB1*06:02, HLA-DRB1*04:01, HLA-DRB1*04:05, HLA-DRB1*07:01, and HLA-DRB1*15:01. Additionally, seven T helper cell autoepitopes (YSEILDKYFKNFDNG, ERTRFQTLLNELDRS, AERTRFQTLLNELDR, RERKVEAEVQAIQEQ, NAINIGLTVLPPPRT, PQSAVYSTGSNGILL, TIRIGIYIGAGICAG) were identified that could be implicated in autoimmune T-cell responses through presentation by class II HLA molecules. These findings highlight the utility of viral B- and T-cell epitope prediction for investigating molecular mimicry as a possible mechanism in virus-associated autoimmunity.

In contrast to the previous belief that autoreactive B cells are eliminated from the normal repertoire of B cells, many autoreactive B cells actually escape clonal deletion and develop into mature B cells. These autoreactive B cells in healthy individuals perform some beneficial functions in the host and are homeostatically regulated by regulatory T and B cells or other mechanisms to prevent autoimmune diseases. Autoreactive B-1 cells constitutively produce polyreactive natural antibodies for tissue homeostasis. Recently, autoreactive follicular B cells were reported to participate actively in the germinal center reaction. Furthermore, the selection and usefulness of autoreactive marginal zone (MZ) B cells found in autoimmune diseases are not well understood, although the repertoire of MZ B-cell receptors (BCRs) is presumed to be biased to detect bacterial antigens. In this review, we discuss the autoreactive B-cell populations among all three major B-cell subsets and their regulation in immune responses and diseases.

Introduction: Cross-reactivity to SARS-CoV-2 antigenic peptides has been detected on T-cells from pre-pandemic donors due to recognition of conserved protein fragments within members of the coronavirus's family. Further, preexisting antibodies recognizing SARS-CoV-2 with conserved epitopes in the spike region have been now seen in uninfected individuals. High-dose Intravenous Immunoglobulin (IVIg), derived from thousands of healthy donors, contains natural IgG antibodies against various antigens which can be detected both within the IVIg preparations and in the serum of IVIg-receiving patients. Whether IVIg preparations from pre-pandemic donors also contain antibodies against pre-pandemic coronaviruses or autoreactive antibodies that cross-react with SARS-CoV-2 antigenic epitopes, is unknown. Methods: 13 samples from 5 commercial IVIg preparations from pre-pandemic donors (HyQvia (Baxalta Innovations GmbH); Privigen (CSL Behring); Intratect (Biotest AG); IgVena (Kedrion S.p.A); and Flebogamma (Grifols S.A.) were blindly screened using a semi-quantitative FDA-approved and validated enzyme-linked immunosorbent assay (ELISA) (Euroimmun, Lubeck, Germany). Results: Nine of thirteen preparations (69.2%), all from two different manufactures, were antibody-positive based on the defined cut-off positivity (index of sample OD to calibrator OD > 1.1). From one manufacturer, 7/7 lots (100%) and from another 2/3 lots (67%), tested positive for cross-reacting antibodies. 7/9 of the positive preparations (77%) had titers as seen in asymptomatically infected individuals or recent COVID19-recovered patients, while 2/9 (23%) had higher titers, comparable to those seen in patients with active symptomatic COVID-19 infection (index > 2.2). Conclusion: Pre-pandemic IVIg donors have either natural autoantibodies or pre-pandemic cross-reactive antibodies against antigenic protein fragments conserved among the “common cold” - related coronaviruses. The findings are important in: (a) assessing true anti-SARS-CoV-2-IgG seroprevalence avoiding false positivity in IVIg-receiving patients; (b) exploring potential protective benefits in patients with immune-mediated conditions and immunodeficiencies receiving acute or chronic maintenance IVIg therapy, and (c) validating data from a recent controlled study that showed significantly lower in-hospital mortality in the IVIg- treated group.

Immunoglobulins (IGs) made by chronic lymphocytic leukemia (CLL) B cells are unique in that they bind themselves (homo-dimerize). This interaction leads to signal transduction with functional consequences that depend on the affinity of homo-dimerization. We have studied the antigen-binding properties of the IGs from a subset of patients with CLL (Subset #4) that homo-dimerize at high affinity. Previously, we had found that subset #4 IGs bound viable lymphocytes. Our new studies, probing an array of >8,000 antigens, indicate that these IGs also bind influenza virus. Because of the IGs high-affinity homo-dimerization, we asked if the defined foreign- and self-antigenic interactions were mediated by conventional B-cell receptor (BCR) domains or a non-conventional receptor created by homo-dimerization. The studies indicated the latter since abrogation of homo-dimerization eliminated binding to influenza virus and its hemagglutinin and to viable lymphocytes. Using these findings, we modeled a developmental path whereby a naive IgM + B cell with subset #4 heavy and light chain variable domains used the conventional BCR to interact with auto- and foreign antigens and acquire homo-dimerization capacity to create the non-conventional antigen-receptor when transitioning to a leukemic cell. Future studies will determine if this process is an idiosyncratic occurrence or a physiologic principle.