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The thymus prevents autoimmune diseases through mechanisms that operate in the cortex and medulla, comprising positive and negative selection and the generation of regulatory T-cells (Tregs). Egress from the thymus through the perivascular space (PVS) to the blood is another possible checkpoint, as shown by some autoimmune/immunodeficiency syndromes. In polygenic autoimmune diseases, subtle thymic dysfunctions may compound genetic, hormonal and environmental cues. Here, we cover (a) tolerance-inducing cell types, whether thymic epithelial or tuft cells, or dendritic, B- or thymic myoid cells; (b) tolerance-inducing mechanisms and their failure in relation to thymic anatomic compartments, and with special emphasis on human monogenic and polygenic autoimmune diseases and the related thymic pathologies, if known; (c) polymorphisms and mutations of tolerance-related genes with an impact on positive selection (e.g. the gene encoding the thymoproteasome-specific subunit, PSMB11), promiscuous gene expression (e.g. AIRE, PRKDC, FEZF2, CHD4), Treg development (e.g. SATB1, FOXP3), T-cell migration (e.g. TAGAP) and egress from the thymus (e.g. MTS1, CORO1A); (d) myasthenia gravis as the prototypic outcome of an inflamed or disordered neoplastic ‘sick thymus’.

The autoimmune regulator (AIRE) gene influences thymic self-tolerance induction. In autoimmune polyendocrinopathy syndrome type 1 (APS1; OMIM 240300), recessive AIRE mutations lead to autoimmunity targetting endocrine and other epithelial tissues, although chronic candidiasis usually appears first. Autoimmunity and chronic candidiasis can associate with thymomas as well. Patients with these tumours frequently also have high titre immunoglobulin G autoantibodies neutralising type I interferon (IFN)-alpha and IFN-omega, which are secreted signalling proteins of the cytokine superfamily involved in both innate and adaptive immunity. We tested for serum autoantibodies to type I IFNs and other immunoregulatory cytokines using specific binding and neutralisation assays. Unexpectedly, in 60/60 Finnish and 16/16 Norwegian APS1 patients with both AIRE alleles mutated, we found high titre neutralising immunoglobulin G autoantibodies to most IFN-alpha subtypes and especially IFN-omega (60% homologous to IFN-alpha)-mostly in the earliest samples. We found lower titres against IFN-beta (30% homologous to IFN-alpha) in 23% of patients; two-thirds of these (from Finland only) also had low titres against the distantly related \"type III IFN\" (IFN-lambda1; alias interleukin-29). However, autoantibodies to the unrelated type II IFN, IFN-gamma, and other immunoregulatory cytokines, such as interleukin-10 and interleukin-12, were much rarer and did not neutralise. Neutralising titres against type I IFNs averaged even higher in patients with APS1 than in patients with thymomas. Anti-type I IFN autoantibodies preceded overt candidiasis (and several of the autoimmune disorders) in the informative patients, and persisted for decades thereafter. They were undetectable in unaffected heterozygous relatives of APS1 probands (except for low titres against IFN-lambda1), in APS2 patients, and in isolated cases of the endocrine diseases most typical of APS1, so they appear to be APS1-specific. Looking for potentially autoimmunising cell types, we found numerous IFN-alpha(+) antigen-presenting cells-plus strong evidence of local IFN secretion-in the normal thymic medulla (where AIRE expression is strongest), and also in normal germinal centres, where it could perpetuate these autoantibody responses once initiated. IFN-alpha2 and IFN-alpha8 transcripts were also more abundant in antigen-presenting cells cultured from an APS1 patient's blood than from age-matched healthy controls. These apparently spontaneous autoantibody responses to IFNs, particularly IFN-alpha and IFN-omega, segregate like a recessive trait; their high \"penetrance\" is especially remarkable for such a variable condition. Their apparent restriction to APS1 patients implies practical value in the clinic, e.g., in diagnosing unusual or prodromal AIRE-mutant patients with only single components of APS1, and possibly in prognosis if they prove to predict its onset. These autoantibody responses also raise numerous questions, e.g., about the rarity of other infections in APS1. Moreover, there must also be clues to autoimmunising mechanisms/cell types in the hierarchy of preferences for IFN-omega, IFN-alpha8, IFN-alpha2, and IFN-beta and IFN-lambda1.

Proteasome inhibitors can eliminate malignant, alloreactive, or autoreactive plasma cells. These cells are key players in antibody-mediated autoimmune disorders and thus suitable therapeutic targets for these drugs. However, certain proteasome inhibitors cause toxic peripheral neuropathy in patients. Ixazomib (MLN9708, Ninlaro), an oral proteasome inhibitor, has a more favorable safety profile in multiple myeloma patients. Here we tested its efficacy in preventing and treating experimental autoimmune myasthenia gravis (EAMG). Female Lewis rats were treated with two subcutaneous doses of 0.35 mg/kg of ixazomib per week, starting either 4 weeks before or at disease onset; both substantially lowered final total IgG and rat acetylcholine receptor (AChR) autoantibody levels. Interestingly, two weekly doses of 0.20 mg/kg of ixazomib for the last 4 weeks did not reduce autoantibody levels. A single dose of 0.50 mg/kg was acutely toxic in rats. In cultures of thymic cells from early-onset myasthenia gravis (EOMG) patients, 30 nM ixazomib or higher almost completely eliminated plasma cells and halted their IgG and AChR antibody production. We conclude that proteasome inhibition with ixazomib effectively depletes plasma cells from MG patients in vitro and in a rat model in vivo . These results encourage further investigations into therapeutic plasma cell targeting for MG patients.

Trigger for autoimmunity The human thymus is tasked to teach T-cells which antigens are foreign and which are 'self', a process that appears to go wrong in autoimmune disorders. A study of the variation in the promoter of one gene expressed in the thymus shows that a single nucleotide change can disrupt gene regulation, and increase susceptibility to autoimmune disease. The gene, CHRNA1 , encodes a subunit of the muscle acetylcholine receptor, a target for autoantibodies in the neuromuscular disease autoimmune myasthenia gravis. The human thymus is given the difficult task of teaching T-cells which antigens are 'foreign' and which are 'self', a process which seems to go wrong in autoimmune disorders. A study of variation in the promoter of one gene expressed in thymus shows that one nucleotide change can disrupt gene regulation, and might lead to increased risk for autoimmune disease. Promiscuous expression of tissue-restricted auto-antigens in the thymus imposes T-cell tolerance and provides protection from autoimmune diseases 1 , 2 , 3 . Promiscuous expression of a set of self-antigens occurs in medullary thymic epithelial cells 4 , 5 and is partly controlled by the autoimmune regulator (AIRE), a nuclear protein for which loss-of-function mutations cause the type 1 autoimmune polyendocrine syndrome 6 , 7 . However, additional factors must be involved in the regulation of this promiscuous expression. Here we describe a mechanism controlling thymic transcription of a prototypic tissue-restricted human auto-antigen gene, CHRNA1 . This gene encodes the α-subunit of the muscle acetylcholine receptor, which is the main target of pathogenic auto-antibodies in autoimmune myasthenia gravis 8 , 9 . On re-sequencing the CHRNA1 gene, we identified a functional bi-allelic variant in the promoter that is associated with early onset of disease in two independent human populations (France and United Kingdom). We show that this variant prevents binding of interferon regulatory factor 8 (IRF8) and abrogates CHRNA1 promoter activity in thymic epithelial cells in vitro . Notably, both the CHRNA1 promoter variant and AIRE modulate CHRNA1 messenger RNA levels in human medullary thymic epithelial cells ex vivo and also in a transactivation assay. These findings reveal a critical function of AIRE and the interferon signalling pathway in regulating quantitative expression of this auto-antigen in the thymus, suggesting that together they set the threshold for self-tolerance versus autoimmunity.

Dendritic cells (DC) are crucial for the induction of immune responses and thus an inviting target for modulation by pathogens. We have previously shown that Plasmodium falciparum-infected erythrocytes inhibit the maturation of DCs. Intact P. falciparum-infected erythrocytes can bind directly to CD36 and indirectly to CD51. It is striking that these receptors, at least in part, also mediate the phagocytosis of apoptotic cells. Here we show that antibodies against CD36 or CD51, as well as exposure to early apoptotic cells, profoundly modulate DC maturation and function in response to inflammatory signals. Although modulated DCs still secrete tumor necrosis factor-α, they fail to activate T cells and now secrete IL-10. We therefore propose that intact P. falciparum-infected erythrocytes and apoptotic cells engage similar pathways regulating DC function. These findings may have important consequences for the treatment of malaria and may suggest strategies for modulating pathological immune responses in autoimmune diseases.

The malaria parasite Plasmodium falciparum is one of the most successful human pathogens. Specific virulence factors remain poorly defined, although the adhesion of infected erythrocytes tothe venular endothelium has been associated with some of thesyndromes of severe disease 1 . Immune responses cannot prevent the development of symptomatic infections throughout life, and clinical immunity to the disease develops only slowly during childhood. An understanding of the obstacles to the development of protective immunity is crucial for developing rational approaches to prevent the disease. Here we show that intact malaria-infected erythrocytes adhere to dendritic cells, inhibit the maturation of dendritic cells and subsequently reduce their capacity to stimulate T cells. These data demonstrate both a novel mechanism by which malaria parasites induce immune dysregulation and a functional role beyond endothelial adhesion for the adhesive phenotypes expressed at the surface of infected erythrocytes.

Introduction Both autoimmune polyendocrinopathy‐candidiasis‐ectodermal dystrophy (APECED) and the rare thymoma patients with chronic mucocutaneous candidiasis (CMC) have neutralizing autoantibodies to Th17 cytokines and significant defects in production of IL‐22 and IL‐17F by their T cells. The cause of these defects is unknown. We hypothesized that they might result from autoimmunity against upstream cytokines normally responsible for generating and maintaining Th17 cells. Methods Luciferase immunoprecipitation (LIPS) was used to screen for autoantibodies to IL‐6, IL‐1β, TGF‐β3, IL‐21, and IL‐23 in patients with APECED or thymoma. We used Western blotting to assess the conformation‐dependence of the IL‐6 autoantibodies and flow cytometric analysis of intracellular phospho‐STAT3 induction to assess IL‐6‐neutralizing capacity in IgGs isolated from patient and control sera. We also used Luminex xMAP to measure serum cytokine levels. Results We found autoantibodies binding to conformational epitopes of IL‐6 in 19.5% of 41 patients with APECED and 12.5% of 104 with thymoma—especially in those with long disease durations. The autoantibodies were predominantly of IgG1 subclass and failed to neutralize IL‐6 activity. Notably, serum levels of the IL‐6 and IL‐17A cytokines were higher in anti‐IL‐6 seropositive than—negative APECED patients or healthy controls. We also detected autoantibody binding to IL‐23 in 27.9% of thymoma patients, resulting from cross‐recognition through the p40 subunit it shares with IL‐12. Conclusions IL‐6 and IL‐17A elevation in these seropositive patients suggests that antibody‐binding may protect IL‐6 from degradation and prolong its half‐life in vivo. Autoantibodies to IL‐6 in APECED and thymoma patients are mainly of IgG1 isotype, bind to conformational epitopes, and are not neutralizing. Autoreactivity toward IL‐23 in thymoma patients is explained by crossreactivity with IL‐12 p40 subunit.

Patients with autoimmune polyendocrine syndrome type I (APS I) or acquired thymoma-associated myasthenia gravis (MG) surprisingly share several common features, including defective expression of the transcription factor AIRE and autoantibodies against type I interferons. Here, we have adapted and validated the radioligand-binding assay we recently developed against 35 S-Met-interferon-ω, for rapid and specific screening for autoantibodies against interferons-α2 and -α8. We then investigated their potential for diagnosis and for predicting clinical manifestations in patients with APS I and different subgroups of MG. Autoantibodies against interferons-ω, -α2, and -α8 occurred more often in patients with APS I (100%) and MG with thymoma (73%) than in late-onset MG (39%) and early-onset MG (5%). These autoantibodies showed preferences for interferon-ω in APS I and for the interferon-αs in MG, hinting at thymic aberrations in both groups. The exact profile of type I interferon antibodies may indicate MG subtype and may hint at thymoma recurrence.

Partly because they are vital but vulnerable, neuromuscular receptors/ion channels are frequently the focus of attack in autoimmune diseases. With such well defined targets and patient subgroups, and with such clear antibody-mediated pathogeneses, these diseases offer excellent scope for highly specific diagnostic tests, which already help to point patients towards optimal treatments. This review focuses on the autoantibodies and their detection, and briefly considers prospects for novel therapeutic approaches. These disorders have also proved fertile ground for detailed studies on pathogenic mechanisms. Moreover, it is hoped that the distinct patient subgroups and the characteristic tumor associations therein will hold valuable clues to pathways of autoimmunization.

The weakness in myasthenia gravis (MG) is mediated by autoantibodies against adult muscle acetylcholine receptors (AChR) at the neuromuscular junction; most of these antibodies also bind to fetal AChR, which is present in the thymus. In rare cases, babies of mothers with MG, or even of asymptomatic mothers, develop a severe developmental condition, arthrogryposis multiplex congenita, caused by antibodies that inhibit the ion channel function of the fetal AChR while not affecting the adult AChR. Here we show that these fetal AChR inhibitory antibodies are significantly more common in females sampled after pregnancy than in those who present before pregnancy, suggesting that they may be induced by the fetus. Moreover, we were able to clone high-affinity combinatorial Fab antibodies from thymic cells of two mothers with MG who had babies with arthrogryposis multiplex congenita. These Fabs were highly specific for fetal AChR and did not bind the main immunogenic region that is common to fetal and adult AChR. The Fabs show strong biases to VH3 heavy chains and to a single Vκ1 light chain in one mother. Nevertheless, they each show extensive intraclonal diversification from a highly mutated consensus sequence, consistent with antigen-driven selection in successive steps. Collectively, our results suggest that, in some cases of MG, initial immunization against fetal AChR is followed by diversification and expansion of B cells in the thymus; maternal autoimmunity will result if the immune response spreads to the main immunogenic region and other epitopes common to fetal and adult AChR.