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Primary Sjögren's disease (pSD) (also referred to as Sjögren's syndrome) is an autoimmune disease that primarily occurs in women. In addition to exocrine gland dysfunction, pSD patients exhibit B cell hyperactivity. B cell–intrinsic TLR7 activation is integral to the pathogenesis of systemic lupus erythematosus, a disease that shares similarities with pSD. The role of TLR7-mediated B cell activation in pSD, however, remains poorly understood. We hypothesized that age-associated B cells (ABCs) were expanded in pSD and that TLR7-stimulated ABCs exhibited pathogenic features characteristic of disease. Our data revealed that ABC expansion and TLR7 expression were enhanced in a pSD mouse model in a Myd88-dependent manner. Splenocytes from pSD mice showed enhanced sensitivity to TLR7 agonism as compared with those derived from control animals. Sort-purified marginal zone B cells and ABCs from pSD mice showed enhanced inflammatory cytokine secretion and were enriched for antinuclear autoantibodies following TLR7 agonism. Finally, IgG from pSD patient sera showed elevated antinuclear autoantibodies, many of which were secreted preferentially by TLR7-stimulated murine marginal zone B cells and ABCs. These data indicate that pSD B cells are hyperresponsive to TLR7 agonism and that TLR7-activated B cells contribute to pSD through cytokine and autoantibody production. Thus, therapeutics that target TLR7 signaling cascades in B cells may have utility in pSD patients. [ABSTRACT FROM AUTHOR]

Post-acute cardiac sequelae, following SARS-CoV-2 infection, are well recognized as complications of COVID-19. We have previously shown the persistence of autoantibodies against antigens in skin, muscle, and heart in individuals following severe COVID-19; the most common staining on skin tissue displayed an inter-cellular cement pattern consistent with antibodies against desmosomal proteins. Desmosomes play a critical role in maintaining the structural integrity of tissues. For this reason, we analyzed desmosomal protein levels and the presence of anti-desmoglein (DSG) 1, 2, and 3 antibodies in acute and convalescent sera from patients with COVID-19 of differing clinical severity. We find increased levels of DSG2 protein in sera from acute COVID-19 patients. Furthermore, we find that DSG2 autoantibody levels are increased significantly in convalescent sera following severe COVID-19 but not in hospitalized patients recovering from influenza infection or healthy controls. Levels of autoantibody in sera from patients with severe COVID-19 were comparable to levels in patients with non-COVID-19-associated cardiac disease, potentially identifying DSG2 autoantibodies as a novel biomarker for cardiac damage. To determine if there was any association between severe COVID-19 and DSG2, we stained post-mortem cardiac tissue from patients who died from COVID-19 infection. This confirmed DSG2 protein within the intercalated discs and disruption of the intercalated disc between cardiomyocytes in patients who died from COVID-19. Our results reveal the potential for DSG2 protein and autoimmunity to DSG2 to contribute to unexpected pathologies associated with COVID-19 infection. We find raised levels of anti-DSG2 autoantibodies in sera from individuals following severe COVID-19. Staining of post-mortem cardiac tissue from individuals that died from COVID-19 with an anti-DSG2 antibody revealed disruption of the intercalated disc between cardiomyocytes that was consistent with separation of the DSG2 protein homodimer. Our results reveal the potential for DSG2 protein and autoimmunity to DSG2 to contribute to unexpected pathologies associated with COVID-19 infection. [ABSTRACT FROM AUTHOR]

The HLA region is the major genetic risk determinant of Type 1 diabetes. How non-HLA loci contribute to the genetic risk is incompletely understood, but there are indications that at least some impact progression of asymptomatic autoimmunity. We examined whether SNPs in 7 susceptibility loci (INS , SH2B3 , PTPN2 , PTPN22 , CTLA4 , CLEC16A, and IL2RA) could improve prediction of the progression from single to multiple autoantibody positivity, and from there on to diagnosis. SNPs were genotyped in persistently autoantibody positive relatives by allelic discrimination qPCR and disease progression was studied by multivariate Cox regression analysis. In our cohort, only the CTLA4 GA genotype (rs3087243, P = 0.002) and the CLEC16A AA genotype (rs12708716, P = 0.021) were associated with accelerated progression from single to multiple autoantibody positivity, but their effects were restricted to presence of HLA-DQ2/DQ8, and IAA as first autoantibody, respectively. The interaction of CTLA4 and HLA-DQ2/DQ8 overruled the effect of DQ2/DQ8 alone. The HLA-DQ2/DQ8-mediated risk of progression to multiple autoantibodies nearly entirely depended on heterozygosity for CTLA4. The SH2B3 TT genotype (rs3184504) was protective for HLA-DQ8 positive subjects (P = 0.003). At the stage of multiple autoantibodies, only the CTLA4 GA genotype was a minor independent risk factor for progression towards clinical diabetes (P = 0.034). Our study shows that non-HLA polymorphisms impact progression of islet autoimmunity in a subgroup-, stage- and SNP-specific way, suggesting distinct mechanisms. If confirmed, these findings may help refine risk assessment, follow-up, and prevention trials in risk groups. [ABSTRACT FROM AUTHOR]

Type 1 diabetes (T1D) is an autoimmune disease resulting in the destruction of the insulin-producing pancreatic beta cells. Disease progression occurs along a trajectory from genetic risk, the development of islet autoantibodies, and autoreactive T cells ultimately progressing to clinical disease. Natural history studies and mechanistic studies linked to clinical trials have provided insight into the role of the immune system in disease pathogenesis. Here, we review our current understanding of the underlying etiology of T1D, focusing on the immune cell types that have been implicated in progression from pre-symptomatic T1D to clinical diagnosis and established disease. This knowledge has been foundational for the development of immunotherapies aimed at the prevention and treatment of T1D. This review summarizes the current understanding of the underlying immunopathology of T1D, focusing on the immune cell types implicated in progression from pre-symptomatic T1D to clinical diagnosis and established disease. It also highlights how this knowledge is driving the development of immunotherapies aimed at the prevention and treatment of T1D. [ABSTRACT FROM AUTHOR]

The clinical usefulness of post-diagnosis islet autoantibody levels is unclear and factors that drive autoantibody persistence are poorly defined in type 1 diabetes (T1D). Our aim was to characterise the longitudinal loss of islet autoantibody responses after diagnosis in a large, prospectively sampled UK cohort. Participants with T1D [n = 577] providing a diagnosis sample [range −1.0 to 2.0 years] and at least one post-diagnosis sample (<32.0 years) were tested for autoantibodies to glutamate decarboxylase 65 (GADA), islet antigen-2 (IA-2A), and zinc transporter 8 (ZnT8A). Select HLA and non-HLA SNPs were considered. Non-genetic and genetic factors were assessed by multivariable logistic regression models for autoantibody positivity at initial sampling and autoantibody loss at final sampling. For GADA, IA-2A, and ZnT8A, 70.8%, 76.8%, and 40.1%, respectively, remained positive at the final sampling. Non-genetic predictors of autoantibody loss were low baseline autoantibody titres (P < 0.0001), longer diabetes duration (P < 0.0001), and age-at-onset under 8 years (P < 0.01–-0.05). Adjusting for non-genetic covariates, GADA loss was associated with low-risk HLA class II genotypes (P = 0.005), and SNPs associated with autoimmunity RELA/11q13 (P = 0.017), LPP/3q28 (P = 0.004), and negatively with IFIH1/2q24 (P = 0.018). IA-2A loss was not associated with genetic factors independent of other covariates, while ZnT8A loss was associated with the presence of HLA A*24 (P = 0.019) and weakly negatively with RELA/11q13 (P = 0.049). The largest longitudinal study of islet autoantibody responses from diagnosis of T1D shows that autoantibody loss is heterogeneous and influenced by low titres at onset, longer duration, earlier age-at-onset, and genetic variants. These data may inform clinical trials where post-diagnosis participants are recruited. Loss of islet autoantibodies after diabetes onset is heterogeneous but influenced by non-genetic and genetic factors. [ABSTRACT FROM AUTHOR]

Background: Autoimmune endocrine diseases can be thought of as a case of mistaken identity. The immune system mistakenly attacks one's own cells, as if they were foreign, which typically results in endocrine gland hypofunction and inadequate hormone production. Type 1 diabetes mellitus and autoimmune thyroid disorders (Hashimoto and Graves diseases) are the most common autoimmune endocrine disorders, while conditions such as Addison disease are encountered less frequently. Autoantibody production can precede clinical presentation, and their measurement may aid verification of an autoimmune process and guide appropriate treatment modalities. Content: In this review, we discuss type 1 diabetes mellitus, autoimmune thyroid disorders, and Addison disease, emphasizing their associated autoantibodies and methods for clinical detection. We will also discuss efforts to standardize measurement of autoantibodies. Conclusions: Autoimmune endocrine disease progression may take months to years and detection of associated autoantibodies may precede clinical onset of disease. Although detection of autoantibodies is not necessary for diagnosis, they may be useful to verify an autoimmune process. [ABSTRACT FROM AUTHOR]

Background: Autoantibodies that bind self-antigens are a hallmark of autoimmune diseases, but can also be present in healthy individuals. Clinical assays that detect and titer antigen-specific autoantibodies are an important component of the diagnosis and monitoring of autoimmune diseases. Autoantibodies may contribute to disease pathogenesis via effector functions that are dictated by both the antigen-binding site and constant domain. Content: In this review, we discuss features of antibodies, in addition to antigen-binding specificity, which determine effector function. These features include class, subclass, allotype, and glycosylation. We discuss emerging data indicating that analysis of these antibody features may be informative for diagnosis and monitoring of autoimmune diseases. We also consider methodologies to interrogate these features and consider how they could be implemented in the clinical laboratory. Summary: Future autoantibody assays may incorporate assessment of additional antibody features that contribute to autoimmune disease pathogenesis and provide added clinical value. [ABSTRACT FROM AUTHOR]

The major histocompatibility complex (MHC) is a central molecule in the immune system. The MHC is also a highly polymorphic gene that is the most strongly involved in susceptibility to many autoimmune diseases. Therefore, the elucidation of the mechanism by which specific MHC alleles are involved in autoimmune disease susceptibility is important to our understanding of the pathogenesis of autoimmune diseases. Specific autoantibody production is observed in many autoimmune diseases, but the mechanism underlying their production remains unclear. We have found that MHC class II molecules exhibit a chaperone-like function to transport misfolded proteins in the endoplasmic reticulum to the outside of cells. Furthermore, misfolded proteins transported to the cell surface by MHC class II molecules of autoimmune disease risk alleles are major autoantibody targets. In this article, I propose a novel mechanism underlying autoimmune diseases mediated by misfolded proteins complexed with MHC class II molecules. [ABSTRACT FROM AUTHOR]

Context: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a severe chronic illness that reduces the quality of life. A potential role of neuroendocrine autoimmune dysfunction has been hypothesized.Objective: This work aims to investigate the occurrence of antipituitary (APA) and antihypothalamic (AHA) antibodies and possible related hypothalamic/pituitary dysfunctions in ME/CSF patients.Methods: This is a case-control study conducted in a university hospital setting (Stanford, California, USA; and Naples, Italy). Thirty women with ME/CSF (group 1) diagnosed according to Fukuda, Canadian, and Institute of Medicine criteria, at Stanford University, were enrolled and compared with 25 age-matched healthy controls. APA and AHA were detected by immunofluorescence; moreover, we investigated hormonal secretions of anterior pituitary and respective target glands. APA and AHA titers both were assessed and the prevalence of pituitary hormone deficiencies was also investigated.Results: Patients in group 1 showed a high prevalence of AHA (33%) and APA (56%) and significantly lower levels of adrenocorticotropin (ACTH)/cortisol, and growth hormone (GH) peak/insulin-like growth factor-1 (IGF-1) vs controls (all AHA/APA negative). Patients in group 1A (13 patients positive at high titers, ≥ 1:32) showed ACTH/cortisol and GH peak/IGF-1 levels significantly lower and more severe forms of ME/CFS with respect to patients in group 1B (7 positive at middle/low titers, 1:16-1:8) and 1C (10 antibody-negative patients).Conclusion: Both AHA and/or APA at high titers were associated with hypothalamic/pituitary dysfunction, suggesting that hypothalamic/pituitary autoimmunity may play an important role in the manifestations of ME/CFS, especially in its more severe forms. [ABSTRACT FROM AUTHOR]