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Women are more likely to develop autoimmune diseases than men. Contribution from microchimerism (Mc) has been proposed, as women naturally acquire Mc from more sources than men because of pregnancy. Women with Rheumatoid Arthritis (RA) who lack RA-associated HLA alleles have been found to harbor Mc with RA-associated HLA alleles in higher amounts than healthy women in prior work. However, an immunological impact of Mc remains to be elucidated. To test the hypothesis that Mc with RA-risk associated HLA alleles can result in the production of RA-associated autoantibodies, when host genetic risk is absent. DBA/2 mice are unable to produce RA-specific anti-citrullinated autoantibodies (ACPAs) after immunization with the enzyme peptidyl arginine deiminase (PAD) in a previously developed model. DBA/2 females were mated with C57BL/6 males humanized to express HLA-DR4, which is associated with RA-risk and production of ACPAs, to evaluate DR4+ fetal Mc contribution. Next, DBA/2 females born of heterozygous DR4+/− mothers were evaluated for DR4+ Mc of maternal or littermate origin. Finally, DBA/2 females from DR4+/− mothers were crossed with DR4+ males, to evaluate the contribution of any Mc source to ACPA production. After PAD immunization, between 20 % and 43 % of DBA/2 females (otherwise unable to produce ACPAs) had detectable ACPAs (CCP2 kit) after exposure to sources of Mc with RA-associated HLA alleles, compared to 0 % of unmated/unexposed DBA/2 females. Further the microchimeric origin of the autoantibodies was confirmed by detecting a C57BL/6-specific immunoglobulin isotype in the DBA/2 response. Our study demonstrates that Mc cells can produce "autoantibodies" and points to a role of Mc in the biology of autoimmune diseases, including RA. • DBA/2 mice "unable" to produce RA-specific autoantibodies in a previously described model, manage to do it when exposed to maternal, littermate and fetal microchimerism from humanized C57BL/6 mice carrying RA susceptibility genes. • The microchimeric origin of the autoantibodies was confirmed by detecting a C57BL/6-specific immunoglobulin isotype in the DBA/2 response. • Our results show that microchimeric cells can produce RA-specific autoantibodies. [ABSTRACT FROM AUTHOR]

To investigate the association between autoimmune diseases (AIDs) and bladder cancer (BC) at the genetic level using Mendelian randomization (MR). Single nucleotide polymorphisms (SNPs) associated with the seven AIDs were extracted from the IEU GWAS database, and the SNPs were quality-controlled using strict screening criteria. The association between AIDs and BC risk was assessed by inverse-variance weighted (IVW), MR-Egger regression and Weighted median method. The heterogeneity of SNPs was evaluated by Cochran Q test. MR-Egger intercept test and MR-PRESSO global test were used to test the horizontal pleiotropy of SNPs. Both sides with potential causal associations were validated using the validation set. Our result showed that genetically predicted RA was significantly associated with an increased risk of BC (IVW OR = 1.214, 95 % CI = 1.062–1.388, P = 0.005). MS nominally increased the risk of BC (IVW OR = 1.095, 95 % CI = 1.005–1.193, P = 0.037), consistent with the results of the MR analysis of the BC validation cohort. However SLE, T1D, UC, CD, and MG were not causally associated with BC risk (P > 0.05). The sensitivity analyses showed that there was no heterogeneity or horizontal pleiotropy in our findings. This study provides evidence of a causal relationship between AIDs and BC risk at the genetic level, confirming a causal relationship between RA and MS in increasing the risk of BC. • This study provides evidence of a causal relationship between autoimmune diseases and bladder cancer risk. • MR can overcome the limitations of traditional epidemiological methods for observational studies. • First genetic study of the relationship between autoimmune diseases and urologic cancers. [ABSTRACT FROM AUTHOR]

CD6 is a glycoprotein expressed on CD4 and CD8 T cells involved in immunoregulation. CD318 has been identified as a CD6 ligand. The role of CD318 in T cell immunity is restricted as it has only been investigated in a few mice autoimmune models but not in human diseases. CD318 expression was thought to be limited to mesenchymal-epithelial cells and, therefore, contribute to CD6-mediated T cell activation in the CD318-expressing tissue rather than through interaction with antigen-presenting cells. Here, we report CD318 expression in a subpopulation of CD318+ myeloid dendritic (mDC), whereas the other peripheral blood populations were CD318 negative. However, CD318 can be induced by activation: a subset of monocytes treated with LPS and IFNγ and in vitro monocyte derived DCs were CD318+. We also showed that recombinant CD318 inhibited T cell function. Strikingly, CD318+ DCs suppressed the proliferation of autoreactive T cells specific for GAD65, a well-known targeted self-antigen in Type 1 Diabetes (T1D). Our study provides new insight into the role of the CD318/CD6 axis in the immunopathogenesis of inflammation, suggesting a novel immunoregulatory role of CD318 in T cell-mediated autoimmune diseases and identifying a potential novel immune checkpoint inhibitor as a target for intervention in T1D which is an unmet therapeutic need. • CD318 is expressed on a subset of human dendritic cells and activated monocytes. • CD318+ dendritic cells suppress autoreactive T cells. • CD318 in normal human pancreatic islets is enhanced by inflammation. [ABSTRACT FROM AUTHOR]

Inflammatory T cells contribute to the pathogenesis of autoimmune diseases such as systemic lupus erythematosus (SLE). Analysis of the T-cell transcriptomics data of two independent SLE patient cohorts by three machine learning models revealed the pseudogene UHRF1P as a novel SLE biomarker. The pseudogene-encoded UHRF1P protein was overexpressed in peripheral blood T cells of SLE patients. The UHRF1P protein lacks the amino-terminus of its parental UHRF1 protein, resulting in missing the proteasome-binding ubiquitin-like (Ubl) domain of UHRF1. T-cell-specific UHRF1P transgenic mice manifested the induction of IL-17A and autoimmune inflammation. Mechanistically, UHFR1P prevented UHRF1-induced Lys48-linked ubiquitination and degradation of MAP4K3 (GLK), which is a kinase known to induce IL-17A. Consistently, IL-17A induction and autoimmune phenotypes of UHRF1P transgenic mice were obliterated by MAP4K3 knockout. Collectively, UHRF1P overexpression in T cells inhibits the E3 ligase function of its parental UHRF1 and induces autoimmune diseases. • Using three machine learning statistical models, the pseudogene UHRF1P was identified as a novel biomarker for human SLE. • T-cell-specific UHRF1P transgenic mice spontaneously developed autoimmune disease. • UHFR1P prevented UHRF1-induced K48-linked ubiquitination and degradation of MAP4K3, which is a kinase known to induce IL-17A. • IL-17A induction and autoimmune phenotypes of UHRF1P transgenic mice were obliterated by MAP4K3 knockout. [ABSTRACT FROM AUTHOR]

Lupus erythematosus (LE) is a heterogeneous, antibody-mediated autoimmune disease. Isolate discoid LE (IDLE) and systematic LE (SLE) are traditionally regarded as the two ends of the spectrum, ranging from skin-limited damage to life-threatening multi-organ involvement. Both belong to LE, but IDLE and SLE differ in appearance of skin lesions, autoantibody panels, pathological changes, treatments, and immunopathogenesis. Is discoid lupus truly a form of LE or is it a completely separate entity? This question has not been fully elucidated. We compared the clinical data of IDLE and SLE from our center, applied multi-omics technology, such as immune repertoire sequencing, high-resolution HLA alleles sequencing and multi-spectrum pathological system to explore cellular and molecular phenotypes in skin and peripheral blood from LE patients. Based on the data from 136 LE patients from 8 hospitals in China, we observed higher damage scores and fewer LE specific autoantibodies in IDLE than SLE patients, more uCDR3 sharing between PBMCs and skin lesion from SLE than IDLE patients, elevated diversity of V-J recombination in IDLE skin lesion and SLE PBMCs, increased SHM frequency and class switch ratio in IDLE skin lesion, decreased SHM frequency but increased class switch ratio in SLE PBMCs, HLA-DRB1*03:01:01:01, HLA-B*58:01:01:01 , HLA-C*03:02:02:01 , and HLA-DQB1*02:01:01:01 positively associated with SLE patients, and expanded Tfh-like cells with ectopic germinal center structures in IDLE skin lesions. These findings suggest a significant difference in the immunopathogenesis of skin lesions between SLE and IDLE patients. SLE is a B cell-predominate systemic immune disorder, while IDLE appears limited to the skin. Our findings provide novel insights into the pathogenesis of IDLE and other types of LE, which may direct more accurate diagnosis and novel therapeutic strategies. • SLE is a B cell-dominated systemic immune disorder, whereas IDLE is a B cell-dominated skin-localized autoimmune dermatosis. • IDLE and SLE are different diseases with distinct pathogenesis. • IDLE is a tissue-restricted disease, in which tissue-specific autoantibodies originate from skin-localized ectopic GCs. [ABSTRACT FROM AUTHOR]

Peripheral helper T cells (Tph) are a specialized subset of CD4+ T cells with the ability to help B cells and induce antibody production. Although usually located in ectopic lymphoid-like structures (ELS), inside the peripheral blood, Tph cells can also be identified. The aberrant proliferation and functions of Tph cells are commonly found in the patients with disease. In this review, first we will summarize the biological characteristics of Tph cells, such as the expression of surface molecules, transcription factors and cytokines, and discuss its B cell help functions. Tph cells also have roles in a wide range of human diseases, including autoimmune diseases, infectious diseases, malignancies etc. Therefore, there is a strong interest in targeting Tph cells to improve treat strategies of human diseases. • Tph cells are a subset of CD4+ T cells that can promote B cell maturation via IL-21 and SLAMF5 in inflamed tissues. • Tph cells paly critical roles in human diseases, including autoimmune diseases, infectious diseases and malignancies. • Tph cells are promising targets for therapeutic intervention in the treatment of human diseases. [ABSTRACT FROM AUTHOR]

Previous studies on the relationship between systemic lupus erythematosus (SLE) and autoimmune liver diseases (AILDs) are inconclusive. Therefore, we employed Mendelian randomization (MR) to explore the causal associations between SLE and AILDs. A two-sample MR analysis was performed using summary-level statistics sourced from genome-wide association study (GWAS) datasets. Inverse-variance weighting (IVW), MR‒Egger, and weighted median (WM) were further supported by several sensitivity analyses. We detected causal genetic associations between SLE and primary biliary cholangitis (PBC) (odds ratio (OR) = 1.31, 95% CI = 1.15–1.51, P < 0.01; adjusted OR = 1.63, 95% CI = 1.39–1.90, P < 0.01) and between SLE and primary sclerosing cholangitis (PSC) (OR = 1.09, 95% CI = 1.01–1.08, P = 0.03; adjusted OR = 1.10, 95% CI = 1.00–1.21, P = 0.04). No causal association was found between SLE and autoimmune hepatitis. We are the first to use MR analysis to explore the causal relationships between SLE and various AILDs, revealing an increased risk of PBC and PSC in individuals with SLE. • Previous studies have shown that the coexistence of AILDs in patients with SLE is common, indicating a potential causal relationship between these two conditions; however, that relationship is still unclear. • This is the first study to identify the causal effects of SLE on AILDs using two-sample Mendelian randomization analysis. • Our results may provide new evidence for diagnostic and therapeutic strategies in clinical practice. [ABSTRACT FROM AUTHOR]

Understanding the regulation of efferocytosis by myeloid phagocytes is important in identifying novel targets in systemic lupus erythematosus (SLE). Cadherin-11 (CDH11), a cell adhesion molecule, is implicated in inflammatory arthritis and fibrosis and recently been shown to regulate macrophage phagocytosis. The extent and mechanism of this regulation is unknown. Our objective was to examine the extent to which CDH11 regulates myeloid phagocytes and contributes to autoimmunity and tissue inflammation. We analyzed efferocytosis in macrophages and dendritic cells (DCs) from WT and Cdh11 −/− mice and investigated the mechanisms in vitro. We investigated the role of CDH11 in disease development in vivo using the pristane induced lupus model. To translate the clinical relevance of CDH11 in human disease, we measured serum CDH11 levels in two independent pediatric SLE (pSLE) cohorts and healthy controls. Using bone marrow derived macrophages (BMDMs) and DCs (BMDCs), we found impaired efferocytosis in phagocytes from Cdh 11 −/− mice, mediated by downregulated efferocytosis receptor expression and RhoGTPase activation. Specifically, loss of CDH11 downregulated Mertk expression and Rac1 activation in BMDMs, and integrin αVβ3 expression and Cdc42 activation in BMDCs, highlighting distinct pathways. In vivo , Cdh11−/− mice displayed defective efferocytosis and increased accumulation of apoptotic debris in pristane-induced lupus. Further, Cdh11−/− mice had enhanced systemic inflammation and autoimmune inflammation with increased anti-dsDNA autoantibodies, splenomegaly, type I interferons, and inflammatory cytokines. Paradoxically, at the tissue level, Cdh11−/− mice were protected against glomerulonephritis, indicating a dual role in murine lupus. Finally, SLE patients had increased serum CDH11 compared to controls. This study highlights a novel role of CDH11 in regulating myeloid cells and efferocytosis and its potential as a contributor to development in autoimmunity murine lupus. Despite the increase in autoimmunity, Cdh11 −/− mice developed decreased tissue inflammation and damage. [Display omitted] • Absence of Cadherin-11 impairs macrophage and dendritic cell efferocytosis in vitro • Cadherin-11 deficiency impairs efferocytosis and promotes systemic inflammation in pristane-induced lupus. • Cadherin-11 deficiency enhances autoantibody production in pristane-induced lupus. • Loss of Cadherin-11 protects against renal and lung inflammation in pristane-induced lupus. • Increased serum Cadherin-11 in pediatric SLE patients. [ABSTRACT FROM AUTHOR]

Among the over 80 different autoimmune diseases, psoriasis (PsO), rheumatoid arthritis (RA), and ankylosing spondylitis (AS) are common representatives. Previous studies indicated a potential link with cancer risk, but suffered often from low statistical power. Thus, we aimed to synthesize the evidence and quantify the association to different female-specific cancer sites. The systematic review was performed according to PRISMA guidelines. A search string was developed for the databases PubMed, Web of Science, Cochrane Library and Embase. Results were screened independently by two investigators and the risk of bias was assessed using the ROBINS-E tool. Meta-analyses were performed using inverse variance weighted random-effects models. Statistical between-study heterogeneity was quantified by calculating Cochran's Q, τ 2 , and Higgins' I2 statistics. Sources of heterogeneity were analyzed and adjusted for within an intensive bias assessment in the form of meta-regression, outlier, influential, and subgroup analyses. A range of methods were used to test and adjust for publication bias. Of 10,096 records that were originally identified by the search strategy, 45 were included in the meta-analyses. RA was inversely associated with both breast and uterine cancer occurrence, while PsO was associated with a higher breast cancer risk. Outlier-adjusted estimates confirmed these findings. Bias assessment revealed differences in geographic regions, particularly in RA patients, with higher estimates among Asian studies. An additional analysis revealed no association between psoriatic arthritis and breast cancer. RA seems to reduce the risk of breast and uterine cancers, while PsO appears to increase breast cancer risk. Further large studies are required to investigate potential therapy-effects and detailed biological mechanisms. • Patients with rheumatoid arthritis show a reduced risk of breast and uterine cancer. • Patients with psoriasis may have a slightly increased risk of breast cancer. • Female-specific cancer risk differs depending on the geographic region. • Bias assessment, outlier and subgroup analyses ensured the robustness of results. [ABSTRACT FROM AUTHOR]

Macrophage activation syndrome (MAS) is a potentially fatal consequence of adult-onset Still's disease (AOSD), driven by a cytokine storm. Efficient early diagnosis of AOSD-associated MAS requires a sensitive and specific biomarker. In this study, we demonstrated that pentraxin 3 (PTX3), an acute phase protein, was associated with AOSD disease activity and served as a biomarker for AOSD-MAS. PTX3 levels were significantly increased in AOSD patients compared to other autoimmune diseases and healthy controls. Plasma PTX3 levels showed positive correlations with inflammatory markers, the systemic score and the HScore. In active AOSD with MAS, PTX3 levels were higher compared to those in non-AOSD haemophagocytic lymphohistiocytosis (HLH) patients. Moreover, the PTX3's area under the curve value for distinguishing AOSD with MAS exceeded that of soluble interleukin-2 receptor, ferritin and C-reactive protein. Furthermore, plasma levels of PTX3 were associated with circulating NET-DNA levels. To fully understand the underlying mechanism of PTX3 prompting AOSD and AOSD-MAS progression, we discovered that neutrophils exhibited enhanced NET formation and mitogen-activated protein kinases (MAPK) pathway activation upon PTX3 stimulation. More importantly, PTX3-induced NET formation was effectively dampened by MAPK pathway inhibitors. These findings collectively revealed that PTX3 has a favorable correlation with disease activity and may serve as a potential biomarker to differentiate AOSD patients with MAS. Additionally, PTX3 induces NET release via the MAPK pathway, suggesting a pathogenic role in AOSD-MAS. • PTX3 plasma levels elevate in AOSD patients compared to other rheumatic diseases. • PTX3 could serve as a biomarker for AOSD-MAS. • PTX3 induce NET formation, which may contribute to AOSD progression. • PTX3-MAPK-NETs axis has the potential to be a new therapeutic target in AOSD. [ABSTRACT FROM AUTHOR]

Scleritis is a severe and painful ophthalmic disorder, in which a pathogenic role for collagen-directed autoimmunity was repeatedly suggested. We evaluated the presence of sclera-specific antibodies in a large cohort of patients with non-infectious scleritis. Therefore, we prospectively collected serum samples from 121 patients with non-infectious scleritis in a multicenter cohort study in the Netherlands. In addition, healthy (n = 39) and uveitis controls (n = 48) were included. Serum samples were tested for anti-native human type II collagen antibodies using a validated enzyme-linked immunosorbent assay (ELISA). Further, sclera-specific antibodies were determined using indirect immunofluorescence (IIF) on primate retinal/scleral cryosections. Lastly, human leukocyte antigen (HLA) typing was performed in 111 patients with scleritis. Anti-type II collagen antibodies were found in 13% of scleritis patients, in 10% of healthy controls and in 11% of uveitis controls (p = 0.91). A specific reaction to scleral nerve tissue on IIF was observed in 33% of patients with scleritis, which was higher than in healthy controls (11%; p = 0.01), but similar to uveitis controls (25%; p = 0.36). Reactivity to the scleral nerve tissue was significantly associated with earlier onset of scleritis (48 versus 56 years; p < 0.001), bilateral involvement (65% versus 42%; p = 0.01), and less frequent development of scleral necrosis (5% versus 22%; p = 0.02). HLA-B27 was found to be twice as prevalent in patients with scleritis (15.3%) compared to a healthy population (7.2%). In conclusion, scleral nerve autoantibody reactivity was more common in scleritis and uveitis patients in contrast to healthy controls. Further research is needed to characterize these scleral-nerve directed antibodies and assess their clinical value. [Display omitted] • Scleral nerve autoantibody reactivity is more common in patients with scleritis and uveitis compared to healthy controls. • Type II collagen antibodies were not found to occur more frequently in patients with scleritis compared to healthy controls. • A significant association with HLA-B27 is present in patients with scleritis compared to healthy controls. [ABSTRACT FROM AUTHOR]

In many autoimmune diseases, autoantigen-specific Th17 cells play a pivotal role in disease pathogenesis. Th17 cells can transdifferentiate into other T cell subsets in inflammatory conditions, however, there have been no attempts to target Th17 cell plasticity using vaccines. We investigated if autoantigen-specific Th17 cells could be specifically targeted using a therapeutic vaccine approach, where antigen was formulated in all-trans retinoic acid (ATRA)-containing liposomes, permitting co-delivery of antigen and ATRA to the same target cell. Whilst ATRA was previously found to broadly reduce Th17 responses, we found that antigen formulated in ATRA-containing cationic liposomes only inhibited Th17 cells in an antigen-specific manner and not when combined with an irrelevant antigen. Furthermore, this approach shifted existing Th17 cells away from IL-17A expression and transcriptomic analysis of sorted Th17 lineage cells from IL-17 fate reporter mice revealed a shift of antigen-specific Th17 cells to exTh17 cells, expressing functional markers associated with T cell regulation and tolerance. In the experimental autoimmune encephalomyelitis (EAE) mouse model of MS, vaccination with myelin-specific (MOG) antigen in ATRA-containing liposomes reduced Th17 responses and alleviated disease. This highlights the potential of therapeutic vaccination for changing the phenotype of existing Th17 cells in the context of immune mediated diseases. [Display omitted] • Autoantigen-specific, pathogenic Th17 cells can be targeted by vaccination. • Antigen delivered in ATRA-liposomes targets only autoantigen-specific Th17 cells. • Transcriptomic analysis revealed vaccine-induced conversion of Th17 to Tr1-like cells. • MOG antigen in ATRA liposomes ameliorates EAE disease correlating with reduced Th17 responses. [ABSTRACT FROM AUTHOR]

A Tregs insufficiency is central to autoimmune and inflammatory diseases pathophysiology and low dose interleukin-2 (IL-2 LD) can specifically activate Tregs. To assess IL-2 LD therapeutic potential and select diseases for further clinical development, we performed an open-label, phase 2a, disease-finding, "basket trial" involving patients with one of 13 different autoimmune diseases. 81 patients treated with IL-2 LD (1 million IU/day) for 5 days, followed by fortnightly injections. The first 48 patients received diluted Proleukin®, while the subsequent 33 received ready-to-use ILT-101®. The primary endpoint was the change in Tregs at day-8 compared to baseline. Key secondary endpoints included clinical efficacy assessments using the Clinical Global Impression (CGI) scale, disease-specific scores, and EuroQL-5D-5L. Our study unveiled a universal and significant expansion and activation of Tregs, without concomitant Teffs activation, across all 13 autoimmune diseases. Both Proleukin® and ready-to-use ILT-101® demonstrated identical effects on Tregs. CGI scores reflecting activity, severity, and efficacy were significantly reduced in the overall patient population. Disease-specific clinical scores improved in five of the six disease cohorts with at least six patients, namely ankylosing spondylitis, systemic lupus erythematosus, Behçet's disease, Sjögren's syndrome, and systemic sclerosis. Urticaria was the only severe adverse event related to treatment. IL-2 LD was well-tolerated, exhibiting specific Treg activation and clinical improvements across the 13 autoimmune diseases. Tregs stimulation by IL-2 LD is a promising therapeutic strategy and IL-2 LD holds considerable promise for integration into combinatorial therapeutic approaches. • IL-2 LD can safely and selectively expand Tregs without differences between diseases. • Significant reduction in CGI for activity, severity, and efficacy across all diseases. • These results robustly support the broad therapeutic potential of IL-2 LD. [ABSTRACT FROM AUTHOR]

Celiac disease (CeD) has been linked to an increased risk of other autoimmune diseases, yet the impact of delayed CeD diagnosis on risk of developing additional autoimmune diseases remains uncertain. We investigated this through a nationwide matched case-control study. Using the ESPRESSO cohort with histophatology data from Sweden's 28 pathology departments, we assessed 46,575 biopsy-confirmed CeD cases from 1964 to 2017. We extracted 225,295 matched controls without histopathology information from the Swedish Total Population Register. Autoimmune disease was defined through diagnostic codes in the National Patient Register. Through conditional logistic regression we estimated odds ratio (OR) of autoimmune disease up until CeD diagnosis/matching date comparing CeD cases to controls across different age strata. A total of 3059 (6.6 %) CeD patients and 4076 (1.8 %) controls had earlier autoimmune disease. The overall OR for autoimmune disease in CeD was 3.50 (95%CI 3.32–3.70). The risk of autoimmune disease did not escalate with increasing age at CeD diagnosis. Compared with controls, the OR of autoimmune disease in CeD patients was 7.70 (95%CI 4.71–12.57) in those diagnosed with CeD in 0–4 years, 19.02 (95%CI 13.80–26.23) in 5–9 years, 6.18 (95%CI 5.14–7.44) in 10–14 years, 4.80 (95%CI 3.97–5.79) in 15–19 years, 4.24 (95%CI 3.55–5.07) in 20–29 years, 4.65 (95%CI 3.93–5.51) in 30–39 years, 3.67 (95%CI 3.30–4.09) in 40–59 years, and 1.67 (95%CI 1.50–1.85) in ≥60 years. This study revealed an increased risk of autoimmune disease among CeD patients compared with controls. However, older age at CeD diagnosis did not seem to escalate the risk of autoimmune diseases. • The diagnosis of celiac disease peaked at age 2 and subsequently declined as age progresses. • Celiac disease patients exhibited a higher prevalence of autoimmune diseases compared to their controls. • The risk of autoimmune disease did not escalate with increasing age at the celiac disease diagnosis. [ABSTRACT FROM AUTHOR]

CD57+ CD8+ T cells, also referred as effector memory cells, are implicated in various conditions including tumor immunity, virus immunity, and most recently with autoimmunity. However, their roles in the progression and remission of T1D are still unclear. Here, we noted an increase in peripheral CD57+ CD8+ T cells in a T1D patient harboring an activator of transcription 3 (STAT3) mutation. Our in-depth study on the role of CD57+ CD8+ T cells within a T1D patient cohort revealed that these cells undergo significant compositional shifts during the disease's progression. Longitudinal cohort data suggested that CD57+ CD8+ T cell prevalence may be a harbinger of β-cell function decline in T1D patients. Characterized by robust cytotoxic activity, heightened production of pro-inflammatory cytokines, and increased intracellular glucose uptake, these cells may be key players in the pathophysiology of T1D. Moreover, in vitro assays showed that the CXCL12-CXCR4 axis promotes the expansion and function of CD57+ CD8+ T cells via Erk1/2 signaling. Notably, the changes of serum CXCL12 concentrations were also found in individuals during the peri-remission phase of T1D. Furthermore, treatment with the CXCR4 antagonist LY2510924 reduced the immunological infiltration of CD57+ CD8+ T cells and mitigated hyperglycemia in a STZ-induced T1D mouse model. Taken together, our work has uncovered a novel role of the CXCL12-CXCR4 axis in driving CD57+ CD8+ T cells responses in T1D, and presented a promising therapeutic strategy for delaying the onset and progression of diabetes. [Display omitted] • The CXCL12-CXCR4 axis shapes CD57+ CD8+ T cell responses in T1D, hinting at a strategy to decelerate the disease progression. [ABSTRACT FROM AUTHOR]

IL-23-activation of IL-17 producing T cells is involved in many rheumatic diseases. Herein, we investigate the role of IL-23 in the activation of myeloid cell subsets that contribute to skin inflammation in mice and man. IL-23 gene transfer in WT, IL-23RGFP reporter mice and subsequent analysis with spectral cytometry show that IL-23 regulates early innate immune events by inducing the expansion of a myeloid MDL1+CD11b+Ly6G+ population that dictates epidermal hyperplasia, acanthosis, and parakeratosis; hallmark pathologic features of psoriasis. Genetic ablation of MDL-1, a major PU.1 transcriptional target during myeloid differentiation exclusively expressed in myeloid cells, completely prevents IL-23-pathology. Moreover, we show that IL-23-induced myeloid subsets are also capable of producing IL-17A and IL-23R+MDL1+ cells are present in the involved skin of psoriasis patients and gene expression correlations between IL-23 and MDL-1 have been validated in multiple patient cohorts. Collectively, our data demonstrate a novel role of IL-23 in MDL-1-myelopoiesis that is responsible for skin inflammation and related pathologies. Our data open a new avenue of investigations regarding the role of IL-23 in the activation of myeloid immunoreceptors and their role in autoimmunity. • IL-23 induces pathogenic IL-17A+ MDL-1/CLEC5A+ neutrophil population. • IL-23R+MDL-1+ neutrophils are identified in psoriasis/psoriatic arthritis patient. • IL-23 and MDL-1 expression are correlated in multiple patient cohorts. • MDL-1+ neutrophil could be a novel treatment target for psoriasis/psoriatic arthritis. [ABSTRACT FROM AUTHOR]

The complement system plays a central role in the pathogenesis of Systemic Lupus Erythematosus (SLE), but most studies have focused on the classical pathway. Ficolin-3 is the main initiator of the lectin pathway of complement in humans, but its role in systemic autoimmune disease has not been conclusively determined. Here, we combined biochemical and genetic approaches to assess the contribution of ficolin-3 to SLE risk and disease manifestations. Ficolin-3 activity was measured by a functional assay in serum or plasma samples from Swedish SLE patients (n = 786) and controls matched for age and sex (n = 566). Genetic variants in an extended 300 kb genomic region spanning the FCN3 locus were analyzed for their association with ficolin-3 activity and SLE manifestations in a Swedish multicenter cohort (n = 985). Patients with ficolin-3 activity in the highest tertile showed a strong enrichment in an SLE cluster defined by anti -Sm/DNA/nucleosome antibodies (OR 3.0, p < 0.001) and had increased rates of hematological disease (OR 1.4, p = 0.078) and lymphopenia (OR = 1.6, p = 0.039). Genetic variants associated with low ficolin-3 activity mapped to an extended haplotype in high linkage disequilibrium upstream of the FCN3 gene. Patients carrying the lead genetic variant associated with low ficolin-3 activity had a lower frequency of hematological disease (OR 0.67, p = 0.018) and lymphopenia (OR 0.63, p = 0.031) and fewer autoantibodies (p = 0.0019). Loss-of-function variants in the FCN3 gene were not associated with SLE, but four (0.5 %) SLE patients developed acquired ficolin-3 deficiency where ficolin-3 activity in serum was depleted following diagnosis of SLE. Taken together, our results provide genetic and biochemical evidence that implicate the lectin pathway in hematological SLE manifestations. We also identify lectin pathway activation through ficolin-3 as a factor that contributes to the autoantibody response in SLE. • Ficolin-3 is the main initiator of the lectin pathway of complement in humans. • SLE patients with elevated ficolin-3 activity have an increased rate of hematological disease. • Genetic determinants of ficolin-3 activity associate with SLE phenotype. • Acquired ficolin-3 deficiency occurs in a small subset of SLE patients. [ABSTRACT FROM AUTHOR]

Although type 1 diabetes (T1D) results from the autoimmune destruction of the insulin-producing β-cells, its treatment is largely restricted to exogenous insulin administration. Only few therapies targeting the autoaggressive immune system have been introduced into clinical practice or are considered in clinical trials. Here, we provide a gene expression profile of the islet microenvironment obtained by laser-dissection microscopy in an inducible mouse model. Thereby, we have identified novel targets for immune intervention. Increased gene expression of most inflammatory proteins was apparent at day 10 after T1D induction and largely paralleled the observed degree of insulitis. We further focused on genes involved in leukocyte migration, including chemokines and their receptors. Besides the critical chemokine CXCL10, we found several other chemokines upregulated locally in temporary or chronic manner. Localization of the chemokine ligand/receptor pairs to the islet microenvironment has been confirmed by RNAscope. Interference with the CXCL16-CXCR6 and CX 3 CL1-CX 3 CR1 axes, but not the CCL5-CCR1/3/5 axis, resulted in reduced insulitis and lower T1D incidence. Further, we found that the receptors for the differentially expressed chemokines CXCL10, CXCL16 and CX 3 CL1 are distributed unevenly among islet autoantigen-specific T cells, which explains why the interference with just one chemokine axis cannot completely abrogate insulitis and T1D. [Display omitted] • The autoaggressive immune response is still a neglected target in T1D. • By laser-dissecting microscopy of islet microenvironments we have identified novel targets for a therapeutic intervention. • Interference with the CXCL16-CXCR6 and CX 3 CL1-CX 3 CR1 axes resulted in reduced insulitis and lower T1D incidence. • There is uneven distribution of chemokine receptors on autoaggressive T cells. • Combination therapies targeting more than one chemokine axes might be more successful than monotherapies. [ABSTRACT FROM AUTHOR]

Autoimmune uveitis (AU) is a severe disorder causing poor vision and blindness. However, the cellular dynamics and pathogenic mechanisms underlying retinal injury in uveitis remain unclear. In this study, single-cell RNA sequencing of the retina and cervical draining lymph nodes in experimental autoimmune uveitis mice was conducted to identify the cellular spatiotemporal dynamics and upregulation of the glycolysis-related gene LDHA. Suppression of LDHA can rescue the imbalance of T effector (Teff) cells/T regulator (Treg) cells under inflammation via downregulation of the glycolysis-PI3K signaling circuit and inhibition of the migration of CXCR4+ Teff cells towards retinal tissue. Furthermore, LDHA and CXCR4 are upregulated in the peripheral blood mononuclear cells of Vogt-Koyanagi-Harada patients. The LDHA inhibitor suppresses CD4+ T cell proliferation in humans. Therefore, our data indicate that the autoimmune environment of uveitis regulates Teff cell accumulation in the retina via glycolysis-associated LDHA. Modulation of this target may provide a novel therapeutic strategy for treating AU. • Glycolysis-associated LDHA promotes inflammation in uveitis. • LDHA promotes glycolysis-PI3K loop to induce Teff/Treg cells imbalance in uveitis. • LDHA fuels CXCR4+ Teff cells trafficking towards retina. [ABSTRACT FROM AUTHOR]

Anti-nuclear antibodies are the hallmark of autoimmune diseases such as systemic lupus erythematosus (SLE) and scleroderma. However, the molecular mechanisms of B cell tolerance breakdown in these pathological contexts are poorly known. The study of rare familial forms of autoimmune diseases could therefore help to better describe common biological mechanisms leading to B cell tolerance breakdown. By Whole-Exome Sequencing, we identified a new heterozygous mutation (p.R594C) in ERN1 gene, encoding IRE1α (Inositol-Requiring Enzyme 1α), in a multiplex family with several members presenting autoantibody-mediated autoimmunity. Using human cell lines and a knock-in (KI) transgenic mouse model, we showed that this mutation led to a profound defect of IRE1α ribonuclease activity on X-Box Binding Protein 1 (XBP1) splicing. The KI mice developed a broad panel of autoantibodies, however in a subclinical manner. These results suggest that a decrease of spliced form of XBP1 (XBP1s) production could contribute to B cell tolerance breakdown and give new insights into the function of IRE1α which are important to consider for the development of IRE1α targeting strategies. • We described a heterozygous ERN1 c.1780C>T (IRE1a p.R594C) in a multiplex family of autoimmune patients. • IRE1a R594C mutation leads to a profound impairment of XBP1 splicing activity of IRE1a in human cells and in mice. • R594C transgenic mice displayed a broad breakdown of B cell tolerance. • Immune cell compartments were deeply analysed with CITEseq/FlowSOM technologies and VDJ repertoire by ImmunoSEQ technology. [ABSTRACT FROM AUTHOR]

Rheumatoid arthritis (RA) is a chronic autoimmune disorder that affects the joints and produces pain, swelling, and stiffness. It has a lifetime prevalence of up to 1% worldwide. An extract of Tripterygium wilfordii Hook F (TwHF), a member of the Celastraceae herbal family widely available in south China, has been used for treatment of RA since 1960s. The current consensus practice guidance (CPG) aims to offer guidance on the application of TwHF in the clinical management of active RA. The CPG followed World Health Organisation (WHO)'s recommended process, carried out three systematic reviews to synthesize data from 19 randomised controlled trials (RCT) involving 1795 participants. We utilized Grading of Recommendations, Assessment, Development and Evaluation (GRADE) to evaluate certainty of evidence and derive recommendations. We rigorously followed The Appraisal of Guidelines for Research and Evaluation II (AGREE II) as conduct guides to minimise bias and promote transparency. There was no obvious difference between TwHF monotherapy and methotrexate (MTX) monotherapy on ACR20 (RCT = 2, N = 390, RR = 1.06, 95%CI 0.90–1.26, moderate certainty), ACR50 (RCT = 3, N = 419, RR = 1.03, 95%CI 0.80–1.34, moderate certainty), ACR70 (RCT = 2, N = 390, RR = 1.12, 95%CI 0.69–1.79, low certainty). TwHF monotherapy may be better than salicylazosulfapyridine monotherapy on ACR20 and the effect may be similar on ACR50 and ACR70. Seven RCTs compared MTX combined with TwHF versus MTX monotherapy, and the meta-analysis results favoured combination therapy group on ACR20 (RCT = 3, N = 470, RR = 1.44, 95%CI 1.28–1.62, moderate certainty), ACR50 (RCT = 4, N = 500, RR = 1.88, 95%CI 1.56–2.28, moderate certainty) and ACR70 (RCT = 2, N = 390, RR = 2.12, 95%CI 1.40–3.19, low certainty). We found no obvious difference between groups on critical safety outcomes, including infection (RCT = 3, N = 493, RR = 1.37, 95%CI 0.84–2.23), liver dysfunction (RCT = 5, N = 643, RR = 1.14, 95%CI 0.71–1.85), renal damage (RCT = 3, N = 450, RR = 2.20, 95%CI 0.50–9.72). Upon full review of the evidence, the guidance panel reached consensus on recommendations for the use of TwHF in people with active RA, either as monotherapy or as combination therapy with MTX. • This is the first evidence-based guidance following WHO guideline handbook to review the efficacy and safety of TwHF relative to other DMARDs. • Among herbal or conventional synthetic DMARDs, TwHF monotherapy may be similarly effective as other conventional synthetic DMARDs for active RA. • For people with active RA, particularly those who are MTX treatment naïve, adding TwHF to MTX may further improve clinical outcomes. • For people with gestation expectation, who places a higher value on the avoidance of reproductive toxicity, TwHF should be avoided. The participants in most studies were women over the age of 50, and there is a lack of evidence on reproductive toxicity in women of childbearing age. Thus, for people who place a higher value on the avoidance of reproductive toxicity, TwHF should be avoided in accordance with individual preferences. [ABSTRACT FROM AUTHOR]

Rheumatoid factors (RFs), polyreactive antibodies canonically known to bind two conformational epitopes of IgG Fc, are a hallmark of rheumatoid arthritis but also can arise in other inflammatory conditions and infections. Also, infections may contribute to the development of rheumatoid arthritis and other autoimmune diseases. Recently, RFs only in rheumatoid arthritis were found to bind novel linear IgG epitopes as well as thousands of other rheumatoid arthritis autoantigens. Specific epitopes recognized by infection-induced polyreactive RFs remain undefined but could provide insights into loss of immune tolerance. Here, we identified novel linear IgG epitopes bound by RFs in COVID-19 but not rheumatoid arthritis or other conditions. The main COVID-19 RF was polyreactive, binding two IgG and multiple viral peptides with a tripeptide motif, as well as IgG Fc and SARS-CoV-2 spike proteins. In contrast, a rheumatoid arthritis-specific RF recognized IgG Fc, but not tripeptide motif-containing peptides or spike. Thus, RFs have disease-specific IgG reactivity and distinct polyreactivities that reflect the broader immune response. Moreover, the polyreactivity of a virus-induced RF appears to be attributable to a very short peptide motif. These findings refine our understanding of RFs and provide new insights into how viral infections may contribute to autoimmunity. • COVID-19 rheumatoid factors (RFs) bind IgG epitopes not bound in rheumatoid arthritis or other conditions. • The main COVID-19 RF was polyreactive, binding two IgG and multiple viral peptides with a tripeptide motif, as well as IgG Fc and SARS-CoV-2 spike proteins. • A rheumatoid arthritis-specific RF recognizes IgG Fc, but not motif-containing peptides or spike. • Thus, RFs have disease-specific IgG Fc reactivity and distinct polyreactivities that reflect the broader immune response. • Moreover, a very short motif appears to underlie the polyreactivity of a virus-induced RF. [ABSTRACT FROM AUTHOR]

Programmed-cell-death 1 (PD-1) expression is associated not only with T-cell activation but with exhaustion. Specifically, PD-1+ T cells present an exhausted phenotype in conditions of chronic antigen exposure, such as tumor microenvironments and chronic viral infection. However, the immune status regarding exhaustion of PD-1+CD8+ T cells in chronic autoimmune diseases including idiopathic inflammatory myopathies (IIMs) remains unclear. We aimed to clarify the role of PD-1+CD8+ T cells and PD-1 ligand (PD-L1) in IIMs. We showed that PD-1+ cells infiltrated into PD-L1-expressing muscles in patients with IIMs and immune checkpoint inhibitor-related myopathy. According to the peripheral blood immunophenotyping, the PD-1+CD8+ cell proportions were comparable between the active and inactive patients. Of note, PD-1+CD8+ cells in the active patients highly expressed cytolytic molecules, indicating their activation, while PD-1−CD8+ cells expressed low levels of cytolytic molecules in the active and inactive patients. A part of PD-1+CD8+ cells expressed the HMG-box transcription factor TOX highly and presented the exhausted phenotype in the active patients. Among PD-1+CD4+ T cells, PD-1highCXCR5−CD45RO+CD4+ peripheral helper T cells were increased in the active patients. PD-L1-deficient mice developed severer C-protein-induced myositis (CIM), a model of polymyositis, with abundant infiltration of PD-1+CD8+ cells expressing cytolytic molecules than wild-type mice, indicating pathogenicity of the PD-1+CD8+ cells and the protective role of PD-L1. The deficiency of IFNγ, a general PD-L1-inducer, impaired muscular PD-L1 expression and exacerbated CIM, indicating IFNγ-dependent muscular PD-L1 regulation. IFNγ-induced PD-L1 on myotubes was protective in an established muscle injury model. In conclusion, PD-1+CD8+ T cells rather than PD-1−CD8+ T cells were a pathogenic subset of IIMs. Muscular PD-L1 was regulated by IFNγ and exerted protective properties in IIMs. [Display omitted] • PD-1+CD8+ T cells presented an effector phenotype in active IIM patients. • PD-1−CD8+ T cells expressed low levels of effector molecules in IIM patients. • PD-1+CD8+T cells were pathogenic in the murine model of myositis. • Muscular PD-L1 was regulated IFNγ-dependently and was protective in IIMs. [ABSTRACT FROM AUTHOR]

Pemphigus, an autoimmune bullous disease affecting the skin and mucosal membranes, is primarily driven by anti-desmoglein (Dsg) autoantibodies. However, the underlying immune mechanisms of this disease remain largely elusive. Here, we compile an unbiased atlas of immune cells in pemphigus cutaneous lesions at single-cell resolution. We reveal clonally expanded antibody-secreting cells (ASCs) that exhibit variable hypermutation and accumulation of IgG4 class-switching in their immunoglobulin genes. Importantly, pathogenic Dsg-specific ASCs are localized within pemphigus lesions and can evolve from both Dsg-autoreactive and non-binding precursors. We observe an altered distribution of CD4+ T cell subsets within pemphigus lesions, including an imbalance of Th17/Th2 cells. Significantly, we identify a distinct subpopulation of Th17 cells expressing CXCL13 and IL-21 within pemphigus lesions, implying its pivotal role in B cell recruitment and local production of autoantibodies. Furthermore, we characterize multiple clonally expanded CD8+ subpopulations, including effector GMZB+ and GMZK+ subsets with augmented cytotoxic activities, within pemphigus lesions. Chemokine-receptor mapping uncovers cell-type-specific signaling programs involved in the recruitment of T/B cells within pemphigus lesions. Our findings significantly contribute to advancing the understanding of the heterogeneous immune microenvironment and the pathogenesis of pemphigus cutaneous lesions, thereby providing valuable insights for potential therapeutic interventions in this disease. • Pemphigus lesions display extensive expansion and heterogeneity in T/B cell populations. • Lesional ASCs exhibit clonal expansion, variable hypermutation and IgG4 class-switching. • ASCs can locally produce pathogenic Dsg-specific autoantibodies within pemphigus lesions. • Pemphigus lesions have an imbalance of Th17/Th2 cells and recruit a unique Th17 subset. • Cell-type-specific signaling programs control T/B cell infiltration in pemphigus lesions. [ABSTRACT FROM AUTHOR]

Autoimmune diseases (AIDs) are a series of immune-mediated lethal diseases featured by over-activated immune cells attacking healthy self-tissues and organs due to the loss of immune tolerance, which always causes severe irreversible systematical organ damage and threatens human health heavily. To date, there are still no definitive cures for the treatment of AIDs due to their pathogenesis has not been clearly understood. Besides, the current clinical treatments of AIDs majorly rely on glucocorticoids and immune suppressors, which can lead to serious side effects. In the past years, there are increasing studies demonstrating that an imbalance of gut microbiota is intimately related to the pathogenesis of various AIDs, shedding light on the development of therapeutics by targeting the gut microbiota for the management of AIDs. Among all the approaches targeting the gut microbiota, fecal microbiota transplantation (FMT) has attracted increasing interest, and it has been proposed as a possible strategy to intervene in the homeostasis of gut microbiota for the treatment of various diseases. However, despite the reported good curative effects and clinical studies conducted on FMT, the detailed mechanisms of FMT for the effective treatment of those diseases have not been figured out. To fully understand the mechanisms of the therapeutic effects of FMT on AIDs and improve the therapeutic efficacy of FMT treatment, a systematic review of this topic is necessary. Hence, in this review paper, the potential mechanisms of FMT for the treatment of various AIDs were summarized, including promotion, shaping, activation, or inhibition of the host immune system via the interactions between the microorganisms and the gut immune system, gut-brain, gut-liver, gut-kidney axis, and so on. Then, applications of FMT for the treatment of various AIDs were detailed presented. Finally, the current challenges and potential solutions for the development of FMT formulations and FMT therapeutics were comprehensively discussed. • The potential mechanisms of FMT in the treatment of autoimmune diseases were summarized. • Applications of FMT for the treatment of various autoimmune diseases were detailedly reviewed. • The current challenges and potential solutions for the development of FMT therapeutic strategies were comprehensively discussed. [ABSTRACT FROM AUTHOR]

The role of gut microbiome and metabolic substances in the development of autoimmune diseases has gradually been revealed. However, the relevant gut features in pemphigus have not been well clarified. We collected stool samples from pemphigus patients and healthy controls (HCs). Metagenomic sequencing and liquid chromatography-mass spectrometry (LC/MS) metabolome sequencing were performed to analyze the compositional and metabolic alternations of the gut microbiome in pemphigus patients and HCs. We observed the reduced richness and diversity and greater heterogeneity in pemphigus patients, which was characterized by a significant decrease in Firmicutes and an increase in Proteobacteria. At the species level, Intestinal pathogenic bacteria such as Escherichia coli and Bacteroides fragilis were significantly enriched, while anti-inflammatory bacteria and butyric acid-producing bacteria were significantly reduced, which were related to clinical indicators (Dsg1/3 and PDAI). 4 species were selected by the machine learning algorithm to better distinguish pemphigus patients from healthy people. Metabolomic analysis showed that the composition of pemphigus patients was different from that of HCs. PE (18:3 (6 Z ,9 Z , 12 Z)/14:1 (9Z)) was the main metabolic substance in pemphigus and involved in a variety of metabolic pathways. While Retinol, flavonoid compounds and various amino acids decreased significantly compared with HCs. Furthermore, we found that differences in the levels of these metabolites correlated with changes in the abundance of specific species. Our study provides a comprehensive picture of gut microbiota and metabolites in pemphigus patients and suggests a potential mechanism of the aberrant gut microbiota and metabolites in the pathogenesis of pemphigus. • Pemphigus patients have intestinal flora disorder with decreased diversity and richness, and increased heterogeneity. • Intestinal pathogenic bacteria were enriched, while anti-inflammatory bacteria were reduced in pemphigus patients. • Fecal metabolite composition was altered in pemphigus patients, which was correlated with intestinal microbial changes. [ABSTRACT FROM AUTHOR]

Both genetic susceptibility and environmental factors are important contributors to autoimmune disease pathogenesis. As an environmental factor, the gut microbiome plays a crucial role in the development and progression of autoimmune diseases. Thus, strategies targeting gut microbiome alterations can potentially be used to treat autoimmune disease. Microbiota-based interventions, such as prebiotics, probiotics, dietary interventions, and fecal microbiota transplantation (FMT), have attracted growing interest as novel treatment approaches. FMT is an effective method for treating recurrent Clostridioides difficile infections; moreover, it is emerging as a promising treatment for patients with inflammatory bowel disease and other autoimmune diseases. Although the mechanisms underpinning the interaction between the gut microbiome and host are not fully understood in patients with autoimmune disease, FMT has been shown to restore altered gut microbiota composition, rebuild the intestinal microecosystem, and mediate innate and adaptive immune responses to achieve a therapeutic effect. In this review, we provide an overview of FMT and discuss how FMT can be used as a novel treatment approach for autoimmune diseases. Furthermore, we discuss recent challenges and offer future research directions. • The gut microbiota plays a crucial role in the pathogenesis of autoimmune diseases. • Fecal microbiota transplantation (FMT) is currently being considered for use in the treatment of various autoimmune diseases. • FMT can restore the gut microbiota and rebuild the function of the immune system, thus yielding a therapeutic effect. • The tailoring of therapies to individualized microbiomes and circumstances will become possible. [ABSTRACT FROM AUTHOR]

Interleukin-2 (IL-2) therapies targeting the high affinity IL-2 receptor expressed on regulatory T cells (Tregs) have shown promising therapeutic benefit in autoimmune diseases through nonselective expansion of pre-existing Treg populations, but are potentially limited by the inability to induce antigen-specific Tregs, as well as by dose-limiting activation of effector immune cells in settings of inflammation. We recently developed biodegradable nanoparticles encapsulating rapamycin, called ImmTOR, which induce selective immune tolerance to co-administered antigens but do not increase total Treg numbers. Here we demonstrate that the combination of ImmTOR and an engineered Treg-selective IL-2 variant (termed IL-2 mutein) increases the number and durability of total Tregs, as well as inducing a profound synergistic increase in antigen-specific Tregs when combined with a target antigen. We demonstrate that the combination of ImmTOR and an IL-2 mutein leads to durable inhibition of antibody responses to co-administered AAV gene therapy capsid, even at sub-optimal doses of ImmTOR, and provides protection in autoimmune models of type 1 diabetes and primary biliary cholangitis. Importantly, ImmTOR also increases the therapeutic window of engineered IL-2 molecules by mitigating effector immune cell expansion and preventing exacerbation of disease in a model of graft-versus-host-disease. At the same time, IL-2 mutein shows potential for dose-sparing of ImmTOR. Overall, these results establish that the combination of ImmTOR and an IL-2 mutein show synergistic benefit on both safety and efficacy to provide durable antigen-specific immune tolerance to mitigate drug immunogenicity and to treat autoimmune diseases. • ImmTOR particles and engineered IL-2 synergistically induce antigen-specific Tregs. • ImmTOR expands the therapeutic window of IL-2 by inhibiting effector cells. • ImmTOR + IL-2 protect in models of type 1 diabetes and primary biliary cholangitis. [ABSTRACT FROM AUTHOR]

The role of autoreactive T cells on the course of Coronavirus disease-19 (COVID-19) remains elusive. Type II pneumocytes represent the main target cells of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Autoimmune responses against antigens highly expressed in type II pneumocytes may influence the severity of COVID-19 disease. The aim of this study was to investigate autoreactive T cell responses against self-antigens highly expressed in type II pneumocytes in the blood of COVID-19 patients with severe and non-severe disease. We collected blood samples of COVID-19 patients with varying degrees of disease severity and of pre-pandemic controls. T cell stimulation assays with peptide pools of type II pneumocyte antigens were performed in two independent cohorts to analyze the autoimmune T cell responses in patients with non-severe and severe COVID-19 disease. Target cell lysis assays were performed with lung cancer cell lines to determine the extent of cell killing by type II PAA-specific T cells.Results: We identified autoreactive T cell responses against four recently described self-antigens highly expressed in type II pneumocytes, known as surfactant protein A, surfactant protein B, surfactant protein C and napsin A, in the blood of COVID-19 patients. These antigens were termed type II pneumocyte-associated antigens (type II PAAs). We found that patients with non-severe COVID-19 disease showed a significantly higher frequency of type II PAA-specific autoreactive T cells in the blood when compared to severely ill patients. The presence of high frequencies of type II PAA-specific T cells in the blood of non-severe COVID-19 patients was independent of their age. We also found that napsin A-specific T cells from convalescent COVID-19 patients could kill lung cancer cells, demonstrating the functional and cytotoxic role of these T cells. Our data suggest that autoreactive type II PAA-specific T cells have a protective role in SARS-CoV-2 infections and the presence of high frequencies of these autoreactive T cells indicates effective viral control in COVID-19 patients. Type II-PAA-specific T cells may therefore promote the killing of infected type II pneumocytes and viral clearance. Type II pneumocytes represent the main target cells of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and other respiratory viruses. The killing of infected type II pneumocytes leads to the release of not only viral antigens, but also of self-antigens, such as type II pneumocyte-associated antigens (type II PAAs). These self-antigens can lead to the priming and activation of CD8+ T cells. Patients with non-severe Coronavirus disease-19 (COVID-19) have an efficient and targeted viral clearance of SARS-CoV-2, suggesting a previous infection with other respiratory viruses, such as influenza. In the case of a subsequent infection with a virus like SARS-CoV-2, the swift T cell response by pre-existing autoreactive T cells could have a protective effect in these pre-immunized patients by promoting the killing of infected type II pneumocytes. This suggests that autoreactive type II PAA-specific and COVID-19-specific T cells may synergistically protect from severe COVID-19 infection, although this theory will require further studies for validation. On the other hand, patients that do not harbor such protective autoreactive T cells have an impaired viral clearance and develop severe COVID-19. [Display omitted] • Type II PAA-specific T cells are present in the blood of COVID-19 patients. • Patients with non-severe COVID-19 harbor increased numbers of type II PAA-specific T cells. • The protective effect of type II PAA-specific T cells is independent of patient age. • A T cell-mediated autoimmune response against type II PAAs may be protective in COVID-19. [ABSTRACT FROM AUTHOR]

Molecular mimicry is one mechanism by which infectious agents are thought to trigger islet autoimmunity in type 1 diabetes. With a growing number of reported infectious agents and islet antigens, strategies to prioritize the study of infectious agents are critically needed to expedite translational research into the etiology of type 1 diabetes. In this work, we developed an in-silico pipeline for assessing molecular mimicry in type 1 diabetes etiology based on sequence homology, empirical binding affinity to specific MHC molecules, and empirical potential for T-cell immunogenicity. We then assess whether potential molecular mimics were conserved across other pathogens known to infect humans. Overall, we identified 61 potentially high-impact molecular mimics showing sequence homology, strong empirical binding affinity, and empirical immunogenicity linked with specific MHC molecules. We further found that peptide sequences from 32 of these potential molecular mimics were conserved across several human pathogens. These findings facilitate translational evaluation of molecular mimicry in type 1 diabetes etiology by providing a curated and prioritized list of peptides from infectious agents for etiopathologic investigation. These results may also provide evidence for generation of infectious and HLA-specific preclinical models and inform future screening and preventative efforts in genetically susceptible populations. [Display omitted] • This work assesses molecular mimicry in type 1 diabetes using computational methods • We empirically evaluate sequence homology, binding affinity, and immunogenicity • This method identified 61 potential molecular mimics in type 1 diabetes etiology • 32 potential molecular mimics were conserved across other human pathogens • This pipeline can be adapted to investigate mimicry in other autoimmune diseases [ABSTRACT FROM AUTHOR]

Mechanistic studies of autoimmune disorders have identified circulating T follicular helper (cTfh) cells as drivers of autoimmunity. However, the quantification of cTfh cells is not yet used in clinical practice due to the lack of age-stratified normal ranges and the unknown sensitivity and specificity of this test for autoimmunity. We enrolled 238 healthy participants and 130 patients with common and rare disorders of autoimmunity or autoinflammation. Patients with infections, active malignancy, or any history of transplantation were excluded. In 238 healthy controls, median cTfh percentages (range 4.8%–6.2%) were comparable among age groups, sexes, races, and ethnicities, apart from a significantly lower percentages in children less than 1 year of age (median 2.1%, CI: 0.4%–6.8, p < 0.0001). Among 130 patients with over 40 immune regulatory disorders, a cTfh percentage exceeding 12% had 88% sensitivity and 94% specificity for differentiating disorders with adaptive immune cell dysregulation from those with predominantly innate cell defects. This threshold had a sensitivity of 86% and specificity of 100% for active autoimmunity and normalized with effective treatment. cTfh percentages exceeding 12% distinguish autoimmunity from autoinflammation, thereby differentiating two endotypes of immune dysregulation with overlapping symptoms and different therapies. [Display omitted] • Circulating follicular helper T cell (cTfh) expansion is seen in multiple autoimmune disorders. • We define the normal ranges for cTfh% in a large cohort of healthy individuals. • CTfh >12% distinguishes active autoimmunity from active autoinflammation with high sensitivity/specificity. • CTfh% >12% distinguishes active vs quiescent autoimmunity with high sensitivity/specificity. • CTfh% is well-positioned for widespread adoption as a clinical test. [ABSTRACT FROM AUTHOR]

Idiopathic inflammatory myopathies (IIM) are a heterogeneous group of rare autoimmune diseases, with increasing incidence rates observed in the recent years. The pathogenesis of IIM remains not fully understood, and the interaction of genetic and environmental factors is suspected. It is unclear whether the observed upward trend in the IIM incidence is solely due to improved access to effective diagnostics or perhaps due to increased exposure to external risk factors. The PUBMED database was thoroughly searched for articles describing environmental exposures potentially triggering the onset of IIM. The article summarizes the current knowledge available on this subject, taking into account various environmental factors, including among others UV radiation, infectious agents with SARS-CoV-2, inhaled particles, or iatrogenic effects. Limitations and unmet needs requiring further studies were highlighted. [Display omitted] • Environmental exposures serve a significant role in the pathogenesis of IIM • Seasonal variability of IIM incidence supports the idea of environmental triggers • Exposure to UV radiation is associated with the risk for IIM in susceptible ones • Preceding infections are considered as one of the strongest risk factors for IIM • Impact differs depending on IIM subtype, demographical data and serological profile [ABSTRACT FROM AUTHOR]

Small ubiquitin-like modifier (SUMO) proteins, as a subgroup of post-translational modifiers, act to change the function of proteins. Through their interactions with different targets, immune pathways, and the responses they elicit, can be affected by these SUMO conjugations. Thus, both a change to protein function and involvement in immune pathways has the potential to promote an efficient immune response to either a pathogenic challenge, or the development of an imbalance that could lead to an autoimmune-based disease. Also, a variety of changes such as mutations and polymorphisms can interfere with common functions of these modifications and move an effective immune response in the direction of an autoimmune disease. The present review discusses the general characteristics of SUMO proteins and focuses on their involvement in rheumatoid arthritis as an autoimmune disease. • Small ubiquitin-like modifier (SUMO) proteins change proteins functions. • SUMO proteins can interact with immune pathways, thus eliciting responses under different autoimmune diseases. • SUMOylation is a novel pathway implicated in the phenotypic differences in autoimmune disorders. [ABSTRACT FROM AUTHOR]

Lupus glomerulonephritis (GN) is an autoimmune disease characterized by immune complex-deposition, complement activation and glomerular inflammation. In lupus-prone NZM2328 mice, the occurrence of lupus GN was accompanied by a decrease in Treg cells and an increase in proinflammatory cytokine-producing T cells. Because IL-33 in addition to IL-2 has been shown to be important for Treg cell proliferation and ST2 (IL-33 receptor) positive Treg cells are more potent in suppressor activity, a hybrid cytokine with active domains of IL-2 and IL-33 was generated to target the ST2+ Treg cells as a therapeutic agent to treat lupus GN. Three mouse models were used: spontaneous and Ad-IFNα- accelerated lupus GN in NZM2328 and the lymphoproliferative autoimmune GN in MRL/ lpr mice. Daily injections of IL233 for 5 days prevented Ad-IFNα-induced lupus GN and induced remission of spontaneous lupus GN. The remission was permanent in that no relapses were detected. The remission was accompanied by persistent elevation of Treg cells in the renal lymph nodes. IL233 is more potent than IL-2 and IL-33 either singly or in combination in the treatment of lupus GN. The results of this study support the thesis that IL233 should be considered as a novel agent for treating lupus GN. • Lupus prone NZM2328 mice have a deficit in IL-2, IL-10 and Foxp3+ST2+ Tregs. • IL-2 and IL-33 combination in the form of IL-2 and IL-33 fusion cytokine (IL233) induced a sustained increase in Tregs and suppressed inflammation without affecting autoantibodies. • IL233, as a single agent not only prevented the onset, but also induced persistent remission in ongoing lupus glomerulonephritis (GN) in IFNα-accelerated and spontaneous models in NZM2328 mice and in MRL/ lpr mice. [ABSTRACT FROM AUTHOR]

Chronic inflammatory demyelinating polyneuropathy (CIDP) is an autoimmune disease characterized by neurological symptoms and signs of progressive weakness, paresthesias, and sensory dysfunction. Other symptoms include reduced or absent tendon reflexes, cranial nerve involvement, autonomic symptoms, ataxia, and neuropathic pain. Unlike other autoimmune diseases, CIDP generally affects older individuals and has a male predominance. The onset is generally insidious and can take up to 8 weeks with a relapsing-recovery pattern. Like all autoimmune diseases, the etiology is multifactorial, with both genetic and environmental factors contributing to it. Case reports of CIDP have found associations with multiple pathogenic organisms including Hepatitis B and C viruses, Bartonella henselae , Mycoplasma pneumoniae , Human immunodeficiency virus, Cytomegalovirus and Epstein-Barr virus. Possible antigenic self-targets include myelin protein 0, myelin protein 2, peripheral myelin protein 22, Connexin 32, and myelin basic protein. Antibodies targeting the Ranvier node proteins such as contactin-1, contactin-associated protein 1, and neurofascin 155 have been described. CIDP is treated with rehabilitation and pharmacological modalities. Pharmacological treatments target autoimmune dysfunction and include corticosteroids, intravenous immunoglobulin, subcutaneous immunoglobulin, plasma exchange, immunosuppressive and immunomodulatory agents such as methotrexate, cyclophosphamide, rituximab, and mycophenolate mofetil. Although there are few observational studies and randomized clinical trials with limited evidence supporting the use of immunosuppressive drugs, they are widely used in clinical practice. A comprehensive review of CIDP is presented herein in light of the autoimmune tautology. • CIDP is an autoimmune neurological disease in which both genetic and environmental factors influence its etiology. • Although CIDP generally affects older individuals with a male predominance it fits the premises of the autoimmune tautology. • Unlike Guillain-Barré syndrome, CD8+ T cells seem to play an important role in the pathophysiology of CIDP. • To date, the use of corticosteroids, IVIg, and plasma exchange are the mainstay of CIDP management. [ABSTRACT FROM AUTHOR]

Primary biliary cholangitis (PBC) is a classic autoimmune disease in which humoral, cytotoxic, and innate immune responses have been implicated with the specific targeting of a mitochondrial antigen. The mainstay of treatment remains the bile acid ursodeoxycholic acid (UDCA). Corticosteroids may have some benefits, but to date, clinical trials of biologics targeting B cells and IL-12/23 have not shown any efficacy. Because activated T cells target the intrahepatic bile ducts in PBC and pre-clinical models suggested that blocking CD80/CD86 with CTLA-4 Ig might have therapeutic benefit in PBC, we performed an open-label trial to determine if CTLA-4 Ig (abatacept) is safe and potentially efficacious in PBC patients with an incomplete response to UDCA. PBC patients with an alkaline phosphatase (ALP) > 1.67 × the upper limit of normal after 6 months on UDCA treatment or who were intolerant of UDCA received abatacept 125 mg s.q. weekly for 24 weeks. The co-primary endpoint was ALP normalization or a >40% reduction from baseline. Among 16 subjects enrolled and who received at least 1 dose of abatacept, 1 (6.3%) met the co-primary endpoint. Absolute and percent changes in ALP [median (95% CI)] were +2.8 U/L (−90.9–96.6) and −0.28% (−21.1–15.5), respectively. No significant changes were observed in ALP, ALT, total bilirubin, albumin, immunoglobulins, or liver stiffness. Abatacept treatment decreased several non-terminally differentiated CD4+ but not CD8+ T cell populations, including decreases in CD4+ CCR5+ (p = 0.02) and CD4+ PD1+ (p = 0.03) lymphocytes. In contrast there were increases in CD4+ CCR7+ lymphocytes (p = 0.034). Treatment emergent adverse events occurred in 4 subjects. Abatacept was well tolerated in this population of PBC patients but like other biologics in PBC was ineffective in achieving biochemical responses associated with improved clinical outcomes. • Primary biliary cholangitis (PBC) is an autoimmune disease with loss of humoral and cellular tolerance to mitochondrial self-antigens. • Abatacept (CLTA-4 Ig) suppressed T cell activation in PBC patients with an incomplete response to first-line therapy. • However, abatacept failed to demonstrate clinical efficacy reflected in liver biochemical profiles. • Biologics, including those targeting T and B cells and IL-12/23, have been unsuccessful in PBC. [ABSTRACT FROM AUTHOR]

Obesity-induced chronic inflammation has been linked to several autoimmune diseases, including rheumatoid arthritis, type 1 diabetes, and multiple sclerosis. The underlying mechanisms are not yet fully understood, but it is believed that chronic inflammation in adipose tissue can lead to the production of pro-inflammatory cytokines and chemokines, which can trigger immune responses and contribute to the development of autoimmune diseases. However, the underlying mechanisms that lead to the infiltration of immune cells into adipose tissue are not fully understood. In this study, we observed a time-dependent response to a high-fat diet in the liver and epididymal white adipose tissue using gene set enrichment analysis. Our findings revealed a correlation between early abnormal innate immune responses in the liver and late inflammatory response in the adipose tissue, that eventually leads to systemic inflammation. Specifically, our data suggest that the dysregulated NADH homeostasis in the mitochondrial matrix, interacting with the mitochondrial translation process, could serve as a sign marking the transition from liver inflammation to adipose tissue inflammation. Taken together, our study provides valuable insights into the molecular mechanisms underlying the development of chronic inflammation and associated autoimmune diseases in obesity. • 1. This study provides a comprehensive perspective of time-dependent responses to HFD between liver and adipose tissue. 2. Early chronic liver inflammation is causally linked to subsequent immune cell infiltration in the adipose tissue. • 3. Disturbance of NADH homeostasis and mitochondrial translation emerges as a crucial mechanism driving this transition. [ABSTRACT FROM AUTHOR]

Systemic Lupus Erythematosus (SLE) is a chronic, multisystem, inflammatory autoimmune disease that disproportionately affects women. Trends in SLE prevalence and clinical course differ by ancestry, with those of African American ancestry presenting with more active, severe and rapidly progressive disease than European Americans. Previous research established altered epigenetic signatures in SLE patients compared to controls. However, the contribution of aberrant DNA methylation (DNAm) to the risk of SLE by ancestry and differences among patients with SLE-associated Lupus Nephritis (LN) has not been well described. We evaluated the DNA methylomes of 87 individuals including 41 SLE patients, with and without LN, and 46 controls enrolled in an ancestry diverse, well-characterized cohort study of established SLE (41 SLE patients [20 SLE-LN+, 21 SLE-LN-] and 46 sex-, race- and age-matched controls; 55% African American, 45% European American). Participants were genotyped using the Infinium Global Diversity Array (GDA), and genetic ancestry was estimated using principal components. Genome-wide DNA methylation was initially measured using the Illumina MethylationEPIC 850K Beadchip array followed by methylation-specific qPCR to validate the methylation status at putative loci. Differentially Methylated Positions (DMP) were identified using a case-control approach adjusted for ancestry. We identified a total of 51 DMPs in CpGs among SLE patients compared to controls. Genes proximal to these CpGs were highly enriched for involvement in type I interferon signaling. DMPs among European American SLE patients with LN were similar to African American SLE patients with and without LN. Our findings were validated using an orthogonal, methyl-specific PCR for three SLE-associated DMPs near or proximal to MX1 , USP18 , and IFITM1. Our study confirms previous reports that DMPs in CpGs associated with SLE are enriched in type I interferon genes. However, we show that European American SLE patients with LN have similar DNAm patterns to African American SLE patients irrespective of LN, suggesting that aberrant DNAm alters activity of type I interferon pathway leading to more severe disease independent of ancestry. • Buffy coats from AA SLE patients and EA with LN exhibit similar methylation profiles with enrichment of CpGs near IFN genes. • Findings were validated using methylation-specific qPCR designed for CpGs in MX1, IFITM1, and USP18. • Local ancestry at SLE-associated CpGs does not explain the observed differences in methylation signatures between ancestries. [ABSTRACT FROM AUTHOR]

Systemic lupus erythematosus (SLE) is a chronic systemic autoimmune disease characterized by genetic heterogeneity and an interferon (IFN) signature. The overall landscapes of the heritability of SLE remains unclear. To identify and elucidate the biological functions of rare variants underlying SLE, we conducted analyses of patient-derived induced pluripotent stem cells (iPSCs) in combination with genetic analysis. Two familial SLE patient- and two healthy donor (HD)-derived iPSCs were established. Type 1 IFN-secreting dendritic cells (DCs) were differentiated from iPSCs. Genetic analyses of SLE-iPSCs, and 117 SLE patients and 107 HDs in the ImmuNexUT database were performed independently. Genome editing of the variants on iPSCs was performed with the CRISPR/Cas9 system. Type 1 IFN secretion was significantly increased in DCs differentiated from SLE-iPSCs compared to HD-iPSCs. Genetic analyses revealed a rare variant in the 2′-5′-Oligoadenylate Synthetase Like (OASL) shared between SLE-iPSCs and another independent SLE patient, and significant accumulation of OASL variants among SLE patients (HD 0.93%, SLE 6.84%, OR 8.387) in the database. Genome editing of mutated OASL 202Q to wild-type 202 R or wild-type OASL 202 R to mutated 202Q resulted in reduced or enhanced Type 1 IFN secretion of DCs. Three other OASL variants (R60W, T261S and A447V) accumulated in SLE patients had also capacities to enhance Type 1 IFN secretion in response to dsRNA. We established a patient-derived iPSC-based strategy to investigate the linkage of genotype and phenotype in autoimmune diseases. Detailed case-based investigations using patient-derived iPSCs provide information to unveil the heritability of the pathogenesis of autoimmune diseases. [Display omitted] • Differentiation of Type 1 IFN-producing DCs from SLE patients and HD-derived iPSC. • Combined biological (iPSC disease model) and genomic (ImmuNexUT data base) analysis. • Accumulation of rare variants in OASL that enhance IFN production in SLE patients. • Strategy to investigate the linkage of genotype and phenotype in autoimmune diseases. • Contribute to further understanding of the heritability and the pathogenesis of SLE. [ABSTRACT FROM AUTHOR]

Systemic lupus erythematosus (SLE) is a highly female-biased systemic autoimmune disease, but the molecular basis for this female bias remains incompletely elucidated. B and T lymphocytes from patients with SLE and female-biased mouse models of SLE exhibit features of epigenetic dysregulation on the X chromosome which may contribute to this strong female bias. We therefore examined the fidelity of dynamic X-chromosome inactivation maintenance (dXCIm) in the pathogenesis of two murine models of spontaneous lupus—NZM2328 and MRL/lpr—with disparate levels of female-bias to determine whether impaired dXCIm contributes to the female bias of disease. CD23+ B cells and CD3+ T cells were purified from age-matched C57BL/6 (B6), MRL/lpr, and NZM2328 male and female mice, activated in vitro , and processed for Xist RNA fluorescence in situ hybridization, H3K27me3 immunofluorescence imaging, qPCR, and RNA sequencing analyses. The dynamic relocalization of Xist RNA and the canonical heterochromatin mark, H3K27me3, to the inactive X chromosome was preserved in CD23+ B cells, but impaired in activated CD3+ T cells from the MRL/lpr model (p < 0.01 vs. B6), and even more impaired in the heavily female-biased NZM2328 model (p < 0.001 vs. B6; p < 0.05 vs. MRL/lpr). RNAseq of activated T cells from NZM2328 mice revealed the female-biased upregulation of 32 X-linked genes distributed broadly across the X chromosome, many of which have roles in immune function. Many genes encoding Xist RNA-interacting proteins were also differentially expressed and predominantly downregulated, which may account for the observed mislocalization of Xist RNA to the inactive X chromosome. Although evident in T cells from both the MRL/lpr and NZM2328 models of spontaneous SLE, impaired dXCIm is more severe in the heavily female-biased NZM2328 model. The aberrant X-linked gene dosage in female NZM2328 mice may contribute towards the development of female-biased immune responses in SLE-prone hosts. These findings provide important insights into the epigenetic mechanisms contributing to female-biased autoimmunity. • The dynamic localization of Xist RNA to the inactive X chromosome is preserved in B cells from MRL/lpr and NZM2328 mice. • Xist RNA and heterochromatic marks are impaired in T cells from both strains, and more so in NZM2328 mice, which exhibit female-biased disease. • Activated T cells from NZM2328 mice show female-biased upregulation of X-linked genes with immune functions. [ABSTRACT FROM AUTHOR]

Butyrophilins are surface receptors belonging to the immunoglobulin superfamily. While several members of the butyrophilin family have been implicated in the development of unconventional T cells, butyrophilin 2a2 (Btn2a2) has been shown to inhibit conventional T cell activation. Here, we demonstrate that in steady state, the primary source of Btn2a2 are thymic epithelial cells (TEC). Absence of Btn2a2 alters thymic T cell maturation and bypasses central tolerance mechanisms. Furthermore, Btn2a2−/− mice develop spontaneous autoimmunity resembling human primary Sjögren's Syndrome (pSS), including formation of tertiary lymphoid structures (TLS) in target organs. Ligation of Btn2a2 on developing thymocytes is associated with reduced TCR signaling and CD5 levels, while absence of Btn2a2 results in increased TCR signaling and CD5 levels. These results define a novel role for Btn2a2 in promoting central tolerance by modulating TCR signaling strength and indicate a potential mechanism of pSS development. • Thymic epithelial cells (TEC) are the primary source of Btn2a2 in steady state. • Absence of Btn2a2 impacts thymic T cell maturation and central tolerance. • Btn2a2 promotes central tolerance by modulating TCR signaling strength. • Btn2a2 absence leads to spontaneous autoimmunity resembling Sjögren's Syndrome. [ABSTRACT FROM AUTHOR]

Infectious diseases are commonly implicated as potential initiators of autoimmune diseases (ADs) and represent the most commonly known factor in the development of autoimmunity in susceptible individuals. Epidemiological data and animal studies on multiple ADs suggest that molecular mimicry is one of the likely mechanisms for the loss of peripheral tolerance and the development of clinical disease. Besides molecular mimicry, other mechanisms such as defects in central tolerance, nonspecific bystander activation, epitope-determinant spreading, and/or constant antigenic stimuli, may also contribute for breach of tolerance and to the development of ADs. Linear peptide homology is not the only mechanism by which molecular mimicry is established. Peptide modeling (i.e., 3D structure), molecular docking analyses, and affinity estimation for HLAs are emerging as critical strategies when studying the links of molecular mimicry in the development of autoimmunity. In the current pandemic, several reports have confirmed an influence of SARS-CoV-2 on subsequent autoimmunity. Bioinformatic and experimental evidence support the potential role of molecular mimicry. Peptide dimensional analysis requires more research and will be increasingly important for designing and distributing vaccines and better understanding the role of environmental factors related to autoimmunity. • Similarities between foreign and self-peptides can induce antigenic mimicry, leading to the activation of autoreactive cells. • Mimotopes' tridimensional structure and docking with immune receptors are crucial for understanding molecular mimicry. • Autoimmunity following SARS-CoV-2 infection and vaccination is common, and molecular mimicry could play a paramount role. [ABSTRACT FROM AUTHOR]

ObjectiveMultiple spliceosome components are known autoantigens in systemic sclerosis (SSc). Here we aim to identify new and characterize rare anti-spliceosomal autoantibodies in patients with SSc without known autoantibody specificity. MethodsSera that precipitated spliceosome subcomplexes, as detected by immunoprecipitation-mass spectrometry (IP-MS), were identified from a database of 106 patients with SSc without known autoantibody specificity. New autoantibody specificities were confirmed with immunoprecipitation-western blot. The IP-MS pattern of new anti-spliceosomal autoantibodies was compared with anti-U1 RNP-positive sera of patients with different systemic autoimmune rheumatic diseases and anti-SmD-positive sera of patients with systemic lupus erythematosus (n = 24). ResultsThe NineTeen Complex (NTC) was identified and confirmed as new spliceosomal autoantigen in one patient with SSc. U5 RNP, as well as additional splicing factors, were precipitated by the serum of another patient with SSc. The IP-MS patterns of anti-NTC and anti-U5 RNP autoantibodies were distinct from those of anti-U1 RNP- and anti-SmD-positive sera. Furthermore, there was no difference in IP-MS patterns between a limited number of anti-U1 RNP-positive sera of patients with different systemic autoimmune rheumatic diseases. ConclusionAnti-NTC autoantibodies are a new anti-spliceosomal autoantibody specificity, here first identified in a patient with SSc. Anti-U5 RNP autoantibodies are a distinct but rare anti-spliceosomal autoantibody specificity. All major spliceosomal subcomplexes have now been described as target of autoantibodies in systemic autoimmune diseases. [Display omitted] • Autoantibodies against the NineTeen Complex are identified in a patient with systemic sclerosis. • Anti-U5 RNP autoantibodies are rare but distinct anti-spliceosomal autoantibodies. • All major spliceosomal subcomplexes have now been identified as autoantigen in systemic autoimmune rheumatic diseases. [ABSTRACT FROM AUTHOR]

Severe allergic reactions following SARS-COV-2 vaccination are generally rare, but the reactions are increasingly reported. Some patients may develop prolonged urticarial reactions following SARS-COV-2 vaccination. Herein, we investigated the risk factors and immune mechanisms for patients with SARS-COV-2 vaccines-induced immediate allergy and chronic urticaria (CU). We prospectively recruited and analyzed 129 patients with SARS-COV-2 vaccine–induced immediate allergic and urticarial reactions as well as 115 SARS-COV-2 vaccines–tolerant individuals from multiple medical centers during 2021–2022. The clinical manifestations included acute urticaria, anaphylaxis, and delayed to chronic urticaria developed after SARS-COV-2 vaccinations. The serum levels of histamine, IL-2, IL-4, IL-6, IL-8, IL-17 A, TARC, and PARC were significantly elevated in allergic patients comparing to tolerant subjects (P-values = 4.5 × 10−5–0.039). Ex vivo basophil revealed that basophils from allergic patients could be significantly activated by SARS-COV-2 vaccine excipients (polyethylene glycol 2000 and polysorbate 80) or spike protein (P-values from 3.5 × 10−4 to 0.043). Further BAT study stimulated by patients' autoserum showed positive in 81.3% of patients with CU induced by SARS-COV-2 vaccination (P = 4.2 × 10−13), and the reactions could be attenuated by anti-IgE antibody. Autoantibodies screening also identified the significantly increased of IgE-anti–IL-24, IgG-anti–FcεRI, IgG-anti–thyroid peroxidase (TPO), and IgG-anti-thyroid–related proteins in SARS-COV-2 vaccines-induced CU patients comparing to SARS-COV-2 vaccines-tolerant controls (P-values = 4.6 × 10−10–0.048). Some patients with SARS-COV-2 vaccines-induced recalcitrant CU patients could be successfully treated with anti-IgE therapy. In conclusion, our results revealed that multiple vaccine components, inflammatory cytokines, and autoreactive IgG/IgE antibodies contribute to SARS-COV-2 vaccine–induced immediate allergic and autoimmune urticarial reactions. The immune mechanism of COVID-19 vaccines-induced immediate allergy and urticaria. A). The excipient or component of COVID-19 vaccines (such as PEG 2000, poly 80, tris, or spike protein) can be directly recognized by IgE antibodies, which coupled with their receptor-FcεRI on the mast cells or basophils, resulting in mast cell/basophil degranulation and triggering immediate allergic reactions. B). The excipient or component of COVID-19 vaccines can be recognized by B cells or presented to the T cells, resulting in autoreactive IgG/IgE antibodies production and increased cytokine/chemokine release. Moreover, IgG/IgE autoantibodies against self-antigens (e.g., IL24, TPO, etc.), may promote mast cell or basophil degranulation and cause delayed and chronic urticarial reactions. Abbreviation: IgE, immunoglobulin E; IL-24, Interleukin-24, PEG, polyethylene glycol; poly 80, polysorbate 80; TPO, thyroid peroxidase antibody, tris, tromethamine. [Display omitted] • Vaccine excipients as PEG 2000, polysorbate 80, tromethamine, and spike protein are identified as the culprit allergen(s) of SARS-COV-2 vaccines. • Multiple mast cell/T cell-mediated inflammatory cytokines and chemokines are involved in SARS-COV-2 vaccines-induced allergic reactions. • Autoreactive IgE/IgG antibodies (including IgE-anti-IL24, IgG-anti-TPO, IgG-anti-FcεRI, and IgG-anti-thyroid related proteins), contribute to SARS-COV-2 vaccines–induced autoimmune chronic urticaria. • Some patients with recalcitrant chronic urticaria following SARS-COV-2 vaccination can be successfully treated with anti-IgE therapy. [ABSTRACT FROM AUTHOR]

Hepatocyte nuclear factor 4 α (HNF4α), a transcription factor (TF) essential for embryonic development, has been recently shown to regulate the expression of inflammatory genes. To characterize HNF4a function in immunity, we measured the effect of HNF4α antagonists on immune cell responses in vitro and in vivo. HNF4α blockade reduced immune activation in vitro and disease severity in the experimental model of multiple sclerosis (MS). Network biology studies of human immune transcriptomes unraveled HNF4α together with SP1 and c-myc as master TF regulating differential expression at all MS stages. TF expression was boosted by immune cell activation, regulated by environmental MS risk factors and higher in MS immune cells compared to controls. Administration of compounds targeting TF expression or function demonstrated non-synergic, interdependent transcriptional control of CNS autoimmunity in vitro and in vivo. Collectively, we identified a coregulatory transcriptional network sustaining neuroinflammation and representing an attractive therapeutic target for MS and other inflammatory disorders. • HNF4α supports monocyte and T cell function. • HNF4α, SP1 and c-myc are shared transcription factor network hubs among MS stages. • Hub levels are higher in MS immune cells and regulated by environmental risk factors. • Hubs exert non-synergic, interdependent control of CNS autoimmunity in vivo. [ABSTRACT FROM AUTHOR]

Salivary secretory dysfunction in SS-patients is associated with altered proteostasis, upregulation of ATF6α and components of the ERAD complex, such as SEL1L, and downregulation of XBP-1s and GRP78. Hsa-miR-424–5p is downregulated and hsa-miR-513c-3p is overexpressed in salivary glands from SS-patients. These miRNAs emerged as candidates that could regulate ATF6/SEL1L and XBP-1s/GRP78 levels, respectively. This study aimed to evaluate the effect of IFN-γ on hsa-miR-424–5p and hsa-miR-513c-3p expression and how these miRNAs regulate their targets. In labial salivary glands (LSG) biopsies from 9 SS-patients and 7 control subjects and IFN-γ-stimulated 3D-acini were analyzed. hsa-miR-424–5p and hsa-miR-513c-3p levels were measured by TaqMan assays and their localization by ISH. mRNA, protein levels, and localization of ATF6, SEL1L, HERP, XBP-1s and GRP78 were determined by qPCR, Western blot, or immunofluorescence. Functional and interaction assays were also performed. In LSGs from SS-patients and IFN-γ-stimulated 3D-acini, hsa-miR-424–5p was downregulated and ATF6α and SEL1L were upregulated. ATF6α and SEL1L were decreased after hsa-miR-424–5p overexpression, while ATF6α, SEL1L and HERP increased after hsa-miR-424–5p silencing. Interaction assays revealed that hsa-miR-424–5p targets ATF6α directly. hsa-miR-513c-3p was upregulated and XBP-1s and GRP78 were downregulated. XBP-1s and GRP78 were decreased after hsa-miR-513c-3p overexpression, while increases in XBP-1s and GRP78 were observed after hsa-miR-513c-3p silencing. Furthermore, we determined that hsa-miR-513c-3p targets XBP-1s directly. Significant correlations were found between both miRNA levels and clinical parameters. In conclusion, IFN-γ-dependent hsa-miR-424–5p and hsa-miR-513c-3p levels affect the expression of important factors involved in cellular proteostasis that control secretory function in LSG from SS-patients. • Decreased hsa-miR-424–5p regulates ATF6 and SEL1L upregulation in SG from SS-patients. • hsa-miR-513c-3p overexpression regulates XBP-1s/GRP78 levels in SG from SS-patients. • IFN-γ promotes changes in hsa-miR-424–5p and hsa-miR-513c-3p levels in 3D-acini. • hsa-miR-424–5p/hsa-miR-513c-3p/proteostasis molecules correlate with clinical data. • Altered proteostasis could promote secretory dysfunction and autoimmunity development. [ABSTRACT FROM AUTHOR]

As a ligand-activated transcription factor, the aryl hydrocarbon receptor (AhR) is activated by structurally diverse ligands derived from the environment, diet, microorganisms, and metabolic activity. Recent studies have demonstrated that AhR plays a key role in modulating both innate and adaptive immune responses. Moreover, AhR regulates innate immune and lymphoid cell differentiation and function, which is involved in autoimmune pathogenesis. In this review, we discuss recent advances in understanding the mechanism of activation of AhR and its mediated functional regulation in various innate immune and lymphoid cell populations, as well as the immune-regulatory effect of AhR in the development of autoimmune diseases. In addition, we highlight the identification of AhR agonists and antagonists that may serve as potential therapeutic targets for the treatment of autoimmune disorders. [Display omitted] • The AhR signaling modulates the differentiation and function of innate immune cells and lymphoid cells. • Activation of AhR can regulate the development of autoimmune diseases. • AhR agonists and antagonists serve as potential therapeutic targets for the treatment of autoimmune disorders. [ABSTRACT FROM AUTHOR]

TREX1 encodes a major cellular DNA exonuclease. Mutations of this gene in human cause cellular accumulation of DNA that triggers autoimmune diseases including Aicardi–Goutieres Syndrome (AGS) and systemic lupus erythematosus (SLE). We created a lupus mouse model by engineering a D18 N mutation in the Trex1 gene which inactivates the enzyme and has been found in human patients with lupus-like disorders. The Trex1 D18N/D18N mice exhibited systemic inflammation that consistently recapitulates many characteristics of human AGS and SLE. Importantly, ablation of cGas gene in the Trex1 D18N/D18N mice rescued the lethality and all detectable pathological phenotypes, including multi-organ inflammation, interferon stimulated gene induction, autoantibody production and aberrant T-cell activation. These results indicate that cGAS is a key mediator in the autoimmune disease associated with defective TREX1 function, providing additional insights into disease pathogenesis and guidance to the development of therapeutics for human systemic autoimmune disorders. • The Trex1 D18N/D18N mice recapitulates human AGS and SLE symptoms. • Deletion 1 or 2 alleles of cGas gene in the Trex1 D18N/D18N mice rescued all detectable autoimmune phenotypes. • This study supports cGAS as a therapeutic target for autoimmune disorders in human. [ABSTRACT FROM AUTHOR]

Rheumatoid arthritis (RA) is a chronic autoimmune disease, characterised by painful synovium inflammation, bony erosions, immune activation and the circulation of autoantibodies. Despite recent advances in therapeutics enabling disease suppression, there is a considerable demand for alternative therapeutic strategies as well as optimising those available at present. The relatively low concordance rate between monozygotic twins, 20–30% contrasts with heritability estimates of ∼65%, indicating a substantive role of other risk factors in RA pathogenesis. There is established evidence that RA has an infective component to its aetiology. More recently, differences in the commensal microbiota in RA compared to controls have been identified. Studies have shown that the gut, oral and lung microbiota is different in new onset treatment naïve, and established RA patients, compared to controls. Key taxonomic associations are an increase in abundance of Porphyromonas gingivalis and Prevotella copri in RA patients, compared to healthy controls. Host genetics may provide the link between disease and the microbiome. Genetic influence may be mediated by the host immune system; a differential response to RA associated taxa is suggested. The gut microbiome contains elements which are as much as 30% heritable. A better understanding of the influence of host genetics will shed light onto the role of the microbiome in RA. Here we review the role of the microbiome in RA through the lens of host genetics, and consider future research areas addressing microbiome study design and bioinformatics approaches. Putative interactions mediating the link between host genetic factors, the gut and oral microbiome and rheumatoid arthritis. Image 1 • Rheumatoid arthritis (RA) affects 1% of the population and is highly debilitating. • RA is ~65% heritable, yet the concordance rate between monozygotic twins is just 20–30%, indicating a substantive role of other risk factors. • Studies have shown that the gut, oral and lung microbiome is different in treatment naïve and established RA patients, compared to controls. • Current findings suggest an important influence of host genetics on the microbiome, which may contribute to RA via the host immune system. • Associations of the microbiome with RA described thus far are confounded by host genetics, and future studies need to take account of this. [ABSTRACT FROM AUTHOR]

The primary immunodeficiency diseases (PIDs) include many genetic disorders that affect different components of the innate and adaptive responses. The number of distinct genetic PIDs has increased exponentially with improved methods of detection and advanced laboratory methodology. Patients with PIDs have an increased susceptibility to infectious diseases and non-infectious complications including allergies, malignancies and autoimmune diseases (ADs), the latter being the first manifestation of PIDs in several cases. There are two types of PIDS. Monogenic immunodeficiencies due to mutations in genes involved in immunological tolerance that increase the predisposition to develop autoimmunity including polyautoimmunity, and polygenic immunodeficiencies characterized by a heterogeneous clinical presentation that can be explained by a complex pathophysiology and which may have a multifactorial etiology. The high prevalence of ADs in PIDs demonstrates the intricate relationships between the mechanisms of these two conditions. Defects in central and peripheral tolerance, including mutations in AIRE and T regulatory cells respectively, are thought to be crucial in the development of ADs in these patients. In fact, pathology that leads to PID often also impacts the Treg/Th17 balance that may ease the appearance of a proinflammatory environment, increasing the odds for the development of autoimmunity. Furthermore, the influence of chronic and recurrent infections through molecular mimicry, bystander activation and super antigens activation are supposed to be pivotal for the development of autoimmunity. These multiple mechanisms are associated with diverse clinical subphenotypes that hinders an accurate diagnosis in clinical settings, and in some cases, may delay the selection of suitable pharmacological therapies. Herein, a comprehensively appraisal of the common mechanisms among these conditions, together with clinical pearls for treatment and diagnosis is presented. • Primary immunodeficiencies are frequently accompanied by autoimmune disease. • T cell proliferation, and activity can influence the balance between Treg and T helper cells. • Infections play a role via molecular mimicry, innocent bystander, or epitope spreading. • Autoimmunity is a "warning sign" for suspecting an immunodeficiency disorder. [ABSTRACT FROM AUTHOR]