Genome-wide association studies have identified SH2B3 as an important non-MHC gene for islet autoimmunity and type 1 diabetes (T1D). In this study, we found a single SH2B3 haplotype significantly associated with increased risk for human T1D. Fine mapping has demonstrated the most credible causative variant is the single nucleotide rs3184504*T polymorphism in SH2B3. To better characterize the role of SH2B3 in T1D, we used mouse modeling and found a T-cell-intrinsic role for SH2B3 regulating peripheral tolerance. SH2B3 deficiency had minimal effect on T-cell receptor (TCR) signaling or proliferation across antigen doses, yet enhanced cell survival and cytokine signaling including common γ-chain-dependent and interferon-γ receptor signaling. SH2B3-deficient naive CD8+ T cells showed augmented STAT5-MYC and effector-related gene expression partially reversed with blocking autocrine IL-2 in culture. Using the rat insulin promoter-membrane-bound ovalbumin (RIP-mOVA) model, we found CD8+ T cells lacking SH2B3 promoted early islet destruction and diabetes without requiring CD4+ T cell help. SH2B3-deficient cells demonstrated increased survival and reduced activation-induced cell death. Lastly, we created a spontaneous NOD.Sh2b3-/- mouse model and found markedly increased incidence and accelerated T1D across sexes. Collectively, these studies identify SH2B3 as a critical mediator of peripheral T-cell tolerance limiting the T-cell response to self-antigens.

The rs3184504*T polymorphism, encoding a hypomorphic variant of the negative regulator SH2B3, strongly associates with type 1 diabetes. SH2B3 deficiency results in hypersensitivity to cytokines, including IL-2 and IFN-γ, in murine CD4+ and CD8+ T cells, particularly postactivation. SH2B3-deficient CD8+ T cells exhibit a transcriptome comparable to wild-type CD8+ T cells at baseline, but, upon antigen stimulation, SH2B3-deficient cells upregulate genes characteristic of enhanced JAK-STAT signaling and effector functions. T-cell-intrinsic SH2B3 deficiency results in severe islet destruction in an adoptive transfer murine type 1 diabetes model, whereas global SH2B3 deficiency accelerates spontaneous NOD diabetes across sexes.

Type 1 diabetes (T1D) results from T cell-mediated destruction of pancreatic β-cells, requiring lifelong insulin therapy and glycemic monitoring. While genetic risk, particularly HLA class II, is well established, rising T1D incidence and earlier onset suggest environmental modifiers. Mouse models show that microbiome alterations influence β-cell autoimmunity, and human studies link microbiome composition to T1D, though specific microbial regulators remain unidentified. We examine host-microbiome interactions, including studies implicating enteroviruses in modulating islet autoimmunity. Mechanistic discoveries of microbial effects on diabetes have emerged from mouse model studies. We consider clinical applications, including microbiota-targeted therapies and biomarkers of microbiome-immune crosstalk. Future research should integrate microbial, genetic, environmental, and immune data using multi-omic approaches. Collaborative efforts combining immunology, microbiology, and clinical metadata will drive discovery and precision medicine in T1D.

Protein tyrosine phosphatase non-receptor 2 (PTPN2) is a well-established protein tyrosine phosphatase (PTP) that counterbalances protein tyrosine kinases (PTKs) activity by dephosphorylating tyrosine residues. Accumulating evidence demonstrates that dysregulated PTPN2 expression or activity regulates cancer biology, drives immune evasion, and confers resistance to immune checkpoint blockade therapy, establishing it as a compelling therapeutic target for cancer immunotherapy. Mechanistically, PTPN2 exerts immunosuppressive effects by dephosphorylating and negatively regulating immune response signaling, thereby dampening antitumor immunity and fostering an immunosuppressive tumor microenvironment. Recent breakthroughs in PTPN2 inhibitor development, such as small molecules, natural compounds, and PROTAC degraders, have shown promising efficacy in restoring immune-mediated tumor control. However, the anti-tumor therapy targeting PTPN2 still faces challenges, including its controversial role in some tumors, potential side effects, and the lack of highly effective and selective antagonists. In this comprehensive review, we synthesize the crucial functions of PTPN2 in tumor progression and immune regulation, systematically present the latest research progress of PTPN2 inhibitors, critically analyze unresolved hurdles in drug development, and provide strategic perspectives on addressing these challenges, with the hope of accelerating the clinical translation of PTPN2-targeted therapy from bench to bedside.

Type 1 diabetes (T1D) results from the autoimmune destruction of the insulin-producing β cells. Genetic factors account for approximately 50% of the risk for T1D but, by the late 1990s, the genetic basis was limited. The Type 1 Diabetes Genetics Consortium (T1DGC) was formed in 2002 to accelerate discovery of genes contributing to T1D risk through a grant from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) to assemble existing data and samples from affected sib-pair families and to establish new collections. In recognition of the 75th anniversary of the NIDDK, this manuscript highlights the contributions made by the T1DGC to understanding the genetic basis of T1D using both family (for linkage) and case-control (for genome-wide association) designs. The T1DGC conducted large-scale genetic research and used fine mapping to define risk regions. The T1DGC data, results, and samples have been made available to the scientific community, leading to the discovery of more than 100 loci associated with T1D risk, many with small effects and relevant to autoimmune pathways. The T1DGC not only expanded the list of genes contributing to disease risk but also identified noncoding genetic variation in disease-relevant cell types that contribute to the etiology of T1D. The success of the T1DGC and the NIDDK investment in the global consortium is highlighted in its continuing effect on mapping genetic variants to their function and identifying pathways that provide new targets for the prediction, prevention, and treatment of T1D.

Autoimmune destruction of pancreatic β cells results in type 1 diabetes (T1D), with pancreatic immune infiltrate representing a key feature in this process. However, characterization of the immunological processes occurring in human pancreatic lymphatic tissues is lacking. Here, we conduct a comprehensive study of immune cells from pancreatic, mesenteric, and splenic lymphatic tissues of non-diabetic control (ND), β cell autoantibody-positive non-diabetic (AAb+), and T1D donors using flow cytometry and CITEseq. Compared to ND pancreas-draining lymph nodes (pLN), AAb+ and T1D donor pLNs display decreased CD4+ Treg and increased stem-like CD8+ T cell signatures, while only T1D donor pLNs exhibit naive T cell and NK cell differentiation. Mesenteric LNs have modulations only in CD4+ Tregs and naive cells, while splenocytes lack these perturbations. Further, T cell expression of activation markers and IL7 receptor correlate with T1D genetic risk. These results demonstrate tissue-restricted immune changes occur before and after T1D onset.

The interleukin-2 receptor alpha chain (IL2RA) gene has been implicated in multiple sclerosis (MS) susceptibility, particularly through the rs2104286 and rs12722489 SNPs. However, previous studies have yielded inconsistent results across different populations, likely due to small sample sizes and ethnic variations. This study aimed to investigate the association of IL2RA SNPs with MS risk in eastern Iranian population and through a comprehensive meta-analysis. Our case-control study included 400 Iranian individuals from North Khorasan and Sistan & Baluchistan provinces, comprising 200 MS patients across all subtypes and genders and 200 controls. The meta-analysis incorporated pooled odds ratios (ORs) with 95 % confidence intervals (CIs) to assess the strength of these associations. Our case-control findings demonstrated a significant association between rs2104286 and MS risk, which was further supported by the meta-analysis in Iranian populations. Specifically, the association was observed at both the genotype (P = 0.001) and allelic (P = 0.003) levels in North Khorasan and at the genotype level in Sistan & Baluchistan (P = 0.001). A global meta-analysis of rs2104286, encompassing 24,931 MS patients and 36,036 controls, revealed a significant association between the A allele and all genotype models with increased MS risk (P < 0.05). Similarly, a meta-analysis of rs12722489, including 19,797 MS patients and 32,085 controls, identified the CC + CT genotype as a risk factor for MS (P = 0.04). In conclusion, our findings suggest that the rs2104286 A allele and rs12722489 CC + CT genotype are associated with an increased risk of MS in both Caucasian and Asian populations, including Iranians.

Type 1 diabetes (T1D) and other autoimmune diseases (AIDs) often co-occur in families. Leveraging data from 58,284 family trios in Finnish nationwide registers (FinRegistry), we identified that, of 50 parental AIDs examined, 15 were associated with an increased T1D risk in offspring. These identified epidemiological associations were further assessed in 470,000 genotyped Finns from the FinnGen study through comprehensive genetic analyses, partitioned into human leukocyte antigen (HLA) and non-HLA variations. Using FinnGen's 12,563 trios, a within-family polygenic transmission analysis demonstrated that the aggregation of many parental AIDs with offspring T1D can be partially explained by HLA and non-HLA polymorphisms in a disease-dependent manner. We therefore proposed a parental polygenic score (PGS), incorporating both HLA and non-HLA polymorphisms, to characterize the cumulative risk pattern of T1D in offspring. This raises an intriguing possibility of using parental PGS, in conjunction with clinical diagnoses, to inform individuals about T1D risk in their offspring.

Macrophages reside in all organs and participate in homeostatic- and immune regulative processes. Little is known about pancreatic macrophage gene expression. In the present study, global gene expression was characterized in human pancreatic macrophage subpopulations. CD206- and CD206 + macrophages were sorted separately from pancreatic islets and exocrine tissue to high purity using flow cytometry, followed by RNA-seq analysis. Comparing CD206- with CD206 + macrophages, CD206- showed enrichment in histones, proliferation and cell cycle regulation, glycolysis and SPP1-associated immunosuppressive polarization while CD206 + showed enrichment in complement and coagulation-, IL-10 and IL-2RA immune regulation, as well as scavenging-related gene sets. Comparing islet CD206- with exocrine CD206-, enrichments in islet samples included two sets involved in immune regulation, while enrichments in exocrine samples included sets related to extracellular matrix and immune activation. Fewer differences were found between CD206 + macrophages, with enrichments in islet samples including two IL2-RA related gene sets, while enrichments in exocrine samples included sets related to extracellular matrix and immune activation. Comparing macrophages between individuals with normoglycemia, elevated HbA1c or type 2 diabetes, only a few diverse differentially expressed genes were identified. This work characterizes global gene expression and identifies differences between CD206- and CD206 + macrophage populations within the human pancreas.

Rheumatoid arthritis (RA) has become a serious threat to human health and quality of life worldwide. Previous studies have demonstrated that genetic factors play a crucial role in the onset and progression of RA. Due to the rapid development of genome-wide association study (GWAS) and large-scale genetic analysis, GWAS research on RA has received widespread attention in recent years. Therefore, we conducted a comprehensive visualization and bibliometric analysis of publications to identify hotspots and future trends in GWAS research on RA.

Literature on RA and GWAS published between 2002 and 2024 was extracted from the Web of Science Core Collection database by strategic screening. Collected data were further analyzed by using VOSviewer, CiteSpace, and Excel. The collaborations networks of countries, authors, institutions, and the co-citation networks of publications were visualized. Finally, research hotspots and fronts were examined.

A total of 713 publications with 45,773 citations were identified. The number of publications and citations has had a significant surge since 2007. The United States contributed the most publications globally. Okada, Yukinori, was the most influential author. The most productive institution in this field was the University of Manchester. The analysis of keywords revealed that "mendelian randomization analysis", "association", "innate", "instruments", "bias", "pathogenesis", and "genome-wide association study" are likely to be the frontiers of research in this field.

This study can be used to predict future research advances in the fields of GWAS on RA and helps to promote academic collaboration among scholars.

Type 1 diabetes (T1D) is a complex autoimmune disorder distinguished by the infiltration of immune cells into pancreatic islets, primarily resulting in damage to pancreatic β-cells. Despite extensive research, the precise pathogenesis of T1D remains elusive, with its etiology linked to a complex interplay of genetic, immune, and environmental factors. While genetic predispositions, such as HLA and other susceptibility genes, are necessary, they do not fully account for disease development. Environmental influences such as viral infections and dietary factors may contribute to the disease by affecting the immune system and epigenetic modifications. Additionally, endogenous retroviruses (ERVs) might play a role in T1D pathogenesis. Current therapeutic approaches, including insulin replacement therapy, immune omodulatory therapy, autoantigen immunotherapy, organ transplantation, and genetic modification, offer potential to alter disease progression but are still constrained by limitations. This review presents updated knowledge on T1D, with a focus on risk factors, predisposing hypotheses, and recent advancements in therapeutic strategies.

The increased prevalence of chronic metabolic disorders, including obesity and type 2 diabetes and their associated comorbidities, are among the world's greatest health and economic challenges. Metabolic homeostasis involves a complex interplay between hormones that act on different tissues to elicit changes in the storage and utilization of energy. Such processes are mediated by tyrosine phosphorylation-dependent signaling, which is coordinated by the opposing actions of protein tyrosine kinases and protein tyrosine phosphatases (PTPs). Perturbations in the functions of PTPs can be instrumental in the pathophysiology of metabolic diseases. The goal of this review is to highlight key advances in our understanding of how PTPs control body weight and glucose metabolism, as well as their contributions to obesity and type 2 diabetes. The emerging appreciation of the integrated functions of PTPs in metabolism, coupled with significant advances in pharmaceutical strategies aimed at targeting this class of enzymes, marks the advent of a new frontier in combating metabolic disorders.

Coronavirus disease (COVID-19), caused by severe acquired respiratory syndrome-Coronavirus-2 (SARS-CoV-2), triggered a global pandemic with severe medical and socioeconomic consequences. Although fatality rates are higher among the elderly and those with underlying comorbidities, host factors that promote susceptibility to SARS-CoV-2 infection and severe disease are poorly understood. Although individuals with certain autoimmune/inflammatory disorders show increased susceptibility to viral infections, there is incomplete knowledge of SARS-CoV-2 susceptibility in these diseases. The aim of our study was to investigate whether the autoimmunity risk gene, PTPN2, which also confers elevated risk to develop inflammatory bowel disease, affects susceptibility to SARS-CoV-2 viral uptake.

Using samples from PTPN2 genotyped patients with inflammatory bowel disease, PTPN2-deficient mice, and human intestinal and lung epithelial cell lines, we investigated how PTPN2 affects expression of the SARS-CoV-2 receptor angiotensin converting enzyme 2 (ACE2), and uptake of virus-like particles expressing the SARS-CoV2 spike protein and live SARS-CoV-2 virus.

We report that the autoimmune PTPN2 loss-of-function risk variant rs1893217 promotes expression of the SARS-CoV-2 receptor, ACE2, and increases cellular entry of SARS-CoV-2 spike protein and live virus. Elevated ACE2 expression and viral entry were mediated by increased Janus kinase-signal transducers and activators of transcription signaling and were reversed by the Janus kinase inhibitor, tofacitinib.

Collectively, our findings uncover a novel risk biomarker for increased expression of the SARS-CoV-2 receptor and viral entry, and identify a clinically approved therapeutic agent to mitigate this risk.

Type 1 diabetes mellitus (T1D) is a complicated illness marked by the death of insulin- producing pancreatic beta cells, which ultimately leads to insulin insufficiency and hyperglycemia. T lymphocytes are considered to destroy pancreatic beta cells in the etiology of T1D as a result of hereditary and environmental factors. Although the latter factors are very important causes of T1D development, this disease is very genetically predisposed, so there is a significant genetic component to T1D susceptibility. Among the T1D-associated gene mutations, those that affect genes that encode the traditional Human Leukocyte Antigens (HLA) entail the highest risk of T1D development. Accordingly, the results of decades of genetic linkage and association studies clearly demonstrate that mutations in the HLA genes are the most associated mutations with T1D. They can, therefore, be used as biomarkers for prediction strategies and may even prove to be of value for personalized treatments. Other immunity-associated genetic loci are also associated with higher T1D risk. Indeed, T1D is considered an autoimmune disease. Its prevalence is rising globally, especially among children and young people. Given the global rise of, and thus interest in, autoimmune diseases, here we present a short overview of the link between immunity, especially HLA, genes and T1D.

Non-obese diabetic (NOD) mice spontaneously develop autoimmune diabetes and have enabled the identification of several loci associated with diabetes susceptibility, termed insulin-dependent diabetes (Idd). The generation of congenic mice has allowed the characterization of the impact of several loci on disease susceptibility. For instance, NOD.B6-Idd1 and B6.NOD-Idd1 congenic mice were instrumental in demonstrating that susceptibility alleles at the MHC locus (known as Idd1) are necessary but not sufficient for autoimmune diabetes progression. We previously showed that diabetes resistance alleles at the Idd2 locus provide significant protection from autoimmune diabetes onset, second to Idd1. In search of the minimal genetic factors required for T1D onset, we generated B6.Idd1.Idd2 double-congenic mice. Although the combination of Idd1 and Idd2 is not sufficient to induce diabetes onset, we observed immune infiltration in the exocrine pancreas of B6.Idd2 mice, as well as an increase in neutrophils and pancreatic tissue fibrosis. In addition, we observed phenotypic differences in T-cell subsets from B6.Idd1.Idd2 mice relative to single-congenic mice, suggesting epistatic interaction between Idd1 and Idd2 in modulating T-cell function. Altogether, these data show that Idd1 and Idd2 susceptibility alleles are not sufficient for autoimmune diabetes but contribute to inflammation and immune infiltration in the pancreas.

Autoimmune disorders (ADs) pose significant health and economic burdens globally, characterized by the body's immune system mistakenly attacking its own tissues. While the precise mechanisms driving their development remain elusive, a combination of genetic predisposition(s) and environmental triggers is implicated. Interleukin-27 (IL-27), among numerous cytokines involved, has emerged as a key regulator, exhibiting dual roles in immune modulation. This review delves into the molecular structure and signaling mechanisms of IL-27, highlighting its diverse effects on various immune cells. Additionally, it explores the involvement of IL-27 in autoimmune diseases, such as multiple sclerosis (MS) and rheumatoid arthritis (RA), offering insights into its potential therapeutic implications. Moreover, its involvement in autoimmune diseases like type 1 diabetes (T1D), inflammatory bowel disease (IBD), myasthenia gravis (MG), Sjögren's syndrome (SS), and Guillain-Barré syndrome (GBS) is multifaceted, with potential diagnostic and therapeutic implications across these conditions. Further research is essential to fully understand IL-27's mechanisms of action and therapeutic potential in autoimmune diseases.

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a member of the TNF protein superfamily and was initially identified as a protein capable of inducing apoptosis in cancer cells. In addition, TRAIL can promote pro-survival and proliferation signaling in various cell types. Subsequent studies have demonstrated that TRAIL plays several important roles in immunoregulation, immunosuppression, and immune effector functions. Type 1 diabetes (T1D) is an autoimmune disease characterized by hyperglycemia due to the loss of insulin-producing β-cells, primarily driven by T-cell-mediated pancreatic islet inflammation. Various genetic, epigenetic, and environmental factors, in conjunction with the immune system, contribute to the initiation, development, and progression of T1D. Recent reports have highlighted TRAIL as an important immunomodulatory molecule with protective effects on pancreatic islets. Experimental data suggest that TRAIL protects against T1D by reducing the proliferation of diabetogenic T cells and pancreatic islet inflammation and restoring normoglycemia in animal models. In this review, we aimed to summarize the consequences of TRAIL action in T1D, focusing on and discussing its signaling mechanisms, role in the immune system, and protective effects in T1D.

Cancer immunotherapy aims to initiate or amplify immune responses that eliminate cancer cells and create immune memory to prevent relapse. Immune checkpoint inhibitors (ICIs), which target coinhibitory receptors on immune effector cells, such as CTLA-4 and PD-(L)1, have made significant strides in cancer treatment. However, they still face challenges in achieving widespread and durable responses. The effectiveness of anticancer immunity, which is determined by the interplay of coinhibitory and costimulatory signals in tumor-infiltrating immune cells, highlights the potential of costimulatory receptors as key targets for immunotherapy. This review explores our current understanding of the functions of CD2 and CD226, placing a special emphasis on their potential as novel agonist targets for cancer immunotherapy. CD2 and CD226, which are present mainly on T and NK cells, serve important functions in cell adhesion and recognition. These molecules are now recognized for their costimulatory benefits, particularly in the context of overcoming T-cell exhaustion and boosting antitumor responses. The importance of CD226, especially in anti-TIGIT therapy, along with the CD2‒CD58 axis in overcoming resistance to ICI or chimeric antigen receptor (CAR) T-cell therapies provides valuable insights into advancing beyond the current barriers of cancer immunotherapy, underscoring their promise as targets for novel agonist therapy.

Previous genome-wide association studies (GWAS) have indicated the involvement of shared (population-nonspecific) and nonshared (population-specific) susceptibility genes in the pathogenesis of primary biliary cholangitis (PBC) among European and East-Asian populations. Although a meta-analysis of these distinct populations has recently identified more than 20 novel PBC susceptibility loci, analyses of population-specific genetic architecture are still needed for a more comprehensive search for genetic factors in PBC.

Protein tyrosine phosphatase nonreceptor type 2 ( PTPN2) was identified as a novel PBC susceptibility gene locus through GWAS and subsequent genome-wide meta-analysis involving 2181 cases and 2699 controls from the Japanese population (GWAS-lead variant: rs8098858, p = 2.6 × 10 -8 ). In silico and in vitro functional analyses indicated that the risk allele of rs2292758, which is a primary functional variant, decreases PTPN2 expression by disrupting Sp1 binding to the PTPN2 promoter in T follicular helper cells and plasmacytoid dendritic cells. Infiltration of PTPN2-positive T-cells and plasmacytoid dendritic cells was confirmed in the portal area of the PBC liver by immunohistochemistry. Furthermore, transcriptomic analysis of PBC-liver samples indicated the presence of a compromised negative feedback loop in vivo between PTPN2 and IFNG in patients carrying the risk allele of rs2292758.

PTPN2 , a novel susceptibility gene for PBC in the Japanese population, may be involved in the pathogenesis of PBC through an insufficient negative feedback loop caused by the risk allele of rs2292758 in IFN-γ signaling. This suggests that PTPN2 could be a potential molecular target for PBC treatment.

Multiple rodent models have been developed to study the basis of type 1 diabetes (T1D). However, nonobese diabetic (NOD) mice and derivative strains still provide the gold standard for dissecting the basis of the autoimmune responses underlying T1D. Here, we review the developmental origins of NOD mice, and how they and derivative strains have been used over the past several decades to dissect the genetic and immunopathogenic basis of T1D. Also discussed are ways in which the immunopathogenic basis of T1D in NOD mice and humans are similar or differ. Additionally reviewed are efforts to "humanize" NOD mice and derivative strains to provide improved models to study autoimmune responses contributing to T1D in human patients.

Type-1 diabetes is a multifactorial disease characterized by genetic and environmental factors that contribute to its development and progression. Despite progress in the management of type-1 diabetes, the final goal of curing the disease is yet to be achieved. To establish effective methods for the prevention, intervention, and cure of the disease, the molecular mechanisms and pathways involved in its development and progression should be clarified. One effective approach is to identify genes responsible for disease susceptibility and apply information obtained from the function of genes in disease etiology for the protection, intervention, and cure of type-1 diabetes. In this review, we discuss the genetic basis of type-1 diabetes, along with prospects for its prevention, intervention, and cure for type-1 diabetes.

Autoimmune destruction of pancreatic β cells results in type 1 diabetes (T1D), with pancreatic immune infiltrate representing a key feature in this process. Studies of human T1D immunobiology have predominantly focused on circulating immune cells in the blood, while mouse models suggest diabetogenic lymphocytes primarily reside in pancreas-draining lymph nodes (pLN). A comprehensive study of immune cells in human T1D was conducted using pancreas draining lymphatic tissues, including pLN and mesenteric lymph nodes, and the spleen from non-diabetic control, β cell autoantibody positive non-diabetic (AAb+), and T1D organ donors using complementary approaches of high parameter flow cytometry and CITEseq. Immune perturbations suggestive of a proinflammatory environment were specific for T1D pLN and AAb+ pLN. In addition, certain immune populations correlated with high T1D genetic risk independent of disease state. These datasets form an extensive resource for profiling human lymphatic tissue immune cells in the context of autoimmunity and T1D.

An exome sequencing strategy employed to identify pathogenic variants in patients with pediatric-onset systemic lupus or Evans syndrome resulted in the discovery of six novel monoallelic mutations in PTPN2. PTPN2 is a phosphatase that acts as an essential negative regulator of the JAK/STAT pathways. All mutations led to a loss of PTPN2 regulatory function as evidenced by in vitro assays and by hyperproliferation of patients' T cells. Furthermore, patients exhibited high serum levels of inflammatory cytokines, mimicking the profile observed in individuals with gain-of-function mutations in STAT factors. Flow cytometry analysis of patients' blood cells revealed typical alterations associated with autoimmunity and all patients presented with autoantibodies. These findings further supported the notion that a loss of function in negative regulators of cytokine pathways can lead to a broad spectrum of autoimmune manifestations and that PTPN2 along with SOCS1 haploinsufficiency constitute a new group of monogenic autoimmune diseases that can benefit from targeted therapy.

Type 1 diabetes (T1D) mellitus is a chronic illness in children and teens, with rising global incidence rates. It stems from an autoimmune attack on pancreatic β cells, leading to insufficient insulin production. Genetic susceptibility and environmental triggers initiate this process. Early detection is possible by identifying multiple autoantibodies, which aids in predicting future T1D development. A new staging system highlights T1D's onset with islet autoimmunity rather than symptoms. Family members of T1D patients face a significantly increased risk of T1D. Italy recently passed a law mandating national T1D screening for pediatric populations. Measurements of β cell function continue to be essential in assessing efficacy, and different models have been proposed, but more appropriate biomarkers are mandatory for both progression studies before the onset of diabetes and during therapeutic monitoring. Biomarkers like microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs) play key roles in T1D pathogenesis by regulating gene expression. Understanding their roles offers insights into T1D mechanisms and potential therapeutic targets. In this review, we summarized recent progress in the roles of some non-coding RNAs (ncRNAs) in the pathogenesis of T1D, with particular attention to miRNAs, lncRNAs, and circRNAs.

Genome-wide association studies have identified SH2B3 as an important non-MHC gene for islet autoimmunity and type 1 diabetes (T1D). In this study, we found a single SH2B3 haplotype significantly associated with increased risk for human T1D, and this haplotype carries the single nucleotide variant rs3184504*T in SH2B3. To better characterize the role of SH2B3 in T1D, we used mouse modeling and found a T cell-intrinsic role for SH2B3 regulating peripheral tolerance. SH2B3 deficiency had minimal effect on TCR signaling or proliferation across antigen doses, yet enhanced cell survival and cytokine signaling including common gamma chain-dependent and interferon-gamma receptor signaling. SH2B3 deficient CD8+T cells showed augmented STAT5-MYC and effector-related gene expression partially reversed with blocking autocrine IL-2 in culture. Using the RIP-mOVA model, we found CD8+ T cells lacking SH2B3 promoted early islet destruction and diabetes without requiring CD4+ T cell help. SH2B3-deficient cells demonstrated increased survival post-transfer compared to control cells despite a similar proliferation profile in the same host. Next, we created a spontaneous NOD .Sh2b3 -/- mouse model and found markedly increased incidence and accelerated T1D across sexes. Collectively, these studies identify SH2B3 as a critical mediator of peripheral T cell tolerance limiting the T cell response to self-antigens.

The rs3184504 polymorphism, encoding a hypomorphic variant of the negative regulator SH2B3, strongly associates with T1D.SH2B3 deficiency results in hypersensitivity to cytokines, including IL-2, in murine CD4+ and CD8+ T cells.SH2B3 deficient CD8+ T cells exhibit a comparable transcriptome to wild-type CD8+ T cells at baseline, but upon antigen stimulation SH2B3 deficient cells upregulate genes characteristic of enhanced JAK/STAT signaling and effector functions.We found a T-cell intrinsic role of SH2B3 leading to severe islet destruction in an adoptive transfer murine T1D model, while global SH2B3 deficiency accelerated spontaneous NOD diabetes across sexes.

Type 1 diabetes (T1D) results from a complex interplay of genetic predisposition, immunological dysregulation, and environmental triggers, that culminate in the destruction of insulin-secreting pancreatic β cells. This review provides a comprehensive examination of the multiple factors underpinning T1D pathogenesis, to elucidate key mechanisms and potential therapeutic targets. Beginning with an exploration of genetic risk factors, we dissect the roles of human leukocyte antigen (HLA) haplotypes and non-HLA gene variants associated with T1D susceptibility. Mechanistic insights gleaned from the NOD mouse model provide valuable parallels to the human disease, particularly immunological intricacies underlying β cell-directed autoimmunity. Immunological drivers of T1D pathogenesis are examined, highlighting the pivotal contributions of both effector and regulatory T cells and the multiple functions of B cells and autoantibodies in β-cell destruction. Furthermore, the impact of environmental risk factors, notably modulation of host immune development by the intestinal microbiome, is examined. Lastly, the review probes human longitudinal studies, unveiling the dynamic interplay between mucosal immunity, systemic antimicrobial antibody responses, and the trajectories of T1D development. Insights garnered from these interconnected factors pave the way for targeted interventions and the identification of biomarkers to enhance T1D management and prevention strategies.

Forkhead box P3 (FOXP3) is the master fate-determining transcription factor in regulatory T (Treg) cells and is essential for their development, function, and homeostasis. Mutations in FOXP3 cause immunodysregulation polyendocrinopathy enteropathy X-linked (IPEX) syndrome, and aberrant expression of FOXP3 has been implicated in other diseases such as multiple sclerosis and cancer. We previously demonstrated that pre-mRNA splicing of FOXP3 RNAs is highly sensitive to levels of DExD-box polypeptide 39B (DDX39B), and here we investigate the mechanism of this sensitivity. FOXP3 introns have cytidine (C)-rich/uridine (U)-poor polypyrimidine (py) tracts that are responsible for their inefficient splicing and confer sensitivity to DDX39B. We show that there is a deficiency in the assembly of commitment complexes (CCs) on FOXP3 introns, which is consistent with the lower affinity of U2AF2 for C-rich/U-poor py tracts. Our data indicate an even stronger effect on the conversion of CCs to pre-spliceosomes. We propose that this is due to an altered conformation that U2AF2 adopts when it binds to C-rich/U-poor py tracts and that this conformation has a lower affinity for DDX39B. As a consequence, CCs assembled on FOXP3 introns are defective in recruiting DDX39B, and this leads to the inefficient assembly of pre-spliceosome complexes.

Diabetes, a chronic metabolic disorder disrupting blood sugar regulation, has emerged as a prominent silent pandemic. Uncontrolled diabetes predisposes an individual to develop fatal complications like cardiovascular disorders, kidney damage, and neuropathies and aggravates the severity of treatable infections. Escalating cases of Type 1 and Type 2 diabetes correlate with a global upswing in diabetes-linked mortality. As a growing global concern with limited preventive interventions, diabetes necessitates extensive research to mitigate its healthcare burden and assist ailing patients. An altered immune system exacerbated by chronic hyperinflammation heightens the susceptibility of diabetic individuals to microbial infections, including notable viruses like SARS-CoV-2, dengue, and influenza. Given such a scenario, we scrutinized the literature and compiled molecular pathways and signaling cascades related to immune compartments in diabetics that escalate the severity associated with the above-mentioned viral infections in them as compared to healthy individuals. The pathogenesis of these viral infections that trigger diabetes compromises both innate and adaptive immune functions and pre-existing diabetes also leads to heightened disease severity. Lastly, this review succinctly outlines available treatments for diabetics, which may hold promise as preventive or supportive measures to effectively combat these viral infections in the former.

Type 2 innate lymphoid cells (ILC2s) play a pivotal role in type 2 asthma. CD226 is a costimulatory molecule involved in various inflammatory diseases.

We aimed to investigate CD226 expression and function within human and mouse ILC2s, and to assess the impact of targeting CD226 on ILC2-mediated airway hyperreactivity (AHR).

We administered IL-33 intranasally to wild-type mice, followed by treatment with anti-CD226 antibody or isotype control. Pulmonary ILC2s were sorted for ex vivo analyses through RNA sequencing and flow cytometry. Next, we evaluated the effects of CD226 on AHR and lung inflammation in wild-type and Rag2-/- mice. Additionally, we compared peripheral ILC2s from healthy donors and asthmatic patients to ascertain the role of CD226 in human ILC2s.

Our findings demonstrated an inducible expression of CD226 in activated ILC2s, enhancing their cytokine secretion and effector functions. Mechanistically, CD226 alters intracellular metabolism and enhances PI3K/AKT and MAPK signal pathways. Blocking CD226 ameliorates ILC2-dependent AHR in IL-33 and Alternaria alternata-induced models. Interestingly, CD226 is expressed and inducible in human ILC2s, and its blocking reduces cytokine production. Finally, we showed that peripheral ILC2s in asthmatic patients exhibited elevated CD226 expression compared to healthy controls.

Our findings underscore the potential of CD226 as a novel therapeutic target in ILC2s, presenting a promising avenue for ameliorating AHR and allergic asthma.

In the context of inflammation, T cell activation occurs by the concerted signals of the T cell receptor (TCR), co-stimulatory receptors ligation, and a pro-inflammatory cytokine microenvironment. Fine-tuning these signals is crucial to maintain T cell homeostasis and prevent self-reactivity while offering protection against infectious diseases and cancer. Recent developments in understanding the complex crosstalk between the molecular events controlling T cell activation and the balancing regulatory cues offer novel approaches for the development of T cell-based immunotherapies. Among the complex regulatory processes, the balance between protein tyrosine kinases (PTK) and the protein tyrosine phosphatases (PTPs) controls the transcriptional and metabolic programs that determine T cell function, fate decision, and activation. In those, PTPs are de facto regulators of signaling in T cells acting for the most part as negative regulators of the canonical TCR pathway, costimulatory molecules such as CD28, and cytokine signaling. In this review, we examine the function of two close PTP homologs, PTP1B (PTPN1) and T-cell PTP (TCPTP; PTPN2), which have been recently identified as promising candidates for novel T-cell immunotherapeutic approaches. Herein, we focus on recent studies that examine the known contributions of these PTPs to T-cell development, homeostasis, and T-cell-mediated immunity. Additionally, we describe the signaling networks that underscored the ability of TCPTP and PTP1B, either individually and notably in combination, to attenuate TCR and JAK/STAT signals affecting T cell responses. Thus, we anticipate that uncovering the role of these two PTPs in T-cell biology may lead to new treatment strategies in the field of cancer immunotherapy. This review concludes by exploring the impacts and risks that pharmacological inhibition of these PTP enzymes offers as a therapeutic approach in T-cell-based immunotherapies.

We designed a massively parallel reporter assay (MPRA) in an Epstein-Barr virus transformed B cell line to directly characterize the potential for histone post-translational modifications, i.e., histone quantitative trait loci (hQTLs), expression QTLs (eQTLs), and variants on systemic lupus erythematosus (SLE) and autoimmune (AI) disease risk haplotypes to modulate regulatory activity in an allele-dependent manner. Our study demonstrates that hQTLs, as a group, are more likely to modulate regulatory activity in an MPRA compared with other variant classes tested, including a set of eQTLs previously shown to interact with hQTLs and tested AI risk variants. In addition, we nominate 17 variants (including 11 previously unreported) as putative causal variants for SLE and another 14 for various other AI diseases, prioritizing these variants for future functional studies in primary and immortalized B cells. Thus, we uncover important insights into the mechanistic relationships among genotype, epigenetics, and gene expression in SLE and AI disease phenotypes.

Hashimoto's thyroiditis (HT) and Graves' disease (GD) are common autoimmune endocrine disorders in children. Studies indicate that apart from environmental factors, genetic background significantly contributes to the development of these diseases. This study aimed to assess the prevalence of selected single-nucleotide polymorphisms (SNPs) of Il7R, CD226, CAPSL, and CLEC16A genes in children with autoimmune thyroid diseases. We analyzed SNPs at the locus rs3194051, rs6897932 of IL7R, rs763361 of CD226, rs1010601 of CAPSL, and rs725613 of CLEC16A gene in 56 HT patients, 124 GD patients, and 156 healthy children. We observed significant differences in alleles IL7R (rs6897932) between HT males and the control group (C > T, p = 0.028) and between all GD patients and healthy children (C > T, p = 0.035) as well as GD females and controls (C > T, p = 0.018). Moreover, the C/T genotype was less frequent in GD patients at rs6897932 locus and in HT males at rs1010601 locus. The presence of the T allele in the IL7R (rs6897932) locus appears to have a protective effect against HT in males and GD in all children. Similarly, the presence of the T allele in the CAPSL locus (rs1010601) seems to reduce the risk of HT development in all patients.

DNAM-1 (CD226) is an activating receptor expressed in CD8+ T cells, NK cells, and monocytes. It has been reported that two SNPs in the DNAM-1 gene, rs763361 C>T and rs727088 G>A, have been associated with different autoimmune diseases; however, the role of DNAM-1 in ankylosing spondylitis has been less studied. For this reason, we focused on the study of these two SNPs in association with ankylosing spondylitis. For this, 34 patients and 70 controls were analyzed using endpoint PCR with allele-specific primers. Our results suggest that rs763361 C>T is involved as a possible protective factor under the CT co-dominant model (OR = 0.34, 95% CI = 0.13-0.88, p = 0.022) and the CT + TT dominant model (OR = 0.39, 95% CI = 0.17-0.90, p = 0.025), while rs727088 G>A did not show an association with the disease in any of the inheritance models. When analyzing the relationships of the haplotypes, we found that the T + A haplotype (OR = 0.31, 95% CI = 0.13-0.73, p = 0.0083) is a protective factor for developing the disease. In conclusion, the CT and CT + TT variants of rs763361 C>T and the T + A haplotype were considered as protective factors for developing ankylosing spondylitis.

Regulatory T cells (Tregs) are a specialized subgroup of T-cell lymphocytes that is crucial for maintaining immune homeostasis and preventing excessive immune responses. Depending on their differentiation route, Tregs can be subdivided into thymically derived Tregs (tTregs) and peripherally induced Tregs (pTregs), which originate from conventional T cells after extrathymic differentiation at peripheral sites. Although the regulatory attributes of tTregs and pTregs partially overlap, their modes of action, protein expression profiles, and functional stability exhibit specific characteristics unique to each subset. Over the last few years, our knowledge of Treg differentiation, maturation, plasticity, and correlations between their phenotypes and functions has increased. Genetic and functional studies in patients with numeric and functional Treg deficiencies have contributed to our mechanistic understanding of immune dysregulation and autoimmune pathologies. This review provides an overview of our current knowledge of Treg biology, discusses monogenetic Treg pathologies and explores the role of Tregs in various other autoimmune disorders. Additionally, we discuss novel approaches that explore Tregs as targets or agents of innovative treatment options.

Protein tyrosine phosphatase N2 (PTPN2) is a type 1 diabetes (T1D) candidate gene identified from human genome-wide association studies. PTPN2 is highly expressed in human and murine islets and becomes elevated upon inflammation and models of T1D, suggesting that PTPN2 may be important for β-cell survival in the context of T1D. To test whether PTPN2 contributed to β-cell dysfunction in an inflammatory environment, we generated a β-cell-specific deletion of Ptpn2 in mice (PTPN2-β knockout [βKO]). Whereas unstressed animals exhibited normal metabolic profiles, low- and high-dose streptozotocin-treated PTPN2-βKO mice displayed hyperglycemia and accelerated death, respectively. Furthermore, cytokine-treated Ptpn2-KO islets resulted in impaired glucose-stimulated insulin secretion, mitochondrial defects, and reduced glucose-induced metabolic flux, suggesting β-cells lacking Ptpn2 are more susceptible to inflammatory stress associated with T1D due to maladaptive metabolic fitness. Consistent with the phenotype, proteomic analysis identified an important metabolic enzyme, ATP-citrate lyase, as a novel PTPN2 substrate.

In the field of transfusion medicine, the clinical relevance of the metabolic markers of the red blood cell (RBC) storage lesion is incompletely understood. Here, we performed metabolomics of RBC units from 643 donors enrolled in the Recipient Epidemiology and Donor Evaluation Study, REDS RBC Omics. These units were tested on storage days 10, 23, and 42 for a total of 1929 samples and also characterized for end-of-storage hemolytic propensity after oxidative and osmotic insults. Our results indicate that the metabolic markers of the storage lesion poorly correlated with hemolytic propensity. In contrast, kynurenine was not affected by storage duration and was identified as the top predictor of osmotic fragility. RBC kynurenine levels were affected by donor age and body mass index and were reproducible within the same donor across multiple donations from 2 to 12 months apart. To delve into the genetic underpinnings of kynurenine levels in stored RBCs, we thus tested kynurenine levels in stored RBCs on day 42 from 13 091 donors from the REDS RBC Omics study, a population that was also genotyped for 879 000 single nucleotide polymorphisms. Through a metabolite quantitative trait loci analysis, we identified polymorphisms in SLC7A5, ATXN2, and a series of rate-limiting enzymes (eg, kynurenine monooxygenase, indoleamine 2,3-dioxygenase, and tryptophan dioxygenase) in the kynurenine pathway as critical factors affecting RBC kynurenine levels. By interrogating a donor-recipient linkage vein-to-vein database, we then report that SLC7A5 polymorphisms are also associated with changes in hemoglobin and bilirubin levels, suggestive of in vivo hemolysis in 4470 individuals who were critically ill and receiving single-unit transfusions.