The Autoimmune Risk R262W Variant of the Adaptor SH2B3 Improves Survival in Sepsis

Allenspach, Eric J.; Shubin, Nicholas J.; Cerosaletti, Karen; Mikacenic, Carmen; Gorman, Jacquelyn A; MacQuivey, Matthew A; Rosen, Aaron B I; Timms, Andrew E.; Wray-Dutra, Michelle N.; Niino, Kerri; Liggitt, Denny; Wurfel, Mark M.; Buckner, Jane H.; Piliponsky, Adrian M.; Rawlings, David J.

doi:10.4049/jimmunol.2100454

Cited by 6 publications

(7 citation statements)

References 46 publications

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“…Committee approval at the SCRI Animal Facility. Sh2b3 -/and Sh2b3 fl/fl mice were described previously 20 . All other strains were purchased from Jackson Laboratories (Bar Harbor, Maine): RIP-mOVA, CD4Cre, B6 CD45.1, Ai14, OT-I, OT-II, and NOD.…”

Section: Mice All Animal Care and Experimentation Occurred With Insti...mentioning

confidence: 99%

“…The H1 haplotype carrying the T allele of rs3184504 and the G allele of rs653178 conferred risk for T1D. SH2B3 R262W is the major variant in most European populations and is protective in sepsis 20 , thus is predicted to be enriched due to positive selection. Given linkage disequilibrium in the region, enrichment is also observed for rs653178*G [26][27][28] .…”

Section: Separately We Confirmed the Association Of This Locus With T...mentioning

confidence: 99%

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Reduced function of the adaptor SH2B3 promotes T1D via altered gc cytokine-regulated, T cell intrinsic immune tolerance

Watson,

Rosen,

Drow

et al. 2024

Preprint

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Genome-wide association studies have identifiedSH2B3as an important non-MHC gene for islet autoimmunity and type 1 diabetes (T1D). In this study, we found a singleSH2B3haplotype significantly associated with increased risk for human T1D, and this haplotype carries the single nucleotide variant rs3184504*T inSH2B3.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.Article HighlightsThe 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.

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Section: Mice All Animal Care and Experimentation Occurred With Insti...mentioning

confidence: 99%

Section: Separately We Confirmed the Association Of This Locus With T...mentioning

confidence: 99%

Reduced function of the adaptor SH2B3 promotes T1D via altered gc cytokine-regulated, T cell intrinsic immune tolerance

Watson,

Rosen,

Drow

et al. 2024

Preprint

View full text Add to dashboard Cite

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“…GWAS data of the FinnGen release 7 T1D 'wide definition' revealed additional genes significantly associated with T1D; these include CTLA4, BACH2, IL2RA, SH2B3 and AIRE. Inherited mutations in these genes are known to be associated with an increased risk for autoimmune disease, either through effects upstream of, parallel with or downstream of the HLApeptide-TCR interaction [41][42][43][44][45]. Steps 6-7 provide compelling evidence that all genes on GWAS contribute to formation of a cellular pathway that drives autoimmunity.…”

Section: Gwea Steps 4-5mentioning

confidence: 99%

A new, all‐encompassing aetiology of type 1 diabetes

de Groen

2023

Immunology

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The aetiology of type 1 diabetes (T1D) is considered multifactorial with the contribution of the MHC on chromosome 6 being most important. Multiple factors also contribute to the aetiology of colorectal neoplasia, but the final event causing the change from normal mucosa to polyp and from polyp to cancer is due to a single somatic mutation event. Repeated formation of colorectal neoplasia within an at‐risk population results in a predictable, tapering, exponential neoplasia distribution. Critical mutations driving colorectal neoplasia formation occur in mutation‐prone DNA. These observations led to three hypotheses related to T1D. First, a single somatic mutation within the MHC of antigen presenting cells results in a change in phenotype from normal to T1D. Second, the distribution of additional autoimmune diseases (AAIDs) among persons with T1D adheres to a predictable, tapering, exponential distribution. And third, critical mutations driving development of T1D occur in mutation‐prone DNA. To address the hypotheses in an orderly fashion, a new analytical method called genome‐wide aetiology analysis (GWEA) consisting of nine steps is presented. All data required for GWEA of T1D are obtained from peer‐reviewed publications or publicly available genome and proteome databases. Critical GWEA steps include AAID distribution among persons with T1D, analysis of at‐risk HLA loci for mutation‐prone DNA, determination of the role of non‐MHC genes on GWAS, and verification of human data by cell culture or animal experiments. GWEA results show that distribution of AAID among persons with T1D adheres to a predictable, tapering, exponential distribution. A single, critical, somatic mutation within the epitope‐binding groove of at‐risk HLA loci alters HLA‐insulin‐peptide‐T‐cell‐receptor (TCR) complex binding affinity and creates a new pathway that leads to loss of self‐tolerance. The at‐risk HLA loci, in particular binding pockets P1, P4 and P9, are encoded by mutation‐prone DNA: GC‐rich DNA sequence and somatic hypermutation hotspots. All other genes on GWAS can but do not have to amplify the new autoimmune pathway by facilitating DNA mutations, changing peptide binding affinity, reducing signal inhibition or augmenting signal intensity. Animal experiments agree with human studies. In conclusion, T1D is caused by a somatic mutation within the epitope‐binding groove of an at‐risk HLA gene that affects HLA‐insulin‐peptide‐TCR complex binding affinity and initiates an autoimmune pathway. The nature of the peptide that binds to a mutated epitope‐binding groove of an at‐risk HLA gene determines the type of autoimmune disease that develops, that is, one at‐risk HLA locus, multiple autoimmune diseases. Thus, T1D and AAIDs, and therefore common autoimmune diseases, share a similar somatic mutation‐based aetiology.

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“…The SH2B3 encodes LNK (lymphocyte adaptor protein) that takes parts in several signaling pathways controlling the hematopoiesis, cytokine and integrin signaling and cell migration ( 177 ). The functional consequences of the T1D risk variant (rs3184504) that causes a missense mutation remain speculative ( 11 , 59 , 146 ), one study using human cells that reports an augmented lymphocyte proliferation that correlates with the predisposing gene variant ( 178 ) Interestingly though, a recent study shows that the T1D risk-gene variant associates with a reduced mortality from sepsis in individuals with a European decent and suggest based on a mouse model that augmented phagocytosis and myelopoiesis may be underlying mechanisms ( 179 ). The gene IKZF1 codes for the transcription factor Ikaros ( 180 ), and the associated SNPs (rs10277986, rs62447205) are protective for T1D ( 11 ).…”

Section: Tolerogenic Modulation Of Dendritic Cells and The Impact On ...mentioning

confidence: 99%

Functional Impact of Risk Gene Variants on the Autoimmune Responses in Type 1 Diabetes

et al. 2022

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Type 1 diabetes (T1D) is an autoimmune disease that develops in the interplay between genetic and environmental factors. A majority of individuals who develop T1D have a HLA make up, that accounts for 50% of the genetic risk of disease. Besides these HLA haplotypes and the insulin region that importantly contribute to the heritable component, genome-wide association studies have identified many polymorphisms in over 60 non-HLA gene regions that also contribute to T1D susceptibility.Combining the risk genes in a score (T1D-GRS), significantly improved the prediction of disease progression in autoantibody positive individuals. Many of these minor-risk SNPs are associated with immune genes but how they influence the gene and protein expression and whether they cause functional changes on a cellular level remains a subject of investigation. A positive correlation between the genetic risk and the intensity of the peripheral autoimmune response was demonstrated both for HLA and non-HLA genetic risk variants. We also observed epigenetic and genetic modulation of several of these T1D susceptibility genes in dendritic cells (DCs) treated with vitamin D3 and dexamethasone to acquire tolerogenic properties as compared to immune activating DCs (mDC) illustrating the interaction between genes and environment that collectively determines risk for T1D. A notion that targeting such genes for therapeutic modulation could be compatible with correction of the impaired immune response, inspired us to review the current knowledge on the immune-related minor risk genes, their expression and function in immune cells, and how they may contribute to activation of autoreactive T cells, Treg function or β-cell apoptosis, thus contributing to development of the autoimmune disease.

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The Autoimmune Risk R262W Variant of the Adaptor SH2B3 Improves Survival in Sepsis

Cited by 6 publications

References 46 publications

Reduced function of the adaptor SH2B3 promotes T1D via altered gc cytokine-regulated, T cell intrinsic immune tolerance

Reduced function of the adaptor SH2B3 promotes T1D via altered gc cytokine-regulated, T cell intrinsic immune tolerance

A new, all‐encompassing aetiology of type 1 diabetes

Functional Impact of Risk Gene Variants on the Autoimmune Responses in Type 1 Diabetes

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