Pathogenic SNP Network Enhancing IL-2/JAK-STAT Signaling and T-Cell Responses in Celiac Disease
Abstract
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Celiac disease is an immune-mediated enteropathy caused by abnormal activation of T-cells triggered by dietary gluten. The underlying genetic processes that enhance the immune action remain poorly defined. The current paper focuses on studying four immune-regulatory single nucleotide polymorphisms (SNPs), namely rs11712165 (CD80), rs3184504 (SH2B3), rs243323 (SOCS1), and rs2298428 (UBE2L3), to investigate their possible combined effects on cytokine signaling dysregulation in celiac disease. With an integrative bioinformatics strategy that includes functional annotation tools, GTEx eQTL expression analysis, KEGG pathway mapping, and drug-gene interaction databases, the study was able to find a pattern of pathway-level disruption consistent with the IL-2/JAK-STAT axis. Increased CD80 expression correlated with stronger T-cell co-stimulation, augmented IL-2 secretion, and decreased SH2B3 expression inhibited the activity of inhibitory adapters and facilitated hyper-responsiveness to cytokine signaling. Simultaneous reductions in the expression of SOCS1 and UBE2L3 reduced the required negative responses and ubiquitin-mediated signal termination, permitting intracellular signal to be sustained beyond normal regulation. All these variant-induced changes culminated in the formation of a coordinated mechanistic pattern, whereby IL-2/JAK-STAT signaling was augmented and prolonged and T-cell activation and intestinal inflammation increased. The evidence above is consistent with recognized immunopathological characteristics of celiac disease, since overproduction of IL-2 signaling and impaired T-cell responses are factors leading to mucosal damage. The screening of drug interactions also indicated that there are a number of approved therapeutics against CD80 and JAK kinases and could provide more opportunities for pathway-specific interventions. In general, this paper illustrates the role of specific immune-regulatory SNPs interacting together to create a pro-inflammatory signaling space in celiac disease and also offers a genetically informed template to be used in future therapeutic endeavors.
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