Pathogenic SNP Network Enhancing IL-2/JAK-STAT Signaling and T-Cell Responses in Celiac Disease

Abstract

Celiac disease is an immune-mediated enteropathy when there is abnormal activation of T-cells triggered by dietary gluten, yet the underlying genetic processes that enhance the immune action are poorly defined. The paper has focused on studying four immune-regulatory SNPs namely, rs11712165 (CD80), 3184504 (SH2B3), 243323 (SOCS1), and 2299482 (UBE2L3), to investigate the possible combined effects of these SNPs 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, we were able to find a pattern of pathway-level disruption that is consistent around the IL-2/JAK-STAT axis. Increased CD80 expression correlated with stronger T-cell co-stimulation and augmented IL-2 secretion and decreased SH2B3 expression inhibited the activity of the 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 the normal regulation. All these variant-induced changes culminate in the formation of a coordinated mechanistic pattern whereby IL-2/JAK-STAT signaling is augmented and prolonged, and T-cell activation and intestinal inflammation are increased. The evidence above is consistent with recognized immunopathological characteristics of celiac disease as overproduction of IL-2 signaling and impaired T-cell responses are factors leading to mucosal damage. Screening of drug interactions also indicated that there are a number of approved therapeutics against CD80 and JAK kinases and could also pose pathway-specific intervention opportunities. 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 offers a genetically informed template to be used in future therapeutic endeavors.