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

Abstract

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.

Keywords: Tregs; immunoregulation; risk gene variants; tolerogenic dendritic cells; type 1 diabetes; vitamin D.

Figure 1

Model of the discussed effects of T1D risk variants on cellular functions. The figure depicts our interpretation of the consequences for effector T cell (Teff), regulatory T cell (Tregs), and β-cells of the described or assumed change in the gene function caused by a T1D risk variant (RV) as compared to the non-risk variant (NRV) SNP as discussed in the manuscript. While the LYP protein normally controls the effector T cells by a downstream signaling inhibition, the risk variant (rs2476601) induces a change in PTPN22 that promotes Teff responses. The functional effects of PTPN22 remain unclear. The PTPN2 protein plays an anti-apoptotic role in β-cells and controls T cells via IL-2, which may favor Tregs due to a strong sensitivity to IL-2. Indirectly, a good activity of Tregs keeps the effector T cells under control. The PTPN2 risk variant (rs1893217) causes a decrease in PTPN2 expression and contributes to the sensitivity of β-cells to immune- or virus-mediated apoptosis. The risk variant also reduces IL-2 receptor signaling, which decreases FOXP3+ Tregs in T1D patients, and thus dysregulating Treg function. The PTPN2 deficiency (mimicking the rs1893217 variant) results in increased Teff proliferation. The MDA5 (encoded by IFIH1) normally functions to activate stress- and anti-viral response, and by increasing the activity of MDA5, the risk variant (rs1990760) increases the basal IFN-I production leading to β-cell apoptosis. CTLA-4 functions normally to promote Treg function and inhibit Teff activation. The risk variant for CTLA4 (rs231775) results in decreased expression of CTLA-4 on T cells, releasing the control of a Teff cell activation and reducing the suppressive Treg potency. The IL2RA risk variants impair the expression of CD25 and thus the IL-2 response and with the associated lower FOXP3 expression impacts primarily Tregs and their suppressive function. The resulting reduced Treg potency will indirectly release the control on Teff promoting the activation. The CD226 is an activating T cell molecule that promotes the inflammatory activity of Teff and reduces the suppression of Tregs. The CD226 risk variant (rs763361) results in an isoform of CD226 with increased activity, which further increases Teff and CD226+ Tregs, thereby further reducing the overall suppressive capacity of Tregs.