Networking Between Cytokine Gene Polymorphisms Profile and HLA in the Pathogenesis of Type 1 Diabetes (A Pilot Study)

Abstract

Type 1 Diabetes (T1D) is an autoimmune disease with both genetic and environmental components. More than 60 genes have been identified to affect the risk of T1D, with the HLA loci having the greatest impact on susceptibility. The association of T1D with alleles at HLA loci, especially the HLA class II genes DR and DQ, is well-established. However, other candidate genes may also have some significant impact on genetic susceptibility. Cytokines are central mediators of inflammation by controlling innate and adaptive immune responses as well as tissue damage, defense, repair, and remodeling. T1D is an inflammatory disease of the pancreatic islet, in which insulin-producing ?-cells are preferentially destroyed to varying degrees by the concerted action of auto reactive T-cells. A number of cytokines have been shown to be important for the development of T1D both at the level of the immune system and at the level of the target ?-cells. The actual mechanism of ?-cell destruction is still unclear, however, according to the available cytokine genetic studies, ?-cell destruction might be predicted, Figure 1. As an autoimmune disease that starts with inflammation of the pancreatic ?- cells leading to ?- cell death, cytokines may play a significant role in the overall pathogenesis of T1D. To determine the effects of cytokine gene polymorphisms in the pathogenesis of T1D, high risk interferon-gamma (IFN-?), interleukin-6 (IL-6) as well as transforming growth factor ? (TGF-?) gene polymorphisms were considered in HLA DRDQ fixed patients with T1D. In this pilot study, we determined that there may be critical networking among different cytokines and HLA which may play a role in the pathogenesis of T1D. However, a larger scale case control study is required to confirm these findings and to determine the functionality of cytokines and the high-risk HLA patients.