Disease-specific antigen presentation on MHC class II is inhibited by a small molecule in Sjögren’s Syndrome

Abstract

Sjogren’s Syndrome (SjS) is one of the more common autoimmune diseases that has a strong genetic linkage. To date, no vaccine or therapeutic exists to cure SjS, and patients must rely on lifelong therapies to treat symptoms. Class II MHC are the primary susceptibility loci that form the genetic basis for many auto-immune disorders including SjS. I-Ag7 is the MHC in NOD mice that is used for the presentation of autoantigens and plays a critical role in the adaptive immune response. HLA-DQ8 the MHC in humans, is analogous to I-Ag7, in the NOD mouse model and is an important model for the onset of SjS. Using an in-silico molecular docking program a chemical library was screened that defined small molecules that were capable of occupying specific structural pockets along the I-Ag7 binding groove, with the objective of influencing auto-antigen peptide presentation to T cells. In this study we show, that the small molecule TATD can inhibit TCR signaling based on the structural pocket targeting mechanism. TATD previously proven to inhibit the onset of diabetes by blocking the auto-antigen presentation on I-Ag7, was analyzed to observe effects of prevention of SjS by, preventing the accumulation of B and T cells within the salivary gland of NOD mice. Treated mice also showed reduction in the incidence of inflammatory cell infiltration into lacrimal and salivary glands as compared to control mice with notable reduction in of the hallmark SjS anti-nuclear antibodies of Ro52, Ro60 and La. As a result this study presents a novel method for identifying small molecules capable of inhibiting T cell responses, with potentially therapeutic applications.