Belmaliz Cardona Rodriguez

Sjogren’s disease and other autoimmune diseases are caused by immune cell hyperactivation, leading to tissue damage and organ dysfunction. Based on human genetics and biochemical studies, we propose that regulation of the RNA encoding the immune cell-activating protein CD226 affects the development of autoimmunity. Altering the expression of CD226 through its RNA may alter immune cell activation and thereby improve the symptoms of patients with Sjogren’s disease and other autoimmune disorders.

Sjogren’s disease is an autoimmune disease caused by T cells and other immune cells infiltrating the exocrine glands, leading to dry mouth, dry eyes and even systemic conditions. Currently there is no cure for this disease, but research is focused on targeting lymphocytes and their inappropriate activation. CD226 is a costimulatory transmembrane receptor expressed in T cells and other immune cells. TIGIT, a T cell exhaustion-associated inhibitory receptor, compete for common ligands that are expressed in inflamed tissues. Our preliminary data lead us to hypothesize that RNA binding protein (RBP)-occupied cis-regulatory elements in the CD226 3’UTR may play a role in susceptibility to multiple autoimmune and inflammatory diseases by altering the signaling balance between CD226 and TIGIT. We will test this hypothesis using functional studies of RBP binding sites in the CD226 mRNA, and by characterizing CD226 and TIGIT co-expression in immune cells infiltrating the salivary glands in human subjects with Sjogren’s disease and in a mouse model. Understanding which RBPs, interacting with which cis-regulatory elements, play roles in autoimmunity will open the door to novel therapeutic strategies for Sjogren’s disease.