DECTIN-1: a modifier of CTLA-4 function and autoimmune disease

Abstract

The immune system is an intricate network of cells tasked with defending the body from an array of foreign antigens from pathogenic microbes to toxic compounds. Self-tolerance, or the ability to distinguish between these foreign antigens and "self" antigens expressed on the body's own cells, tissues and organs is a key feature of immunity. The absence of self-tolerance induces systemic immune cell infiltration and the development of autoimmune disease. Cytotoxic T-lymphocyte associated protein 4 (CTLA-4), is a co-inhibitory receptor which regulates T cell activation and helps maintain self-tolerance through expression on T-regulatory cells (Tregs). Haploinsufficiency of CTLA-4 mutations is associated with immune dysregulation syndrome (IDS), a complex form of autoimmunity defined by the presentation of multiple autoimmune disorders (e.g. type 1 diabetes and enteritis). Interestingly, incomplete penetrance of these mutations is quite common and proposes a role for modifier genes which exacerbate CTLA-4 deficiency while leading to other clinical manifestations not associated with the disease. Through this thesis, we describe a rare loss of function mutation in DECTIN-1 which accounts for the unusual disease features (e.g. microbial infections) of a patient with severe IDS. We also identify novel roles for DECTIN-1 in Treg induction and T effector cell expansion, suggesting functional epistasis between the receptor and CTLA-4. As such, we offer DECTIN-1 as a modifier gene for CTLA-4 haploinsufficiency and the development of severe autoimmune disease. Show more