Over the recent past, several genome-wide association study (GWAS) analyses have been conducted in connective tissue diseases such as Systemic lupus erythematosus and Systemic Sclerosis. Interestingly, multiple B-cell genes have been uncovered, including BANK1, BLK, CSK, PTPN22 and IRF8. Importantly, the first four represent signaling molecules that play key roles in B-cell signaling, essentially controlling BCR signal strength via a central axis. How these genes function to cause systemic autoimmunity is poorly understood. Both systemic autoimmune diseases are commoner in females, and the reasons for this dimorphism are poorly understood. We have recently generated novel strains that may help elucidate the contributions of disease genes and female gender to heightened B-cell activation, breach of immune tolerance and autoantibody production in systemic connective tissue diseases. A better understanding of the pathogenic mechanisms underlying these disease will also pave the way towards better therapeutics.
Systemic lupus erythematosus is a polygenic autoimmune disease characterized by high levels of anti-nuclear autoantibodies and B-cell hyperactivity. Genetic studies in mice and patients with lupus have led to the identification of several genetic loci and genes that confer susceptibility to lupus. In this proposal, we will examine how one of these genes called BANK1 impact B-cell function and disease.
