ABSTRACT 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.