Systemic lupus erythematosus (SLE) is a devastating multi-organ systemic disease with manifestations that overlap with other autoimmune disorders. Among genes implicated in SLE, major histocompatibility class II (MHCII) HLA alleles are the most firmly established risk factors. The growing number of non-MHC immune­ related genes being identified through large genome-wide association studies underscores the complexity of this illness, but how these elements or MHC itself contributes to SLE pathogenesis remains unclear. These emerging observations also indicate there is a fundamental need to substantiate these genetic relationships biologically. One member of an extended family of immunoregulatory molecules termed Fe receptor-like 3 (FCRL3), harbors both ITAM and ITIM signaling sequences, inhibits B cell receptor signaling, and has been strongly linked to autoimmune diseases and SLE. However, the exact molecular mechanism through which FCRL3 exerts pathogenic effects in B cells and promotes autoimmunity is not known. These studies will examine the functional properties of FCRL3 in innate B cell stimulation and establish models to determine the implications of its physical interaction with a newfound ligand. We expect these fundamental findings to provide new insight in the pathogenesis of SLE and ultimately translate into the development of novel pharmacological interventions for treatment.