2013 B Cells, Human Lupus Biology, Target Identification
Biological Role of FCRL Molecules in SLE Pathogenesis
The Study and What It Means to Patients
"We are investigating why people with alterations in a family of little known proteins found on the surface of immune cells (the FCRL proteins) have a greater risk for developing lupus and other autoimmune diseases. This insight is key to determining if drugs that harness the potentially protective effects of FCRL proteins could be a strategy to treat lupus."
Ten years ago we identified a new family of six closely related proteins present on the surface of immune-system cells that we called the Fc receptor-like (FCRL) proteins. Recently, these little understood proteins have been thrown into the spotlight by human genetic studies showing that small changes in FCRL genes are a risk factor for lupus and other autoimmune diseases. We are testing our novel idea that in healthy people FCRL act to shut down the immune system's antibody-factories (B cells) and prevent the production of antibodies that attack the body, but in lupus this shut-down mechanism doesn't work. Our work will establish if enhancing FCRL is a potential new target for drugs to treat lupus and other immune-system disorders.
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 Fc 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.