OK COBRE: FC RECEPTOR B LYMPHOCYTE SIGNALING IN LUPUS

Oklahoma Medical Research Foundation, Oklahoma City OK

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Abstract

Systemic lupus erythematosus (SLE) is a complex, multigenic autoimmune disease. A strong genetic linkage at 1q23 and association results with lupus reveal the importance of the low-affinity Fc receptor family as genes for lupus susceptibility. Fc-gammaRIIb knock-out mouse studies and two separate, unpublished genetic association studies have implicated the Fc-gammaRIIb as a susceptibility gene for lupus. A polymorphism in the transmembrane domain of Fc-gammaRIIb alters lipid raft association and influences intracellular calcium and CD19 phosphorylation following B cell activation. Two promoter polymorphisms increased Fc-gammaRIIb expression and caused decreased intracellular calcium levels and decreased apoptosis. The effect of the Fc-gammaRIIb knockout in the mouse and the incompletely described enhancing effects of the human Fc-gammaRIIb polymorphisms strongly suggest possible involvement of Fc-gammaRIIb in lupus development by a yet to be described mechanism that we suspect involves the receptor activation pathway. The previous studies relied upon in vitro assays of recombinant Fc-gammaRIIb molecules transfected into model cell systems for characterization of Fc receptor functions. Although informative, these data do not allow us to fully appreciate the functional differences of these polymorphic Fc-gammaRIIb molecules in cells from actual lupus patients or matched normal controls. We will approach these important issues by utilizing the genetic and cellular resources from the OMRF lupus genetics group to directly assess the functional differences in Fc-gammaRIIb in B cells derived from lupus patients and normal matched controls. We propose that polymorphisms in both the Fc-gammaRIIb protein and the Fc-gammaRIIb promoter that alter Fc-gammaRIIb expression will result in functional differences in signaling through this receptor. We anticipate that these differences will be reflected in differences in B cell signaling responses upon engagement of the Fc-gammaRIIb, of the B cell receptor, or of co-engagement of both receptors. We will analyze B cell responses associated with Fc-gammaRIIb related signaling pathways in lupus cases and controls selected by strong 1q23 linkage and group them into signaling classes by type of B cell signaling responses resulting from Fc-gammaRIIb engagement. Genotypes of the signaling classes will be analyzed to determine if there is increased association with lupus. Gene expression or biochemical pathways associated with each signaling class will be assessed and used to identify genes that contribute to lupus susceptibility through epistatic or additive gene effects. Understanding the role of Fc-gammaRIIb in B cell activation will allow us to better explain lupus development and uncover novel therapeutic targets for this devastating disease.