Functional Regulation of Normal and SLE Plasma Cells by DCC (Deleted in Colon Cancer) and its Ligand Netrin-1

RATIONALE: Human B cell populations were examined for the expression of Netrin-1 and DCC, a gene that resides in the 18q12-q21 SLE (Sytemic Lupus Erythematosus) susceptibility locus and has been linked to several autoimmune diseases including SLE. Netrin-1 is a soluble ligand for DCC and has been reported to be a chemoattractant for DCC-expressing cells. METHODS: To examine the potential role of DCC and Netrin-1 in normal and autoimmune human B cell function, quantitative PCR, microarray, multiparameter flow cytometry and immunohistology were used to examine differential expression and gene targets of the Netrin-1- DCC interaction. RESULTS: Both DCC and Netrin-1 were highly expressed by plasma cells from tonsil and SLE peripheral blood. By immunohistological analysis of tonsillar tissue, DCC antibody identifies plasma cells with a typical clockwork pattern in situ. Stimulation of highly purified tonsillar with Netrin-1 induces changes in cytokine receptors, chemokine receptors and immunoglobulin itself. CONCLUSIONS: Together, these results indicate that Netrin-1 interacts directly with DCC expressed on plasma cells to regulate differentiation and function. Dysregulation of DCC function may play a role in the pathogenicity of diseases that are mediated by abnormal plasma cell function such as SLE.