Expression profile of FcγRIIB on leusocytes and its dysregulation in systemic lupus erythematosus

Fc gamma RIIb (CD32B, Online Mendelian Inheritance in Man 604590), an IgG FcR with a tyrosine-based inhibitory motif, plays a critical role in the balance of tolerance and autoimmunity in murine models. However, the high degree of homology between Fc gamma RIIb and Fc gamma RIIa in humans and the lack of specific Abs to differentiate them have hampered study of the normal expression profile of Fc gamma RIIb and its potential dysregulation in autoimmune diseases such as systemic lupus erythematosus (SLE). Using our newly developed anti-Fc gamma RIIb mAb 4F5 which does not react with Fc gamma RIIb, we found that Fc gamma RIIb is expressed on the cell surface of circulating B lymphocytes, monocytes, neutrophils, myeloid dendritic cells (DCs), and at very low levels on plasmacytoid DCs from some donors. Normal donors with the less frequent 2B.4 promoter haplotype have higher Fc gamma RIIb expression on monocytes, neutrophils, and myeloid DCs similar to that reported for B lymphocytes, indicating that Fc gamma RIIb expression on both myeloid and lymphoid cells is regulated by the naturally occurring regulatory single nucleotide polymorphisms in the FCGR2B promoter. Fc gamma RIIb expression in normal controls is up-regulated on memory B lymphocytes compared with naive B lymphocytes. In contrast, in active SLE, Fc gamma RIIb is significantly down-regulated on both memory and plasma B lymphocytes compared with naive and memor phi plasma B lymphocytes from normals. Similar down-regulation of Fc gamma RIIb on myeloid-lineage cells in SLE was not seen. Our studies demonstrate the constitutive regulation of Fc gamma RIIb by natural. gene polymorphisms and the acquired dysregulation in SLE autoimmunity, which may identify opportunities for using this receptor as a therapeutic target.