Expression Profile of FcγRIIb on Leukocytes and Its Dysregulation in Systemic Lupus Erythematosus

Abstract

FcγRIIb (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 FcγRIIb and FcγRIIa in humans and the lack of specific Abs to differentiate them have hampered study of the normal expression profile of FcγRIIb and its potential dysregulation in autoimmune diseases such as systemic lupus erythematosus (SLE). Using our newly developed anti-FcγRIIb mAb 4F5 which does not react with FcγRIIa, we found that FcγRIIb 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 FcγRIIb expression on monocytes, neutrophils, and myeloid DCs similar to that reported for B lymphocytes, indicating that FcγRIIb expression on both myeloid and lymphoid cells is regulated by the naturally occurring regulatory single nucleotide polymorphisms in the FCGR2B promoter. FcγRIIb expression in normal controls is up-regulated on memory B lymphocytes compared with naive B lymphocytes. In contrast, in active SLE, FcγRIIb is significantly down-regulated on both memory and plasma B lymphocytes compared with naive and memory/plasma B lymphocytes from normals. Similar down-regulation of FcγRIIb on myeloid-lineage cells in SLE was not seen. Our studies demonstrate the constitutive regulation of FcγRIIb by natural gene polymorphisms and the acquired dysregulation in SLE autoimmunity, which may identify opportunities for using this receptor as a therapeutic target.

The Ubiquitin Ligase c-Cbl Down-Regulates FcγRIIa Activation in Human Neutrophils

“…In the case of Ab-mediated phagocytosis, macrophages have the capacity to trigger a strong proinflammatory response, which must be tightly controled by Fc␥RIIb. However, the available data indicate that human neutrophils, in contrast to human macrophages, express very little (14) or no (our personal observations) Fc␥RIIb. So, the neutrophil appears to be the only human phagocyte that does not express ITIM-bearing Fc␥Rs, and the mechanism involved in the down-regulation of Fc␥RIIa remains to be elucidated.…”

Antibody-Mediated Coengagement of FcγRIIb and B Cell Receptor Complex Suppresses Humoral Immunity in Systemic Lupus Erythematosus

“…In states of inadequate FcgRIIb function, the ensuing excessive B cell responses could facilitate autoimmunity. Indeed, the importance of FcgRIIb in SLE is highlighted by development of SLE-like disease in mice knocked out for the gene (52), by amelioration of serological and clinical disease in SLEprone MRL-lpr/lpr mice that selectively overexpress FcgRIIb on B cells (6), by decreased FcgRIIb expression on memory B cells in human SLE (12,13), and by impaired function of an FcgRIIb polymorphism associated with human SLE (9). In support of our focused approach of activating this inhibitory pathway specifically on B cells, Brownlie et al (6) showed that FcgRIIb overexpression on macrophages sensitizes mice to Streptococcus pneumoniae infection; in marked contrast, its overexpression on B cells does not reduce survival.…”

“…For example, autoimmune disease is exacerbated in mice lacking FcgRIIb (4,5), and its restoration rescues mice in systemic lupus erythematosus (SLE), arthritis, and asthma models (6)(7)(8). Moreover, FcgRIIb polymorphisms affecting activity or expression are associated with human autoimmunity (9)(10)(11), and B cell expression of FcgRIIb is abnormally low in SLE, leading to inadequate suppression of autoantigen-mediated BCR activation (12)(13)(14). In addition, this receptor has recently been demonstrated to be a tractable drug target, with a dual-affinity diabody against CD79b and FcgRIIb showing efficacy in a mouse collagen-induced arthritis model (15).…”

Expression of the autoimmune Fcgr2b NZW allele fails to be upregulated in germinal center B cells and is associated with increased IgG production

“…Functionally, two recent studies have reported that lupus patients present a defective upregulation of FcgRIIB expression in selected late B-cell developmental stages, namely, memory B cells and plasma cells (PC). 4,5 In the mouse, FcgRIIB is required for the maintenance of systemic tolerance on a C57BL/6 (B6) background, 6 and a B-cell receptor transgenic model has suggested that it constitutes a checkpoint at the post-germinal center (GC)/plasma cell stage. 7 Several lupus-prone strains show reduced FcgRIIB levels attributed to a promoter region polymorphism for NZB, BXSB and MRL.…”