FcγRIIb is an Fc receptor that inhibits B cell activation and, if defective, is associated with autoimmune disease, yet its impact on specific B cell tolerance checkpoints is unknown.
In the context of the FcγRIIb-I232T polymorphism, we investigated the role of FcγRIIb in the deletion of low-affinity germinal center (GC) B cells, an important mechanism for preventing autoimmunity.
This review will provide an update on the role of FcγRIIB in adaptive immune responses in autoimmunity, and then focus on their emerging function in innate immunity.
The inhibitory FcγRIIB plays an important role for the peripheral B cell tolerance and plasma cell homeostasis, and any malfunctioning is predicted to result in humoral autoimmunity.
The human FCGR2/3 locus, containing five highly homologous genes encoding the major IgG receptors, shows extensive copy number variation (CNV) associated with susceptibility to autoimmune diseases.
In this study, we generated mice with selective deletion of FcγRIIB in B cells, DCs, and myeloid effector cells and evaluated these novel strains in models of tolerance and autoimmune diseases.
Interestingly, recent studies involving the generation of Nba2 subcongenic mouse lines and generation of mice deficient for the Fcgr2b or Aim2 gene within the interval have provided evidence that epistatic interactions among the Nba2 genes contribute to increased lupus susceptibility.
Single-nucleotide polymorphisms (SNPs) in the Fc gamma receptor IIB (FCGR2B) gene have recently been found to be associated with several human autoimmune diseases.
In the presence of the Yaa lupus-susceptibility locus, FcγRIIB(B6)(-/-) mice do develop lethal lupus, confirming that FcγRIIB deficiency only amplifies spontaneous autoimmunity determined by other loci.
We investigated frequencies of single nucleotide polymorphisms (SNPs) in the candidate genes protein tyrosine phosphatase, non-receptor type 22 (PTPN22), B-cell scaffold protein with ankyrin repeats (BANK1), B lymphocyte kinase (Blk), and Fc gamma receptor class IIB (FCGR2B), which have been found to be associated with other autoimmune diseases, CD1A and CD1E, important for antigen presentation of glycolipids, and transient axonal glycoprotein 1 (TAG-1), which is associated with responsiveness to intravenous immunoglobulin in patients with chronic inflammatory demyelinating polyneuropathy.
Thus, amplification of the FcγRIIb inhibitory pathway in activated B cells may represent a novel B cell-targeted immunosuppressive therapeutic approach for SLE and other autoimmune diseases that should avoid the complications associated with B cell depletion.
Using FcγRIIB and FcγRIIIB as examples, we demonstrate that variations associated with increased susceptibility to autoimmunity may be maintained in populations for their beneficial effect against infection.
FcgammaRIIb (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.
Polymorphisms of Fcgr2b in mice have been shown to be associated with autoimmune diseases including systemic lupus erythematosus (SLE) and targeted disruption of Fcgr2b renders mice susceptible to induced or spontaneous autoimmunity, depending on the genetic background.
A promoter haplotype of the immunoreceptor tyrosine-based inhibitory motif-bearing FcgammaRIIb alters receptor expression and associates with autoimmunity. I. Regulatory FCGR2B polymorphisms and their association with systemic lupus erythematosus.