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

Abstract

The inhibitory receptor FcgRIIb regulates B-cell functions. Genetic studies have associated Fcgr2b polymorphisms and lupus susceptibility in both humans and murine models, in which B cells express reduced FcgRIIb levels. Furthermore, FcgRIIb absence results in lupus on the appropriate genetic background, and lentiviral-mediated FcgRIIb overexpression prevents disease in the NZM2410 lupus mouse. The NZM2410/NZW allele Fcgr2b is, however, located in-between Sle1a and Sle1b, two potent susceptibility loci, making it difficult to evaluate Fcr2b NZW independent contribution. By using two congenic strains that each carries only Sle1a (B6.Sle1a(15-353)), or Fcr2b NZW in the absence of Sle1a or Sle1b (B6.Sle1(111-148)), we show that the Fcr2b NZW allele does not upregulate its expression on germinal center B cells and plasma cells, as does the C57BL/6 allele on B6.Sle1a(15-353) B cells. Furthermore, in the absence of the flanking Sle1a and Sle1b, Fcr2b NZW does not produce an autoimmune phenotype, but is associated with an increased number of class-switched plasma cells. These results show that while a lower level of FcgRIIb does not by itself induce the development of autoreactive B cells, it has the potential to amplify the contribution of autoreactive B cells induced by other lupus-susceptibility loci by enhancing the production of class-switched plasma cells.

The Inhibiting Fc Receptor for IgG, FcγRIIB, Is a Modifier of Autoimmune Susceptibility

“…Surprisingly, genetic fine mapping placed the Fcgr2b gene not in, but just between, the Sle1a and Sle1b subloci (10). Moreover, a B6 strain congenic for the Fcgr2b allele derived from the NZW autoimmune-prone strain did not develop autoimmunity (11).…”

Animal Models of Molecular Pathology

“…104 Additionally, polymorphisms in the NZM2410/NZW allele of FcgRIIB were associated with decreased expression of FcgRIIB in germinal center (GC) B cells and elevated class-switched plasma cells, although autoimmunity did not develop in the absence of additional lupus-susceptibility loci. 105 FcgRIIBdeficient mice break B-cell tolerance and develop nuclear autoAbs and GN in the B6 but not BALB/c background. 106,107 Additional studies with B6.…”

Comprehensive Gene Expression Profiling in the Prefrontal Cortex Links Immune Activation and Neutrophil Infiltration to Antinociception

“…The highaffinity IgG receptor Fc␥RI (CD64) is expressed on the surface of neutrophils and monocytes (Kakinoki et al, 2004) and smallsized neurons (Andoh and Kuraishi, 2004) and is implicated in pain (Handwerker et al, 1991). Fc␥RIIb (CD32) is expressed on B lymphocytes (Blank et al, 2005) and regulates the function of these cells (Rahman et al, 2007). C1QB is one of the heterotrimers of C1q that is involved in the complement cascade of innate immune response (Sontheimer et al, 2005) and is expressed in neurons (Spielman et al, 2002).…”