Expression of the autoimmune Fcgr2b NZW allele fails to be upregulated in germinal center B cells and is associated with increased IgG production.
The inhibitory receptor FcgammaRIIb 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 FcgammaRIIb levels. Furthermore, FcgammaRIIb absence results in lupus on the appropriate genetic background, and lentiviral-mediated FcgammaRIIb 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 FcgammaRIIb 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.
Rahman
Z S M
ZS
Department of Microbiology and Immunology, The Kimmel Cancer Center, Jefferson Medical College, Philadelphia, PA, USA.
Niu
H
H
Perry
D
D
Wakeland
E
E
Manser
T
T
Morel
L
L
D000483:Alleles; D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology*; D020566:Dendritic Cells, Follicular / Q000166:cytology / Q000276:immunology; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D018858:Germinal Center / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D017578:Immunoglobulin Class Switching; D007074:Immunoglobulin G / Q000096:biosynthesis*; D008180:Lupus Erythematosus, Systemic / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D051379:Mice; D020297:Mice, Congenic; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D010950:Plasma Cells / Q000276:immunology; D017452:Receptors, IgG / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D015854:Up-Regulation
C499172:Fcgr2b protein, mouse; D007074:Immunoglobulin G; D017452:Receptors, IgG