Altered BAFF-receptor signaling and additional modifier loci contribute to systemic autoimmunity in A/WySnJ mice.
Systemic lupus erythematosus pathology reflects autoantibody-mediated damage due to a failure of B-lymphocyte tolerance. We previously reported that B-lymphopenic A/WySnJ mice develop a lupus-like syndrome and linked this syndrome to the B-cell maturation defect-1 (Bcmd-1) mutant allele of the B-cell-activating factor belonging to the TNF family-receptor (Baffr) gene. Here, we further evaluate the genetic basis for autoimmunity in A/WySnJ mice. We produced B6.Bcmd-1 and AW.Baffr(-/-) congenic mice (N5), and compared them with B6.Baffr(-/-) and A/WySnJ mice with respect to B-lymphocyte development. Bcmd-1-expressing mice had more B cells with greater maturity than Baffr(-/-) mice regardless of genetic background, indicating that Bcmd-1 encodes a partially functional BAFF-R. We also compared these mice for lupus phenotypes to determine whether Bcmd-1 is necessary and sufficient for disease, or whether the Baffr(-/-) (-) allele can also cause autoimmunity. The Baffr(-/-) allele did not lead to autoimmunity on either genetic background. In contrast, the Bcmd-1 allele was necessary and sufficient for development of low levels of IgM autoantibodies in B6.Bcmd-1 mice. However, Bcmd-1 plus unidentified A/WySnJ modifier genes were necessary for development of IgG autoantibodies and renal pathology. We propose that in A/WySnJ mice an excess of BAFF per B cell rescues self-reactive B cells through a partially functional BAFF-R in a B-lymphopenic environment.
Mayne
Christopher G
CG
Department of Genetics, University of Wisconsin-Madison, WI 53706, USA.
Nashold
Faye E
FE
Sasaki
Yoshiteru
Y
Hayes
Colleen E
CE
D000483:Alleles; D000595:Amino Acid Sequence; D000818:Animals; D001323:Autoantibodies / Q000097:blood; D015551:Autoimmunity / Q000235:genetics / Q000276:immunology*; D053264:B-Cell Activating Factor / Q000235:genetics / Q000276:immunology*; D053265:B-Cell Activation Factor Receptor / Q000235:genetics / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D008180:Lupus Erythematosus, Systemic / Q000235:genetics / Q000276:immunology*; D051379:Mice; D020297:Mice, Congenic; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D016415:Sequence Alignment; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology
D001323:Autoantibodies; D053264:B-Cell Activating Factor; D053265:B-Cell Activation Factor Receptor