A lupus-suppressor BALB/c locus restricts IgG2 autoantibodies without altering intrinsic B cell-tolerance mechanisms.
FcgammaR2B-deficient mice develop autoantibodies and glomerulonephritis with a pathology closely resembling human lupus when on the C57BL/6 (B6) background. The same mutation on the BALB/c background does not lead to spontaneous disease, suggesting differences in lupus susceptibility between the BALB/c and B6 strains. An F2 genetic analysis from a B6/BALB cross identified regions from the B6 chromosomes 12 and 17 with positive linkage for IgG autoantibodies. We have generated a congenic strain that contains the suppressor allele from the BALB/c chromosome 12 centromeric region (sbb2(a)) in an otherwise B6.FcgammaR2B(-/-) background. None of the B6.FcgammaR2B(-/-)sbb2(a/a) mice tested have developed IgG autoantibodies in the serum or autoimmune pathology. Mixed bone marrow reconstitution experiments indicate that sbb2(a) is expressed in non-B bone marrow-derived cells and acts in trans. sbb2(a) does not alter L chain editing frequencies of DNA Abs in the 3H9H/56R H chain transgenic mice, but the level of IgG2a anti-DNA Abs in the serum is reduced. Thus, sbb2(a) provides an example of a non-MHC lupus-suppressor locus that protects from disease by restricting the production of pathogenic IgG isotypes even in backgrounds with inefficient Ab editing checkpoints.
Tarasenko
Tatyana
T
Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852, USA.
Kole
Hemanta K
HK
Bolland
Silvia
S
D000483:Alleles; D000818:Animals; D001323:Autoantibodies / Q000096:biosynthesis; D001402:B-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D016153:Genes, Suppressor; D005819:Genetic Markers / Q000276:immunology; D020022:Genetic Predisposition to Disease; D007108:Immune Tolerance / Q000235:genetics*; D007074:Immunoglobulin G / Q000096:biosynthesis; D007132:Immunoglobulin Isotypes / Q000096:biosynthesis; D008180:Lupus Erythematosus, Systemic / Q000235:genetics* / Q000276:immunology* / Q000517:prevention & control; D051379:Mice; D020297:Mice, Congenic; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D017452:Receptors, IgG / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics; D019076:Transgenes / Q000276:immunology
D001323:Autoantibodies; C499172:Fcgr2b protein, mouse; D005819:Genetic Markers; D007074:Immunoglobulin G; D007132:Immunoglobulin Isotypes; D017452:Receptors, IgG