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A Lupus-Suppressor BALB/c Locus Restricts IgG2 Autoantibodies without Altering Intrinsic B Cell-Tolerance Mechanisms¹

Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852

FcR2B-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.FcR2B^–/– background. None of the B6.FcR2B^–/–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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health.

² Address correspondence and reprint requests to Dr. Silvia Bolland, Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, 12441 Parklawn Drive, Rockville, MD 20852. E-mail address: sbolland{at}nih.gov

³ Abbreviations used in this paper: B6, C57BL/6; R2, FcR2B; ANA, anti-nuclear autoantibodies.