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* Department of Internal Medicine and Center for Immunology,
Department of Pathology, University of Texas Southwestern Medical School, Dallas, TX 75390;
Department of Microbiology, University of Alabama, Birmingham, AL 35294; and
Jules F. Knapp Center, University of Chicago, Chicago, IL 60637
An NZM2410-derived lupus susceptibility locus on murine chromosome 4, Sle2z, has previously been noted to engender generalized B cell hyperactivity. To study how Sle2z impacts B cell tolerance, two Ig H chain site-directed transgenes, 3H9 and 56R, with specificity for DNA were backcrossed onto the C57BL/6 background with or without Sle2z. Interestingly, the presence of the NZM2410 "z" allele of Sle2 on the C57BL/6 background profoundly breached B cell tolerance to DNA, apparently by thwarting receptor editing. Whereas mAbs isolated from the spleens of B6.56R control mice demonstrated significant usage of the endogenous (i.e., nontargeted) H chain locus and evidence of vigorous L chain editing; Abs isolated from B6.Sle2z.56R spleens were largely composed of the transgenic H chain paired with a spectrum of L chains, predominantly recombined to Jk1 or Jk2. In addition, Sle2z-bearing B cells adopted divergent phenotypes depending on their Ag specificity. Whereas Sle2z-bearing anti-DNA transgenic B cells were skewed toward marginal zone B cells and preplasmablasts, B cells from the same mice that did not express the transgene were skewed toward the B1a phenotype. This work illustrates that genetic loci that confer lupus susceptibility may influence B cell differentiation depending on their Ag specificity and potentially contribute to antinuclear autoantibody formation by infringing upon B cell receptor editing. Taken together with a recent report on Sle1z, these studies suggest that dysregulated receptor-editing of nuclear Ag-reactive B cells may be a major mechanism through which antinuclear Abs arise in lupus.
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 National Institutes of Health Grants AR44894 (to C.M.), AI014782–28 (to J.F.K.), and the Arthritis Foundation.
2 Both Y.L. and L.L. have contributed equally to this manuscript and are co-first authors.
3 Address correspondence and reprint requests to Dr. Chandra Mohan, Department of Internal Medicine/Rheumatology, University of Texas, Southwestern Medical Center, Mail Code 8884, 5323 Harry Hines Boulevard, Dallas, TX 75390. E-mail address: chandra.mohan{at}utsouthwestern.edu
4 Abbreviations used in this paper: ANA, antinuclear autoantibody; BM, bone marrow; B6, C57BL/6; BUN, blood-urea-nitrogen; HC, H chain; LC, L chain; MZ, marginal zone; Tg, transgene.
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