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The Role of Rearrangement at the Second Ig Heavy Chain Locus in Maintaining B Cell Tolerance to DNA

Department of Internal Medicine and Immunology, University of Texas Southwestern Medical School, Dallas, TX 75390

In recently generated B6.56R anti-DNA autoantibody-transgenic mice, it was noted that a substantial fraction of the B cells that had avoided DNA reactivity had done so through the rearrangement and usage of the endogenous, nontargeted H chain (HC) allele. This suggested that rearrangement at the second HC locus might be an important mechanism through which self-reactive B cells might successfully revise their initial Ag specificity. To test the importance of this mechanism in B cell tolerance, we generated B6.56R/56R mice that possessed the 56R anti-DNA H chain transgene inserted into both HC loci. These transgenic homozygotes developed higher titers of anti-DNA Abs, with an expanded population of B220^lowMHC class II^low B cells, enriched for CD21^lowCD23^low preplasmablasts. The analysis of hybridomas from these mice revealed that the only avenue by which these B cells could avoid DNA reactivity was through the use of the editor L chains, V_k20 or V_k21. Hence, in addition to LC editing, rearrangement and usage of the second HC locus/allele constitutes an important safety valve for B cells the primary BCR of which confers DNA reactivity. In contrast to these tolerance mechanisms, editing the first rearranged HC locus (through HC replacement) and somatic mutations appear to be less frequently used to edit/revise self-reactive B cells.

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¹ Address correspondence and reprint requests to Dr. Chandra Mohan, Department of Internal Medicine/Rheumatology, University of Texas Southwestern Medical Center, Mail Code 8884, Y8.204, 5323 Harry Hines Boulevard, Dallas, TX 75390. E-mail address: Chandra.mohan{at}utsouthwestern.edu

² Abbreviations used in this paper: Tg. transgenic; HC, H chain; LC, L chain; ANA, antinuclear autoantibody; int, intermediate.

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