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Selection of Anti-Double-Stranded DNA B Cells in Autoimmune MRL-lpr/lpr Mice¹

Ching Chen^2,*, Hui Li, Qi Tian^*, Michael Beardall^*, Yang Xu^*, Nina Casanova^* and Martin Weigert

^* Department of Pathology, Oregon Health & Science University, Portland, OR 97239; and Gwen Knapp Center for Lupus and Immunology Research, University of Chicago, Chicago, IL 60637

Abs to DNA and nucleoproteins are expressed in systemic autoimmune diseases, whereas B cells producing such Abs are edited, deleted, or inactivated in healthy individuals. Why autoimmune individuals fail to regulate is not well understood. In this study, we investigate the sources of anti-dsDNA B cells in autoimmune transgenic MRL-lpr/lpr mice. These mice are particularly susceptible to lupus because they carry a site-directed transgene, H76R that codes for an anti-DNA H chain. Over 90% of the B cells are eliminated in the bone marrow of these mice, and the few surviving B cells are associated with one of two V editors, V38c and V21D. Thus, it appears that negative selection by deletion and editing are intact in MRL-lpr/lpr mice. However, a population of splenic B cells in the H76R MRL-lpr/lpr mice produces IgG anti-nuclear Abs, and these mice have severe autoimmune organ damage. These IgG Abs are not associated with editors but instead use a unique V gene, V23. The H76R/V23 combination has a relatively high affinity for dsDNA and an anti-nuclear Ab pattern characteristic of lupus. Therefore, this V gene may confer a selective advantage to anti-DNA Abs in diseased mice.

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