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Editing Rescues Autoreactive B Cells Destined for Deletion in Mice Transgenic for a Dual Specific Anti-Laminin Ig¹

Graham F. Brady^2,*, Kendra L. Congdon^2,*, Amy G. Clark^*, Faustina N. A. Sackey^*, Earl H. Rudolph^*, Marko Z. Radic and Mary H. Foster^3,*

^* Departments of Medicine, Duke University and Durham Veterans Administration Medical Centers, Durham, NC 27710; and Molecular Sciences, University of Tennessee, Memphis, TN 38163

We explored mechanisms involved in B cell self-tolerance in a double- and triple-transgenic mouse model bearing the LamH-Cµ Ig H chain conventional transgene and a gene-targeted replacement for a functional V8J5 L chain gene. Whereas the H chain is known to generate anti-laminin Ig in combination with multiple L chains, the H + L Ig binds ssDNA in addition to laminin. Immune phenotyping indicates that H + L transgenic B cells are regulated by clonal deletion, receptor editing via secondary rearrangements at the nontargeted allele, and anergy. Collectively, the data suggest that multiple receptor-tolerogen interactions regulate autoreactive cells in the H + L double-transgenic mice. Generation of H + LL triple-transgenic mice homozygous for the targeted L chain to exclude secondary rearrangements resulted in profound B cell depletion with absence of mature B cells in the bone marrow. We propose that the primary tolerogen of dual reactive B cells in this model is not ssDNA, but a strongly cross-linking tolerogen, presumably basement membrane laminin, that triggers recombination-activating gene activity, L chain editing, and deletion.

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