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V_H Mutant Rabbits Lacking the V_H1a2 Gene Develop a2⁺ B Cells in the Appendix by Gene Conversion-Like Alteration of a Rearranged V_H4 Gene¹

Molecular Immunogenetics Section, Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892

We investigated the molecular basis for the appearance of V_Ha2 allotype-bearing B cells in mutant Alicia rabbits. The mutation arose in an a2 rabbit; mutants exhibit altered expression of V_H genes because of a small deletion encompassing V_H1a2, the 3'-most gene in the V_H locus. The V_H1 gene is the major source of V_Ha allotype because this gene is preferentially rearranged in normal rabbits. In young homozygous ali/ali animals, the levels of a2 molecules found in the serum increase with age. In adult ali/ali rabbits, 20 to 50% of serum Igs and B cells bear a2 allotypic determinants. Previous studies suggested that positive selection results in expansion of a2 allotype-bearing B cells in the appendix of young mutant ali/ali rabbits. We separated appendix cells from a 6-wk-old Alicia rabbit by FACS based on the expression of surface IgM and a2 allotype. The VDJ portion of the expressed Ig mRNA was amplified from the IgM⁺ a2⁺ and IgM⁺ a2^- populations by reverse transcriptase-PCR. The cDNAs from both populations were cloned and sequenced. Analysis of these sequences suggested that, in a2⁺ B cells, the first D proximal functional gene in Alicia rabbits, V_H4a2, rearranged and was altered further by a gene conversion-like mechanism. Upstream V_H genes were identified as potential gene sequence donors; V_H9 was found to be the most frequently used gene donor. Among the a2^- B cells, y33 was the most frequently rearranged gene.

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