Transchromosomally derived Ig heavy chains

During an immune response, activated B cells undergo isotype switching and begin to express isotypes other than IgM and IgD. Isotype switching occurs when downstream C gamma, C alpha, or C epsilon genes are rearranged into the S mu chromosomal region, resulting in the deletion of the region in between. These rearrangements usually occur in cis, i.e., intrachromosomally. In previous studies, we analyzed allotypic specificities of rabbit secretory IgA and identified a substantial number of IgA heavy chains with VH and C alpha allotypes that were encoded by VH and C alpha genes in trans. In those studies, however, we could not determine whether the trans association of VH and C alpha occurred during VDJ gene rearrangement or during isotype switching. Here, we cloned rabbit cDNA which encodes these trans IgA heavy chains and determined the chromosomal origin of the VH, JH, and C alpha regions. To determine whether the trans association occurred during VDJ gene rearrangement, we analyzed the nucleotide polymorphism of the JH region and the VH allotype encoded by the cDNA. We found that the VH and JH genes used in the VDJ gene rearrangements were from the same chromosome, indicating that the VH, D, and JH gene rearrangements occurred in cis. Furthermore, we analyzed the DNA polymorphisms of JH and C alpha and showed that the VDJ and C alpha genes encoding the trans IgA molecules were derived from different parental chromosomes. We suggest that the trans association occurred during isotype switching. This study shows that VH and CH can associate transchromosomally as part of a normal immune response.