Comparison of the Fetal and Adult Functional B Cell Repertoires by Analysis of Vh Gene Family Expression by Hyun Do Jeong and Judy

One of the most fundamental questions in immunology is how the B lymphocyte immune repertoire develops and diversifies. During ontogeny, there is a temporal appearance of B cells responsive to given antigens during ontogeny (1-8). For example, in the BALB/c strain, B cells responsive to DNP appear first in ontogeny followed by fluorescein, 4-hydroxy-3-nitrophenol and phosphorylcholine-responsive B cells (3-8). Importantly, within a given strain, every individual acquires the ability to respond to particular antigens at roughly the same time (4). This suggests a developmental program for immunocompetence . One of the ways in which diversity of the antibody response is created is by the combinational joining of gene segments that encode the variable regions of the antibody molecule . During development, the B cell selects one each of many variable (VH), diversity (D), and joining (JH) gene segments to make the active heavy chain variable region gene (9, 10). A similar event occurs for the light chain (9, 10). The exact mechanism ofthe rearrangement process andhow it is regulated remain unclear. Based on nucleotide sequence similarity, the estimated 100-1,000 murine VH gene segments have been categorized into nine distinct families (11-14). Recombination studies have suggested that the families map as discrete units within the heavy chain locus on chromosome 12 (11-13, 15). However, there is increasing evidence for some degree of interspersion among the families indicating that VH genes in the mouse are encoded in overlapping clusters (16, 17). The clustered organization of VH gene families permitted the following ordering of families : JHD VH 7183, VH Q52, VH 5107, VH J558, VH J606, and VH 36-60 (11, 12, 16, 17). The order was assigned by deletion analyses (16) or studies of recombinant strains (11, 12, 17), and most VH gene families have not been physically linked . An ordered rearrangement of variable region gene segments could be involved in the preprogrammed-like appearance of B cell specificities during development. Recently, it has been shown that BALB/c fetal pre-B cell lines preferentially rearrange VH gene segments belonging to the VH 7183 family (18, 19), the family most proximal to D in BALB/c. The fetal pre-B cell lines studied had either been trans-