Developmentally Controlled Expression of Immunoglobulin V _H Genes

Abstract

Although antibody diversity arises mainly from apparently random combinatorial and somatic mutational mechanisms acting upon a limited number of germline antibody genes, the antibody repertoire develops in an ordered fashion during mammalian ontogeny. A series of early pre-B and B-lymphocyte cell lines were examined to determine whether an ordered rearrangement of gene families of the variable region of immunoglobulin heavy chains (VH) may be the basis for the programmed development of the antibody response. The results indicated that the VH repertoire of fetal B-lineage cells is largely restricted to the VH 7183 gene family and that subsequent recruitment of additional VH gene families occurs during neonatal development. These results have important implications in understanding the ontogeny of immune function.

The VλJλ Repertoire in Human Fetal Spleen: Evidence for Positive Selection and Extensive Receptor Editing

“…Previous reports have indicated that restrictions in Ag specificities are achieved by limited and preferential usage of certain V H and V gene segments (12,28). Preferential gene use reflected the proximity of gene segments in chromosomal position (8,9,12). Fetal diversity was also reported to reflect limited diversification of the CDR3 region during early ontogeny.…”

“…The finding that the two most distal V genes were not detected in the fetal nonproductive repertoire suggests that, as in the mouse, proximity of gene segments in the chromosome position plays a role in preferential V J rearrangements early in human ontogeny. However, it is different in that this positional effect is not as profound as in mouse (8,9,36), because rearrangement of V genes in the human fetus occurred throughout the entire V locus, except the most distal two genes. These findings indicate that nonrandom gene segment use largely reflects a regulatory process that is intrinsic to the specific gene element and is independent of the stage of B cell maturation.…”

“…Analysis of V H and V gene expression in different stages of development, in both humans and mice, has suggested developmentally controlled nonrandom use of V(D)J genes and unique patterns of junctional diversity (7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17). With better understanding of BCR signaling, recent studies have provided direct evidence that bias in the Ab repertoire is a result of selection mediated through pBCR and BCR (18 -20).…”

Biased Vβ Usage in Immature Thymocytes Is Independent of DJβ Proximity and pTα Pairing

“…By analogy with studies of VDJ H recombination in immature B cells, one of the most obvious possibilities would be the relative proximity of a given V␤ segment to the DJ␤ cluster. Indeed, in both fetal and adult mouse pre-B cells, it has been shown that DJ H -proximal V H segments (such as V H 81X) are preferentially rearranged (37)(38)(39)(40)(42)(43)(44). In marked contrast to pre-B cells, the most DJ␤-proximal V␤ segments in DN3 thymocytes (V␤7 and V␤3) are apparently rearranged at relatively low frequency, whereas the relatively distal V␤8.2 segment is rearranged most frequently.…”

“…At the IgH locus, there is a large body of evidence indicating that proximal V H segments rearrange preferentially to DJ H segments during ontogeny (37)(38)(39)(40)(41)(42)(43)(44). Thus it is possible that the variations observed in V␤ usage among DN3 thymocytes reflect proximity to the DJ␤ segments.…”