Restricted use of fetal VH3 immunoglobulin genes by unselected B cells in the adult. Predominance of 56p1-like VH genes in common variable immunodeficiency.

Abstract

The large VH3 family of human immunoglobulin genes is commonly used throughout B cell ontogeny. However, B cells ofthe fetus and certain autoantibody-producing clones are restricted to a recurrent subset of VH3 genes, and VH3 B cells are deficient in certain immunodeficiency diseases. In this study, we have sequenced a set of rearranged VH3 genes generated by genomic polymerase chain reaction (PCR) from normal adults and those with common variable immunodeficiency (CVI). In both groups, all clones were readily identifiable with the fetal VH3 subset, and were further distinguished by limited DH motifs and exclusive use ofJH4. In CVI, the residual population of VH3 B cells were notable for predominant use of 56pl-like VH genes. All clones displayed sequence divergence (including somatic mutation) with evidence of strong selection against complementarity-determining region (CDR) coding change. A survey of other V gene families indicates that human V gene diversity may be restricted in general by germline mechanisms. These findings suggest that the expressed antibody repertoire in the human adult may be much smaller than anticipated, and selected by processes in part distinct from the paradigm of maximal antigen-binding diversity. (J. Clin. Invest. 1992.

Ethnic differences of polymorphism of an immunoglobulin VH3 gene.

“…We observed total gene copy numbers ranging from one to as many as six copies of potentially exact VH26 germline genes (i.e., 7.0 plus 6.8 plus 5.0 kb), and from zero to as many as six to eight copies of the 3.7-kb allele. Because the majority of Caucasians, and many Asians, possessed three or four copies of VH26 in the diploid genome, it seems likely that the relative overexpression of VH26 that has been reported for adult and fetal B cells is at least partly explainable by the relative abundance of the germline template (21,(23)(24)(25). This interpretation is consistent with the finding by Stewart et al, that VH26 was expressed two to three times as frequently as the VH3 gene 56pl (25).…”

“…VH26 is of interest because it is frequently expressed by both fetal and adult B lymphocytes, and often appears to be overexpressed, relative to other VH genes (19,(21)(22)(23)(24)(25). VH26 has frequently been found in autoantibodies, including anti-DNA Ab and rheumatoid factors, and has been associated with systemic lupus erythematosus via the 16/6 idiotype, which it encodes (18,(26)(27)(28).…”

Reconstitution of the B cell repertoire after bone marrow transplantation does not recapitulate human fetal development

“…51 In addition, the most frequently expressed V H segments in fetal liver (such as V3-23 and V3-30.3) are also employed at high frequencies in cord blood and adult peripheral blood. [52][53][54][55] These findings collectively support the conclusion that the human fetal repertoire is not determined by physical proximity of V H segments to the J H elements. 21 analyzed the post-BMT repertoire using quantitative PCR, followed by V H -specific oligonucleotide hybridization.…”

Clinical and laboratory aspects of common variable immunodeficiency

“…In some of the patients with normal levels of B cells these will have a mature phenotype bearing surface immunoglobulins, others will only possess cells with an immature phenotype characterized by an enlarged volume, restricted usage of V H families and decreased mutating capacity at the hypervariable regions of the immunoglobulin genes (Braun et al 1992a(Braun et al , b, 1991.…”