A fetally expressed immunoglobulin VH1 gene belongs to a complex set of alleles.

Abstract

The immunoglobulin V H gene 51p1, a member of the large V H1 gene family, is preferentially expressed by B cells in the fetus and in chronic lymphocytic leukemia (CLL) and appears to be the source for many cryoglobulin rheumatoid factors. Polymorphism of Sipi may therefore be functionally important. We have studied the germline representation of 51pl and closely related V H elements to establish their prevalence and allelic relationship. A panel of oligonucleotide probes directed to the complementarity determining regions (CDR1 and CDR2) of 51pl and a similar gene, hv1263, was used in restriction fragment polymorphism analysis of 48 unrelated individuals and six families. 13 V H alleles to the 51pl locus were identified, each distinguished by its restriction fragment size, hybridization profile, or both. On some haplotypes the locus was duplicated. Null alleles were not seen. The 13 alleles were cloned, yielding nine distinct nucleotide sequences that were > 98.2% identical and included 51pl and hv1263. These germline variations could influence specificity for antigen, because the corresponding protein sequences differed by up to five amino acids, including three nonconservative changes in the CDR. Two of the most prevalent variants contained 51pl. These findings expand the spectrum of polymorphism seen among human VH genes and elucidate the germline origin of V H1 sequences frequently expressed in autoantibodies and CLL. We conclude that the 5lpl locus is polymorphic, and that the 51pl element is the predominant member of a complex set of alleles. (J. Clin.

Analysis of the human VH gene repertoire. Differential effects of selection and somatic hypermutation on human peripheral CD5(+)/IgM+ and CD5(-)/IgM+ B cells.

“…Recently it has been shown that this V H gene, which corresponds to the rearranged 51p1 sequence of the fetal repertoire (20), is present in the genome at varying numbers of copies (44). Using an anti-Id antibody, G6, which reacts with V regions encoded by 51p1 (43), the frequency of G6 ϩ IgD ϩ tonsillar B cells ranged from zero to 11.4% and correlated with the copy number of 51p1-related genes in different donors (45).…”

Immunoglobulin Gene Mutations and Frequent Use of VH1-69 and VH4-34 Segments in Hepatitis C Virus-Positive and Hepatitis C Virus-Negative Nodal Marginal Zone B-Cell Lymphoma

“…The VH1-69 immunoglobulin segment is expressed in the restricted repertoire of fetal liver B lymphocytes and is thought to be involved in natural immunity. 40,41 A productive VH1-69 rearrangement is present in ϳ1.6% of normal B lymphocytes in adults. 42 VH1-69 is rearranged in ϳ10 to 20% of B-cell chronic lymphocytic leukemia 30,43 and a VH1-69 monoclonal rearrangement is present in the majority of patients with type II mixed cryoglobulinemia, a typical HCV-related disorder.…”

Normal B Cells Express51p1-Encoded Ig Heavy Chains That Are Distinct From Those Expressed by Chronic Lymphocytic Leukemia B Cells

“…Assuming an equal expression frequency, the 1263-like alleles would be expected to be present in ϳ30% of V H 1-69-encoded rearrangements. The 1263-like variants primarily differ from 51p1 by only three amino acid substitutions in CDR2 (10). These changes are enough to eliminate binding of the G6 mAb used to define the G6 Id.…”

“…51p1 is an Ig V H 1 gene and is one of several alleles that belong to the V H 1-69 H chain locus. Restriction fragment length polymorphism analysis using oligonucleotide probes identified at least 13 distinct variants (10). These variants represent nine related sequences that can be divided into two groups based on several single-base differences in the second complementaritydetermining region (CDR2).…”