Molecular characterization of a cross-reactive idiotope on human immunoglobulins utilizing the VH4-21 gene segment.

Abstract

SummaryThe anti-idiotypic (anti-Id) antibody (Ab) 9G4 binds a cross-reactive idiotope (CRI) present in a select group of human autoantibodies. This Id has been localized to the portion of immunoglobulin (Ig) heavy (H) chains encoded by the V,4-21 gene segment, a member of the human V.4 family. This gene segment is utilized by essentially all cold agglutinin (CA) Abs with I/i specificity isolated from patients with CA disease stemming from chronic lymphoproliferative disorders. In this study, mutational analysis of a CA has been used to determine the structural basis for 9G4 binding to Abs utilizing the VH4--21 gene segment. Recombinant CA H chain mutants were produced and their 9G4 reactivity determined. Mutants were generated by exchanging V.4-21 sequences in the FK1, CDR1, and CDK2 with corresponding sequences from a closely related gene segment V71-2, a V.4 family member that is associated neither with Abs having CA activity nor with Abs that react with 9G4. The results indicate that the motif AVY at amino acid positions 23-25 in FR1 defines the 9G4 idiotope. Reaction of these recombinant Abs with a polyclonal rabbit anti-CA antiserum absorbed to render it specific for a CA CRI also maps predominantly to FR1. These findings indicate that the solvent-exposed FR1 plays an important role in eliciting an immune response to Igs.

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

“…This gene segment is of interest, since it encodes an antibody that recognizes autologous determinants on red blood cells, the I/i antigens (39). Furthermore, it has been shown that a monoclonal antiidiotype antibody, 9G4, recognizes a conformation-dependent idiotype that is highly associated with the 4-34/DP-63 gene segment (40). In the current study, 4-34/DP-63 was the third most commonly used V H 4 family member, but its frequency in the productive or nonproductive repertoires of peripheral blood B cells was not significantly different than that predicted from random usage.…”

Relatively Normal Human Lymphopoiesis but Rapid Turnover of Newly Formed B Cells in Transplanted Nonobese Diabetic/SCID Mice

“…This member of the V H 4 gene family is extensively used for B cell Ag receptors with specificity for RBC and B lymphocyte carbohydrate Ags (65)(66)(67)(68)(69)(70). Ongoing studies will reveal whether similar patterns develop when mice are transplanted with adult human stem cells and this information may bear on the issue of what drives CD5 expression.…”

Disturbed Peripheral B Lymphocyte Homeostasis in Systemic Lupus Erythematosus

“…Moreover, the gene V H 4 -34 frequently used in the clonally unrelated CD27 high cells analyzed here has been reported previously to be involved in the formation of anti-dsDNA Abs in SLE patients (40 -42) and to be expanded in patients with disease activity (41). This V H 4 gene encodes cold agglutinins (43)(44)(45). It was also frequently used in immune responses of infectious mononucleosis (41,46).…”