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Two acquired immunodeficiency syndrome-associated Burkitt's lymphomas
produce specific anti-i IgM cold agglutinins using somatically mutated
VH4-21 segments
P Riboldi, G Gaidano, EW Schettino, TG Steger, DM Knowles, R Dalla-Favera and P Casali
Department of Pathology, New York University School of Medicine, NY 10016.
We analyzed the reactivity and the structure of the VH and VL segments of
two IgM monoclonal antibodies (MoAbs) produced by spontaneously in vitro
outgrowing cell lines, HBL-2 and HBL-3, established from two acquired
immunodeficiency syndrome (AIDS) patients with Epstein-Barr virus
(EBV)-negative Burkitt's lymphoma (BL). These B-cell clones were
representative of the respective neoplastic parental clones, as determined
by immunophenotypic and molecular genetic analysis. The IgM MoAbs were
highly specific for the i determinant on red blood cells (cold
agglutinins), but bound none of the other eight self and nine foreign
antigens (Ags) tested, including those most commonly recognized by natural
antibodies or autoantibodies. Structural analysis showed that the IgM MoAb
VH segment sequences were 93.5% and 84.2% identical with that of the
germline VH4-21 gene, which encodes the vast majority of cold agglutinins
that are specific for the i/l carbohydrate Ag and are produced under
chronic lymphoproliferative conditions. The HBL-2 MoAb VH4-21 gene segment
was juxtaposed with 20P3 and JH6 genes and paired with a V lambda 1
segment, the sequence of which was 95.5% identical to that of the germline
Humlv117 gene; the HBL-3 MoAb VH4-21 gene segment was juxtaposed with DXP'1
and JH5 genes and paired with a V lambda 1 segment, the sequence of which
was 86.7% identical to that of the germline Humlv1L1 gene. The high degree
of conservation of the VH4-21 gene in the human population, the nature of
the nucleotide differences in the expressed VH4-21 segments, and the
presence of nucleotide substitutions in the HBL-2 and HBL-3 IgM MoAb JH
and/or J lambda segments suggested that the MoAb V segments underwent a
process of somatic hypermutation. This was formally shown in the HBL-3 MoAb
VH segment, by differentially targeted polymerase chain reaction
amplification of the HBL-3 MoAb-producing cell genomic DNA. In addition,
cloning and sequencing of the genomic DNA from fibroblasts of the same
patient whose neoplastic B cells gave rise to the HBL-3 cell line yielded a
germline copy of the VH4-21 gene. Thus, the expression of VH4-21 gene
products may be involved in a self Ag-driven process of clonal B-cell
expansion and selection associated with BL in these AIDS patients.
Volume 83,
Issue 10,
pp. 2952-2961,
05/15/1994
Copyright © 1994 by The American Society of Hematology
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