Somatic hypermutation, clonal diversity, and preferential expression of the VH 51p1/VL kv325 immunoglobulin gene combination in hepatitis C virus-associated immunocytomas.
A high prevalence of chronic hepatitis C virus (HCV) infection has recently been shown in a subset of B-cell non-Hodgkin's lymphomas, most of which belong to the lymphoplasmacytoid lymphoma/immunocytoma subtype and are characterized by the production of a monoclonal IgM cryoglobulin with rheumatoid factor activity. To better define the stage of differentiation of the malignant B cell and to investigate the role of chronic antigen stimulation in the pathogenesis of the HCV-associated immunocytomas, we analyzed the variable (V) region gene repertoire in 16 cases with this type of tumor. The lymphoma-derived V gene sequences were successfully determined in 8 cases; 5 of them expressed the 51p1 VH gene in combination with the kv325 VL gene. Moreover, a monoclonal 51p1-expressing B-cell population was detected in 4 of the remaining immunocytomas by an allele-specific Ig gene fingerprinting assay, indicating that HCV-associated immunocytomas represent clonal proliferations of a highly selected B-cell population. Somatic mutations and intraclonal diversity were observed in all of the lymphoma V genes, and clonally related IgM and IgG VH transcripts indicative of isotype switching were present in one case. These findings are consistent with an antigen-driven process and support a role for chronic antigen stimulation in the growth and clonal evolution of HCV-associated immunocytomas.
Ivanovski
M
M
Molecular Immunology Group, International Centre for Genetic Engineering & Biotechnology, Trieste, Italy.
Silvestri
F
F
Pozzato
G
G
Anand
S
S
Mazzaro
C
C
Burrone
O R
OR
Efremov
D G
DG
D000328:Adult; D000368:Aged; D000595:Amino Acid Sequence; D019070:Cell Lineage / Q000235:genetics / Q000276:immunology; D005260:Female; D005803:Genes, Immunoglobulin; D016174:Hepacivirus / Q000302:isolation & purification*; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000235:genetics*; D007135:Immunoglobulin Variable Region / Q000235:genetics*; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics / Q000276:immunology* / Q000821:virology*; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation
D007143:Immunoglobulin Heavy Chains; D007135:Immunoglobulin Variable Region