Molecular analysis of immunoglobulin variable genes in human immunodeficiency virus-related non-Hodgkin's lymphoma reveals implications for disease pathogenesis and histogenesis.
BACKGROUND
Human immunodeficiency virus (HIV)-related non-Hodgkin's lymphomas (HIV-NHL) are heterogeneous and associated with distinct molecular pathways. Analysis of immunoglobulin variable genes (IGV) may provide insights into the pathogenesis and histogenesis of HIV-NHL.


METHODS
IGV rearrangements were amplified from genomic DNA by polymerase chain reaction and directly sequenced in 87 cases of HIV-NHL (17 Burkitt/Burkitt-like lymphomas, 38 diffuse large B-cell lymphomas, and 32 primary central nervous system lymphomas).


RESULTS
A skewed IGHV repertoire in specific HIV-NHL clinico-pathological categories was observed. Systemic HIV-diffuse large B-cell lymphomas displayed underrepresentation of the IGHV3 family (11/38, 28.9%; p=0.0047) and, in particular, of the IGHV3-23 gene (0/38; p<0.001). These same cases were also characterized by significant overrepresentation of the IGHV4 family (18/38; 47.4%; p=0.0044) and, in particular, of the IGHV4-34 gene (10/38; 26.3%; p=0.003). HIV-primary central nervous system lymphomas displayed a preferential usage of IGLV6-57, with stereotyped B-cell receptor in two cases. Somatic hypermutation of IGHV genes was detected in 81/87 (93.1%) HIV-NHL. Unmutated cases were restricted to six HIV-primary central nervous system lymphomas with immunoblastic plasmacytoid morphology. A mutational profile suggesting a tendency to maintain antigen binding and antigen selection was observed in more than 50% of the cases of IGV mutated HIV-NHL.


CONCLUSIONS
Our data show evidence of a skewed IGHV repertoire in specific HIV-NHL categories and suggest B-cell receptor restriction in some HIV-primary central nervous system lymphomas. The heterogeneous representation of IGHV genes in HIV-NHL may be related to specific pathways of antigen stimulation, or to differences in host's immune dysregulation and lymphoma histogenesis.
Capello
Daniela
D
Division of Hematology, Department of Clinical and Experimental Medicine & BRMA, Amedeo Avogadro University of Eastern Piedmont, Via Solaroli 17, 28100 Novara, Italy. capello@med.unipmn.it
Martini
Maurizio
M
Gloghini
Annunziata
A
Cerri
Michaela
M
Rasi
Silvia
S
Deambrogi
Clara
C
Rossi
Davide
D
Spina
Michele
M
Tirelli
Umberto
U
Larocca
Luigi Maria
LM
Carbone
Antonino
A
Gaidano
Gianluca
G
D001493:Bathing Beaches; D002051:Burkitt Lymphoma / Q000235:genetics / Q000276:immunology / Q000473:pathology; D005784:Gene Amplification; D015321:Gene Rearrangement; D015658:HIV Infections / Q000150:complications* / Q000276:immunology / Q000473:pathology; D006801:Humans; D007135:Immunoglobulin Variable Region / Q000235:genetics*; D008228:Lymphoma, Non-Hodgkin / Q000235:genetics* / Q000276:immunology* / Q000473:pathology; D016133:Polymerase Chain Reaction; D011947:Receptors, Antigen, B-Cell / Q000235:genetics; D027041:Somatic Hypermutation, Immunoglobulin / Q000235:genetics
D007135:Immunoglobulin Variable Region; D011947:Receptors, Antigen, B-Cell