CD40 ligand and autoantigen are involved in the pathogenesis of low-grade B-cell lymphomas of mucosa-associated lymphoid tissue.
Low-grade MALT-type lymphomas are malignancies of mucosal marginal-zone B cells and preceded by reactive inflammatory lymphoid tissue. Experimental observations suggest that antigen and CD40 Ligand act during cognate T/B cell interaction and are crucial for germinal center B-cell maturation generating marginal-zone B cells. To investigate the mechanisms underlying the development of extranodal MALT-type lymphomas, the immunoglobulin receptor was sequenced and analyzed for antigen specificity using heterohybridoma technology. Furthermore, CD40 ligand expression was evaluated by immunohistochemistry and by semiquantitative RT-PCR, and ligand binding to the CD40 of tumor B cells was studied using the CD40 system. Hypermutations were found in low-grade lymphomas throughout CDR1-CDR3 suggestive of positive selection through their antigen receptor. Different VH families were used and more than 69% of tumor immunoglobulins bound different mucosal antigens. CD40L expression was found in the tumor marginal zone in substantial amounts. The in vitro proliferation response of all low-grade MALT-type lymphomas was dependent on anti-CD40-mediated signals and cytokines. Our data provide evidence that autoantigen as well as the CD40L expressed by activated nonneoplastic T cells may drive the evolution of low-grade MALT-type lymphomas either directly or by paracrine mechanisms and that antigen may contribute to lymphoma pathogenesis.
Greiner
A
A
Institute of Pathology, University of Würzburg, Germany.
Knörr
C
C
Qin
Y
Y
Schultz
A
A
Marx
A
A
Kroczek
R A
RA
Müller-Hermelink
H K
HK
D000818:Animals; D000888:Antibodies, Anti-Idiotypic / Q000276:immunology; D000918:Antibody Specificity; D000951:Antigens, Neoplasm / Q000276:immunology; D001324:Autoantigens / Q000276:immunology*; D019013:CD40 Antigens / Q000032:analysis* / Q000276:immunology; D023201:CD40 Ligand; D006801:Humans; D007136:Immunoglobulins / Q000276:immunology; D007150:Immunohistochemistry; D007378:Interleukins / Q000276:immunology; D018442:Lymphoma, B-Cell, Marginal Zone / Q000235:genetics / Q000276:immunology*; D008562:Membrane Glycoproteins / Q000032:analysis*; D051379:Mice; D014066:Palatine Tonsil / Q000276:immunology; D011947:Receptors, Antigen, B-Cell / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000276:immunology; D013953:Thymus Neoplasms / Q000235:genetics / Q000276:immunology
D000888:Antibodies, Anti-Idiotypic; D000951:Antigens, Neoplasm; D001324:Autoantigens; D019013:CD40 Antigens; D007136:Immunoglobulins; D007378:Interleukins; D008562:Membrane Glycoproteins; D011947:Receptors, Antigen, B-Cell; D023201:CD40 Ligand