Among B cell non-Hodgkin's lymphomas, MALT lymphomas express a unique antibody repertoire with frequent rheumatoid factor reactivity

Abstract

We analyzed the structure of antigen receptors of a comprehensive panel of mature B non-Hodgkin's lymphomas (B-NHLs) by comparing, at the amino acid level, their immunoglobulin (Ig)VH-CDR3s with CDR3 sequences present in GenBank. Follicular lymphomas, diffuse large B cell lymphomas, Burkitt's lymphomas, and myelomas expressed a CDR3 repertoire comparable to that of normal B cells. Mantle cell lymphomas and B cell chronic lymphocytic leukemias (B-CLLs) expressed clearly restricted albeit different CDR3 repertoires. Lymphomas of mucosa-associated lymphoid tissues (MALTs) were unique as 8 out of 45 (18%) of gastric- and 13 out of 32 (41%) of salivary gland-MALT lymphomas expressed B cell antigen receptors with strong CDR3 homology to rheumatoid factors (RFs). Of note, the RF-CDR3 homology without exception included N-region–encoded residues in the hypermutated IgV H genes, indicating that they were stringently selected for reactivity with auto-IgG. By in vitro binding studies with 10 MALT lymphoma–derived antibodies, we showed that seven of these cases, of which four with RF-CDR3 homology, indeed possessed strong RF reactivity. Of one MALT lymphoma, functional proof for selection of subclones with high RF affinity was obtained. Interestingly, RF-CDR3 homology and t(11;18) appeared to be mutually exclusive features and RF-CDR3 homology was not encountered in any of the 19 pulmonary MALT lymphomas studied.

HCV-NS3 and IgG-Fc crossreactive IgM in patients with type II mixed cryoglobulinemia and B-cell clonal proliferations

“…Several studies demonstrated infact the presence of IgV genes mutations compatible with a germinal center (GC) or post-GC derivation, a replacement/silent mutation ratio consistent with the maintenance of a functional structure of the BCR, and the presence of intraclonal heterogeneity. 4,5,13,14 These notions are further strongly supported by the observation that a proportion of HCV-related MC and NHL are curable by virus eradication. [15][16][17][18][19] Conceivably, the similarity in the structure of the variable BCR region may account for selection of B cells expressing specific and common reactivity.…”

Molecular pathways in follicular lymphoma

“…However, immunohistochemical staining using four recombinant, FL-derived, soluble Igs did not reveal reactivity with any structures in the corresponding FL tissues nor did these antibodies bind auto-Ags such as IgG and nuclearAgs. 79 In a previous study by Dighiero et al 80 eight out of 31 FL-derived Igs reacted in vitro with nuclear-Ags, IgG, actin and tubulin. As deduced from IgV H /IgV L structures of FLs, no clues were found concerning binding of recurrent antigenic epitopes.…”

The peripheral helper T-cell repertoire in untreated indolent B-cell lymphomas: evidence for antigen-driven lymphomagenesis

“…In contrast to the lymphoma-promoting T cells, however, the antigen receptor of the malignant B cells in MALT-eMZL appears to recognize autoantigens. 4 Beyond MZL, evidence for direct recognition of autoantigen by the malignant B cell has been obtained in chronic lymphocytic leukemia, where the antigen receptors frequently bind autoantigens in common diagnostic assays. 5 To detect a role for antigen-dependent T cells in the immunopathogenesis of indolent B-cell lymphomas in a widely applicable manner, we analyzed the T-cell receptor (TCR) repertoire of circulating CD4 þ T cells in untreated B-cell lymphoma patients in comparison to healthy age-matched control persons in a prospective study.…”