Salivary gland MALT lymphomas of Sjӧgren's syndrome patients in majority express rheumatoid factors affinity-selected for IgG.

Objective Patients with Sjogren's syndrome (SS) have an increased risk of developing malignant B cell lymphomas, particularly mucosa-associated lymphoid tissue (MALT)-type lymphomas. We have previously shown that a predominant proportion of patients withSS-associated salivary glandMALTlymphoma express somatically hypermutated IgM with strong amino acid sequence homology with stereotypic rheumatoid factors (RFs). The present study was undertaken in a larger cohort of patients withSS-associatedMALTlymphoma to more firmly assess the frequency ofRFreactivity and the significance of somaticIGV-region mutations forRFreactivity. Methods B cell antigen receptors (BCRs) of 16 patients withSS-associated salivary glandMALTlymphoma were analyzed. Soluble recombinant IgM was produced of 12 MALT lymphoma samples, including 1MALTlymphoma sample that expressed an IgM antibody fitting in a novelIGHV3-30-encoded stereotypicIGHVsubset. For 4 of the 12 IgM antibodies fromMALTlymphoma samples, the somatically mutatedIGHVandIGKVgene sequences were reverted to germline configurations. TheirRFactivity and binding affinity were determined by enzyme-linked immunosorbent assay and surface plasmon resonance, respectively. Results Nine (75%) of the 12 IgM antibodies identified in patients withSS-associated salivary glandMALTlymphoma displayed strong monoreactiveRFactivity. Reversion of theIGHVandIGKVmutations to germline configuration resulted inRFaffinities for IgG that were significantly lower for 3 of the 4 somatically mutated IgM antibodies. In stereotypicIGHV3-7/IGKV3-15-encodedRFs, a recurrent replacement mutation in theIGKV3-15-third complementarity-determining region was found to play a pivotal role in the affinity for IgG-Fc. Conclusion A majority of patients with SS-associated salivary gland MALT lymphoma express somatically mutated BCRs that are selected for monoreactive, high-affinity binding of IgG-Fc. These data underscore the notion that soluble IgG, most likely in immune complexes in inflamed tissues, is the principal autoantigen in the pathogenesis of a variety of B cell lymphomas, particularly SS-associated MALT lymphomas.