Stereotypic Rheumatoid Factors That Are Frequently Expressed in Mucosa‐Associated Lymphoid Tissue–Type Lymphomas Are Rare in the Labial Salivary Glands of Patients With Sjögren's Syndrome

Abstract

Objective. Among autoimmune diseases, Sjögren's syndrome (SS) is most strongly associated with the development of malignant B cell lymphoma, in particular mucosa-associated lymphoid tissue (MALT)-type lymphoma. Previously, we have shown that in ϳ40% of cases of salivary gland MALT lymphoma, high-affinity stereotypic rheumatoid factor (RF) B cell receptors, specific for IgG-Fc, are expressed. This study was undertaken to investigate whether in the inflamed salivary glands of patients with SS, a similar RF-biased Ig repertoire is present.Methods. Extensive analyses of the B cell Ig V H region repertoire were performed on microdissected tissue samples from the labial salivary glands of 4 patients with SS.Results. All SS labial salivary glands harbored expanded B cell clones, of which 1 or 2 were highly expanded and detected in >50% of the microdissected samples. However, among the identified 464 distinct Ig clonotypes, only 3 stereotypic RF-expressing clones were detected. In 2 patients with SS, an RF-expressing clone was detected at low frequency in 1 of the microdissected samples, whereas 1 patient with SS harbored a highly expanded RF-expressing clone that was detected in all microdissected samples and also detected in the peripheral blood. Two years after analysis of this sample, the latter patient developed a diffuse large B cell lymphoma originating from the same RF clone.Conclusion. Inflamed labial salivary glands in patients with SS generally harbor 1 or 2 highly expanded B cell clones. The repertoire strongly biased toward stereotypic RFs in salivary gland MALT lymphomas is not a reflection of a similar repertoire in the inflamed salivary glands of patients with SS; rather, in the latter, the repertoire is based on a strong selection advantage of incidental stereotypic RF-expressing B cells.

Molecular Profiling and Clonal Tracking of Secreted Rheumatoid Factors in Primary Sjögren's Syndrome

“…The molecular analysis of RFs described here differentiates pathogenic, cryoprecipitable RFs from apparently benign, nonprecipitating RFs, in terms of a higher frequency of amino acid substitutions and identification of matched heavy-chain CDR3 RNAs in the peripheral blood B cells. The cryoprecipitable RF clonotypes, linked to the development of systemic vasculitis and higher mortality in primary SS, expressed stereotypic RF idiotypes of the RF-WOL (Wa) and Ig V H 3-7 RF families that have been reported in MALT lymphomas from primary SS patients, consistent with the notion that chronic stimulation of these RF-positive B cells by circulating anti-Ro/La immune complexes can lead to their transition to malignant lymphoma (9)(10)(11)(12)(13)(14).…”

Structure–function analyses of a stereotypic rheumatoid factor unravel the structural basis for germline-encoded antibody autoreactivity

“…As pointed out in previous reports, the amino acid composition of CDR-H3 in IGHV1-69/IGKV3-20 RFs is diverse, although the length is restricted to 12-15 residues ( Fig. 3D) (14,17,27).…”

“…In serum from healthy human donors immunized with mismatched red blood cells (12) as well as patients with MC caused by hepatitis C virus (HCV) infection (13), mucosa-associated lymphoid tissue-type lymphoma (14), HCV-associated lymphoma (15), and B cell chronic lymphocytic leukemia (16), high frequencies of RFs with combinations of heavy chains and light chains that are from specific germline genes, called "stereotypic RFs", have been reported (17). Of the stereotypic RFs, those from IGHV1-69/IGKV3-20 are the most prominent.…”

Laryngological manifestations of Sjögren’s syndrome

“…Potential explanations for this incidence variation include differences in the criteria used for the diagnosis of SS and the variable duration of follow-up. The emergence of lymphoma is signalled by persistently enlarged parotid glands, regional or general lymphadenopathy, hepatosplenomegaly, pulmonary infiltrates, vasculitis, and hypergammaglobulinaemia [24][25][26][27][28]. None of these features is specific, but any should raise the index of suspicion, particularly if accompanied by serological features such as a falling packed-cell volume, high sedimentation rate, or the presence of monoclonal immunoglobulin.…”