Salivary gland mucosa-associated lymphoid tissue lymphoma immunoglobulin VH genes show frequent use of V1-69 with distinctive CDR3 features

Abstract

Salivary gland mucosa associated lymphoid tissue (MALT) type lymphomas are B-cell neoplasms that develop out of a reactive infiltrate, often associated with Sjögren's syndrome. Previous reports from our laboratory involving 10 patients suggested these lymphomas expressed a restricted immunoglobulin (Ig)VH gene repertoire with over use ofV1-69 gene segments. To better determine the frequency ofV1-69 use and whether there may also be selection for CDR3 structures, we sequenced the VH genes from 15 additional cases. Over half of the potentially functionalVH genes (8 of 14) used aVH1 family V1-69 gene segment, whereas the other cases used different gene segments from theVH1 (V1-46),VH3 (V3-7, V3-11, V3-30.3, V3-30.5), and VH4(V4-39) families. The 8 V1-69 VHgenes used 5 different D segments in various reading frames, but all used a J4 joining segment. The V1-69 CDR3s showed remarkable similarities in lengths (12-14 amino acids) and stretches of 2 to 3 amino acids between the V-D and D-J junctions. They did not resemble CDR3s typical of V1-69 chronic lymphocytic leukemias. This study extends our earlier work in establishing that salivary gland MALT lymphomas represent a highly selected B-cell population. Frequent use of V1-69 appears to differ from MALT lymphomas that develop at other sites. The high degree of CDR3 similarity among the V1-69cases suggests that different salivary gland lymphomas may bind similar, if not identical epitopes. Although the antigen specificities are presently unknown, similar characteristic CDR3 sequences are often seen with V1-69 encoded antibodies that have anti-IgG or rheumatoid factor activity.

Extrasalivary lymphoma development in Sjögren's syndrome: Clonal evolution from parotid gland lymphoproliferation and role of local triggering

“…The presence of somatic mutations and intraclonal diversity indicates that these cells were stimulated to proliferation under conditions in which T cell-derived signals re-quired for mutation were present. The overall number of common mutations detected at the different time points (4-8 mutations, 1.8-3.5%) was not high, similar to the levels observed in nonmalignant IgMϩ/IgDϪ peripheral blood lymphocytes, in SS-associated MESA as well as in salivary gland MALT lymphomas (7,8).…”

“…The meaning of such a feature has been debated. In fact, a low R/S ratio in CDRs in MESA and in some MALT lymphomas was reported in previous studies (7,8). It has been suggested that the residues in the CDRs are conserved to maintain the binding to antigens that are important for B cell stimulation and survival.…”

“…from reactive MESA to malignant lymphoma are not well known. Molecular studies have demonstrated that both MESA and neoplastic B clones show a B cell receptor derived from a restricted subset of V-region (variability) and D-region (diversity) genes with conserved amino acid motifs in the third complementaritydetermining region (CDR3), consistent with B cell stimulation by a common or a restricted set of antigens (7)(8)(9). These features, together with the intraclonal heterogeneity displayed by these clones, support the hypothesis that chronic stimulation by exogenous or self antigens could play an important role in the lymphoproliferative process in SS, by promoting the survival of specific B cell subsets (8)(9)(10).…”

Structural Determination of the Broadly Reactive Anti-IGHV1-69 Anti-idiotypic Antibody G6 and Its Idiotope

“…The G6 CRI may also be useful for monitoring B cells and Abs that bind to and neutralize HCV and MERS-CoV, respectively (Chan et al, 2001;Tang et al, 2014;Ying et al, 2015). In the emerging field of oncoimmunology, the high presence of G6 CRI on unmutated BCRs seen in IGVH1-69-encoded B-CLL (Chang et al, 2016;Hamblin et al, 1999), and the recognition of other IGHV1-69 disorders involving pathophysiologic B cell expansions (Chan et al, 2001;Miklos et al, 2000) could provide an avenue of therapeutic intervention through hG6.3-mediated immune clearance. In addition, hG6.3-based idiotype mapping (Idio-Seq) could add an important new dimension to the field of immune recognition where advances in the high-throughput sequencing and analysis of expressed Ab repertoires (BCR-seq) in peripheral blood B cells and LC-MS/MS proteomic spectrotyping of antigen-specific Abs (IG-seq) allow us to characterize, with unparalleled accuracy, the serological repertoire to each of the Ab components (Lee et al, 2016).…”

“…Remarkably, the anti-Id + G6 51p1 alleles are overwhelmingly predominant in this disease (Johnson et al, 1997;Keating et al, 2003). Several other biased F-allelic IGHV1-69 Ab responses and associations with disease processes have been reported (Chan et al, 2001;Miklos et al, 2000;Steininger et al, 2012;Tang et al, 2014;Yeung et al, 2016;Ying et al, 2015). In influenza infection, the biased use of IGHV1-69 F-alleles in the production and serum titers of broadly neutralizing antibodies to the influenza A hemagglutinin (HA) stem domain (HV1-69-sBnAbs) occurs Pappas et al, 2014).…”