Disease‐biased and shared characteristics of the immunoglobulin gene repertoires in marginal zone B cell lymphoproliferations

Abstract

The B cell receptor immunoglobulin (Ig) gene repertoires of marginal zone (MZ) lymphoproliferations were analyzed in order to obtain insight into their ontogenetic relationships. Our cohort included cases with MZ lymphomas (n = 488), i.e. splenic (SMZL), nodal (NMZL) and extranodal (ENMZL), as well as provisional entities (n = 76), according to the WHO classification. The most striking Ig gene repertoire skewing was observed in SMZL. However, restrictions were also identified in all other MZ lymphomas studied, particularly ENMZL, with significantly different Ig gene distributions depending on the primary site of involvement. Cross‐entity comparisons of the MZ Ig sequence dataset with a large dataset of Ig sequences (MZ‐related or not; n = 65 837) revealed four major clusters of cases sharing homologous (‘public’) heavy variable complementarity‐determining region 3. These clusters included rearrangements from SMZL, ENMZL (gastric, salivary gland, ocular adnexa), chronic lymphocytic leukemia, but also rheumatoid factors and non‐malignant splenic MZ cells. In conclusion, different MZ lymphomas display biased immunogenetic signatures indicating distinct antigen exposure histories. The existence of rare public stereotypes raises the intriguing possibility that common, pathogen‐triggered, immune‐mediated mechanisms may result in diverse B lymphoproliferations due to targeting versatile progenitor B cells and/or operating in particular microenvironments. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

IGHV mutational status of nodal marginal zone lymphoma by NGS reveals distinct pathogenic pathways with different prognostic implications

“…In particular, our data are in accordance with previous studies which showed a biased usage of the IGHV genes in favor of IGHV-1- [30]. Conversely, we found an overrepresentation of VH1-2 gene in our cohort of cases (5 out of 28; 17.8%) which has been found mainly in SMZL [30]. VH1-2 is known to react with antigen exposed on apoptotic cells, suggesting that at least a subset of NMZL may arise from a self-antigen antibody producing B cell [6].…”

“…Here we show that in NMZL cases, the VH1 family genes were significantly overrepresented compared with transitional B cells, naive B cells, and IgM memory B cells [29]. In particular, our data are in accordance with previous studies which showed a biased usage of the IGHV genes in favor of IGHV-1- [30]. Conversely, we found an overrepresentation of VH1-2 gene in our cohort of cases (5 out of 28; 17.8%) which has been found mainly in SMZL [30].…”

“…In line with previous studies, 20 out of 28 cases (71.5%) carried SHM in their immunoglobulin genes [30]. We confirmed ID in all the mutated NMZL subgroup of patients analyzed, supporting the notion that the SHM mechanism remains active post-transformation and outside the germinal centers, further diversifying the clonotypic IG receptors.…”

“…In fact, VH1-69 utilizing antibodies are also found in protective antibody responses to additional viral pathogens such as influenza infection, respiratory syncytial virus infection, and HIV-1 [32]. On the other hand, we could not confirm in this series an overrepresentation of VH4-34, as reported in previous studies [30,33].…”

Immunoglobulins or Antibodies: IMGT® Bridging Genes, Structures and Functions

“…IMGT/V-QUEST is frequently used by clinicians for the analysis of the somatic hypermutations in leukemia, lymphoma and myeloma, and more particularly in chronic lymphocytic leukemia (CLL) [ 291 , 292 , 293 ] in which the percentage of mutations in the patient VH has a prognostic value. The sequences of the V-(D)-J junctions determined by IMGT/JunctionAnalysis are also used in the characterization of stereotypic patterns in CLL and B cell lymphoproliferations [ 291 , 292 , 293 , 294 ] and for the junction synthesis of specific probes for the follow-up of residual diseases in leukemias and lymphomas.…”