Clonal immunoglobulin λ light‐chain gene rearrangements detected by next generation sequencing in POEMS syndrome

Abstract

Polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes (POEMS) syndrome is a rare plasma cell dyscrasia characterized by polyneuropathy, organomegaly, endocrinopathy, extravascular fluid overload, M protein, and a myriad of skin changes. The pathogenesis is poorly understood, but monoclonal plasma cells are λ-restricted and these immunoglobulin λ light chain variable (IGLV) region genes are derived from only two germlines, either IGLV1-44 or 1-40. Here we analyzed the clonal IGLV gene rearrangements of genomic DNA samples of bone marrow mononuclear cells using next-generation sequencing (NGS) to understand the clonal composition of IGLV genes in patients with POEMS syndrome (n = 30). The dominant IGLV gene rearrangement of POEMS syndrome-specific germline sequences were significantly increased in 11 POEMS patients (36.7%; IGLV1-44: n = 9, IGLV1-40: n = 2). In some cases, IGLV gene rearrangement clone was not detected as significant increase but was detected using cDNA samples by heteroduplex (HD) analysis and Sanger sequencing, suggesting that the quite small number of monoclonal plasma cells may produce large quantity of mRNA of monoclonal proteins. However, significant increase of dominant clone sizes was not directly linked to the initial disease status. On the other hand, in cases with significantly increased dominant clones, they decreased and increased accompanying with disease remission and relapse. These data demonstrate that monoclonal plasma cells are related to the pathogenesis of POEMS syndrome.

Light chain skewing in autoantibodies and B-cell receptors of the citrullinated antigen-binding B-cell response in rheumatoid arthritis

“…Notably, the high frequency of IGKV4-1 in ACPA-Igκ clones observed by us is supported by the high prevalence of IGKV4-1 in sequences derived from citrullinated fillagrin (CFC1)/α-enolase (CEP-1)-binding B cells described by Titcombe et al [46]. In the Igλ repertoire we observed a higher frequency of IGLV1-47 in both single cell-and pool-sorted ACPA-Igλ datasets (16% and 31%, respectively), compared to IGLV1-47 expression reported for B cells derived from human cord blood (6%) and normal controls (~10%) [49,50]. Despite these enhanced frequencies for certain V-genes, our findings do not show a highly restricted LC repertoire as observed in mice studies on certain antigen-specific B-cell responses (e.g.…”

Multiparameter Flow Cytometry for the Identification of Neoplastic Plasma Cells in POEMS Syndrome with IgG-kappa Gammopathy: Successful Treatment Using Lenalidomide and Dexamethasone

“…Almost all patients with POEMS syndrome have the lambda-type monoclonal protein (19-21). This is because monoclonal proteins have a specific V lambda subfamily gene that can cause high cytokinemia involving cytokines, such as VEGF via some signals (22). However, the mechanism has not been fully elucidated.…”

Peripheral B cells from patients with hepatitis C virus-associated lymphoma exhibit clonal expansion and an anergic-like transcriptional profile

“…B cell clonal expansion utilizing these V genes has been observed in a number of lymphoproliferative disorders, including HCV-associated conditions, multiple B cell lymphoma histologies, as well as autoimmune diseases, and is often associated with autoreactivity, including RF activity. 24 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 Among BNHL, HCV, and HD diagnosis groups, we observed striking consistency of predicted Ig V gene usage for the 6 genes enriched in our BNHL/HCV samples ( Figure 2 G), demonstrating that expanded gene usage is a unique feature of BNHL/HCV peripheral B cells. Overall, we observed anergic-like properties in peripheral B cells from patients with BNHL/HCV, including gene expression changes and evidence of clonal expansion of Ig genes associated with autoimmunity, lymphoproliferation, and autoreactivity.…”