Antigen receptor stereotypy across B-cell lymphoproliferations: the case of IGHV4-59/IGKV3-20 receptors with rheumatoid factor activity

Kostareli, Efterpi; Gounari, Maria; Janus, Agnieszka; Murray, Fiona; Brochet, Xavier; Giudicelli, Véronique; Pospı́šilová, Šárka; Oscier, David; Foroni, Letizia; Celle, Paola Francia di; Tichý, Boris; Pedersen, Lone Bredo; Jurlander, Jesper; Ponzoni, Maurilio; Kouvatsi, Anastasia; Anagnostopoulos, Achilles; Thompson, Keith M.; Darzentas, Nikos; Lefranc, Marie Paule; Belessi, Chrysoula; Rosenquist, Richard; Davi, Frédéric; Ghia, Paolo; Stamatopoulos, Kostas

doi:10.1038/leu.2011.311

Cited by 61 publications

(58 citation statements)

References 15 publications

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“…2,3,8 The stereotypic V4-59-RFs of HCV lymphomas 103 and 110 were also produced as IgM antibodies, and they did indeed display strong IgG-binding capacity, as previously also shown of a V4-59-RF derived from a CLL, 5 and which is comparable to that of two control lymphoma-derived V1-69-RF IgM antibodies M11 and SG22 originating from Sjögren's syndrome patients.…”

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Identification of a novel stereotypic IGHV4-59/IGHJ5-encoded B-cell receptor subset expressed by various B-cell lymphomas with high affinity rheumatoid factor activity

et al. 2016

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Subsets of mucosa-associated lymphoid tissue (MALT) lymphoma, splenic marginal zone B-cell lymphoma (MZBCL) and chronic lymphocytic leukemia (CLL) have been identified that express near-identical B-cell receptors (BCRs), strongly suggesting selection by restricted antigenic epitopes. We here report a new IGV mutated stereotypic IGHV4-59/IGHJ5-encoded BCR subset expressed in hepatitis C virus (HCV)-related B-cell lymphoma, MALT lymphoma and diffuse large B-cell lymphoma (DLBCL). We demonstrate that these mutated stereotypic IGHV4-59/IGHJ5 BCRs are high affinity monoreactive rheumatoid factors (RFs), underscoring the significance of IgG as a major auto-antigen in the pathogenesis of several types of B-cell lymphoma.Stereotypic BCRs are encoded by highly homologous immunoglobulin variable region (IGV) heavy (H) and light chain rearrangements, having highly similar VH-CDR3. The VH-CDR3 is the most hypervariable region within IGHV, contributing most to the antigenic specificity of an IG. The antigenic binding capacity of an immunoglobulin is also determined by somatic mutations in the IGV regions. The majority of unmutated IG derived of pre-germinal center B cells are of low affinity, whereas somatically hypermutated antibodies of germinal center experienced memory B cells are most often monospecific and of high affinity. It has been shown that antibodies derived from CLL of different unmutated stereotypic BCR subsets display BCR subset-specific polyreactive binding patterns to various auto-antigens. 1In contrast, antibodies from mutated stereotypic CLL subsets have, in general, more restricted binding characteristics. We recently obtained formal proof that antibodies of different members of a mutated stereotypic BCR subset of IGHV3-7-encoded CLL all displayed high affinity binding to a sugar epitope present in fungi. 2MALT lymphomas that express mutated IGV stereotypic RF BCRs were shown to have strong monoreactive RF activity, i.e. autoreactivity with IgG-Fc. © Ferrata Storti Foundationtypic IGV-mutated RFs have been identified, encoded by two different IGHV1-69/IGHJ4 rearrangements, designated V1-69-RF and WOL-RF (also known as RFs of the Wa idiotype), and by two different IGHV3-7/IGHJ3 and IGHV4-59/IGHJ2 rearrangements, named V3-7-RF and V4-59-RF.3,4 Of note, stereotypic V4-59-RFs are identical to CLL subset #13.5 Stereotypic RF BCRs are expressed by 10%-40% of gastric-and Sjogren's syndrome-associated salivary gland-MALT lymphoma, HCV-related B-cell lymphoma, as well as more rarely by ocular adnexal MALT lymphoma, splenic MZBCL, DLBCL and CLL. 3,5-9Polyclonal stereotypic RFs are frequently found in donors immunized with mismatched red blood cells and in HCV-infected patients with type II mixed cryoglobulinemia.10-14 In addition, none of the four groups of RFBCRs have been identified to the same extent among the spectrum of B-cell lymphomas. For example, stereotypic V3-7-RFs and V4-59-RFs have both been identified in approximately 0.2% of CLL, 5,8 whereas V1-69-RFs and WOL-RFs have not been described in CLL. Mor...

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Identification of a novel stereotypic IGHV4-59/IGHJ5-encoded B-cell receptor subset expressed by various B-cell lymphomas with high affinity rheumatoid factor activity

et al. 2016

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“…Furthermore, it raised questions regarding the possible existence of common immune-mediated mechanisms of lymphomagenesis among different entities, reflected in shared Ag-binding sites. 44 To address these questions, we took advantage of our recently published, large Ig sequence datasets from MCL 31 and SMZL 33 and performed crossentity comparisons to search for commonalities between their Ag-binding sites that might allude to common immune pathways to lymphoma development. Through this approach, it became apparent that differences were fundamental regarding both VH CDR3 length and composition.…”

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confidence: 99%

Stereotyped B-cell receptors in one-third of chronic lymphocytic leukemia: a molecular classification with implications for targeted therapies

Agathangelidis

Darzentas

Hadzidimitriou

et al. 2012

Blood

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Mounting evidence indicates that grouping of chronic lymphocytic leukemia (CLL) into distinct subsets with stereotypedBCRs is functionally and prognostically relevant. However, several issues need revisiting, including the criteria for identification of BCR stereotypy and its actual frequency as well as the identification of "CLL-biased" features in BCR Ig stereotypes. To this end, we examined 7596 Ig VH (IGHV-IGHD-IGHJ) sequences from 7424 CLL patients, 3 times the size of the largest published series, with an updated version of our purpose-built clustering algorithm. We document that CLL may be subdivided into 2 distinct categories: one with stereotyped and the other with nonstereotyped BCRs, at an approximate ratio of 1:2, and provide evidence suggesting a different ontogeny for these 2 categories. We also show that subset-defining sequence patterns in CLL differ from those underlying BCR stereotypy in other B-cell malignancies. Notably, 19 major subsets contained from 20 to 213 sequences each, collectively accounting for 943 sequences or one-eighth of the cohort. Hence, this compartmentalized examination of VH sequences may pave the way toward a molecular classification of CLL with implications for targeted therapeutic interventions, applicable to a significant number of patients assigned to the same subset. (Blood. 2012;119(19):4467-4475) IntroductionThe analysis of the Ig genes in chronic lymphocytic leukemia (CLL) has contributed significantly toward deciphering the molecular pathogenesis of the disease. Studies from the 1990s provided the first indications for a possible role of Ag(s) in selecting the CLL progenitor cells, through the discovery of a biased Ig heavy variable (IGHV) gene repertoire, different from that of normal B cells, as well as distinctive Ag-binding sites among unrelated cases. [1][2][3][4][5] By the late 1990s, it emerged that the mutational status of the rearranged IGHV genes directly correlated with patient survival. In particular, patients with unmutated IGHV genes were found to follow a more aggressive clinical course and have significantly shorter survival than patients carrying mutated IGHV genes. 6,7 Yet, there were exceptions to this rule: cases using the IGHV3-21 gene, although mostly expressing mutated Ig, had a survival similar to that of unmutated cases. 8 Intriguingly, approximately half of the IGHV3-21 cases were found to display restricted and, in some instances, essentially identical variable heavy complementarity determining region 3 (VH CDR3) sequences and identical light chains, strongly suggesting recognition of a common antigenic determinant. 9 Soon thereafter, the study of Ig sequences in CLL by groups in both Europe and the United States led to the identification of several other subsets of cases carrying highly similar BCR Igs among both mutated and unmutated cases (stereotyped BCR). [10][11][12][13][14] The identification of stereotypy among unrelated and geographically distant cases was widely accepted as evidence for the Submitted November 26, 2011; accepte...

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“…2,7 V1-69-RF, V3-7-RF, RF-WOL and V4-59-RF rearrangements are also frequently expressed in HCV-associated lymphomas, splenic marginal zone lymphomas and in individual cases of ocular MZBCLs and diffuse-large B-cell lymphomas. 5,6,[8][9][10] Recently, Kostareli et al 10 reported 12 cases of B-cell chronic lymphocytic leukemia (CLL) expressing V4-59-RF and Fazi et al 11 reported two cases of V3-7-RF in monoclonal B-cell lymphocytosis.In this study, we analyzed HCDR3 amino acid sequences of 81 IGHV3-7-expressing CLL and identified 3 cases with strong homology to 25 previously reported V3-7-RFs from both healthy and malignant B-cells (Table 1, Supplementary Table 1). These 25 V3-7-RF cases include 9 with proven RF-activity in vitro.…”

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A novel chronic lymphocytic leukemia subset expressing mutated IGHV3-7-encoded rheumatoid factor B-cell receptors that are functionally proficient

et al. 2012

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Rheumatoid factors (RFs) are auto-antibodies, mostly of the IgM isotype, that specifically bind to the Fc portion of IgG. RFs are transiently produced in healthy individuals in response to infections and after immunization with mismatched red blood cells (RBCs). RFs are chronically produced in patients suffering from rheumatoid arthritis, Sjö gren's syndrome and in hepatitis C virus (HCV)-induced type-II mixed cryoglobulinemia (MC-II) (reviewed in Newkirk 1 ). Analyses of RFs in MC-II and in donors immunized with mismatched RBCs revealed four groups of stereotyped immunoglobulin (Ig) V H -D H -J H rearrangements, each with distinct heavy-chain complementary-determining region 3 (HCDR3) amino acid sequences: two with IGHV1-69/JH4 rearrangements, designated V1-69-RF and RF-WOL, and two with IGHV3-7/JH3 and IGHV4-59/JH2 rearrangements, designated V3-7-RF and V4-59-RF, respectively. [2][3][4] Remarkably, similar stereotyped RF-rearrangements are frequently expressed in malignant B-cell lymphomas. 2,5,6 Previously, we have shown that recombinantly produced V1-69-RF, V3-7-RF and RF-WOL, derived from gastric and salivary gland marginal zone B-cell lymphomas (MZBCL), bind with high-affinity to IgG in vitro. 2,7 V1-69-RF, V3-7-RF, RF-WOL and V4-59-RF rearrangements are also frequently expressed in HCV-associated lymphomas, splenic marginal zone lymphomas and in individual cases of ocular MZBCLs and diffuse-large B-cell lymphomas. 5,6,[8][9][10] Recently, Kostareli et al. 10 reported 12 cases of B-cell chronic lymphocytic leukemia (CLL) expressing V4-59-RF and Fazi et al. 11 reported two cases of V3-7-RF in monoclonal B-cell lymphocytosis.In this study, we analyzed HCDR3 amino acid sequences of 81 IGHV3-7-expressing CLL and identified 3 cases with strong homology to 25 previously reported V3-7-RFs from both healthy and malignant B-cells (Table 1, Supplementary Table 1). These 25 V3-7-RF cases include 9 with proven RF-activity in vitro. The three newly found CLL cases, CLL81, CLL311 and CLL416, utilized the IGHD3-22 gene segment and the IGHJ3 segment shared by 15/24 and 22/24 of V3-7-RFs, respectively. The CLL V3-7-RFs displayed 470% of homology with a V3-7-RF HCDR3 consensus sequence, defined by the amino acids used by the majority of V3-7-RF cases (Table 1). Of note, the V3-7-RFs also shared amino acids encoded by non-templated N-region nucleotides (Figure 1a). Two of the newly identified CLL V3-7-RF cases (CLL81 and CLL416) expressed the stereotyped IGKV3-15 Ig light chain (IgV L ) reported in 10/10 V3-7-RF cases (Table 1). In CLL311, the V3-7-RF Ig heavy chain (IgV H ) was paired with an IGKV3-20-encoded IgV L . Remarkably, similar IGKV3-20 rearrangements were found in the other groups of stereotyped RFs.The CLL V3-7-RFs were heavily mutated (94.5±1.9% average homology to the IGHV3-7 germline) and shared replacement mutations Q58P, Y66F and Q90E (Figure 1a and Supplementary Table S2). Identical somatic mutations are also frequent among

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Antigen receptor stereotypy across B-cell lymphoproliferations: the case of IGHV4-59/IGKV3-20 receptors with rheumatoid factor activity

Cited by 61 publications

References 15 publications

Identification of a novel stereotypic IGHV4-59/IGHJ5-encoded B-cell receptor subset expressed by various B-cell lymphomas with high affinity rheumatoid factor activity

Identification of a novel stereotypic IGHV4-59/IGHJ5-encoded B-cell receptor subset expressed by various B-cell lymphomas with high affinity rheumatoid factor activity

Stereotyped B-cell receptors in one-third of chronic lymphocytic leukemia: a molecular classification with implications for targeted therapies

A novel chronic lymphocytic leukemia subset expressing mutated IGHV3-7-encoded rheumatoid factor B-cell receptors that are functionally proficient

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