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

Abstract

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...

MALT lymphoma: A paradigm of NF-κB dysregulation

“…In vitro binding analysis of the recombinant antibodies from the representative MALT lymphoma associated IGHV1-69 or IGHV3-7 rearrangements confirms their activities to the Fc portion of human IgG [42]. Moreover, strong RF activities are also demonstrated for recombinant antibodies from two MALT lymphomas that harbour classic RF IGHV1-69/IGHJ4 rearrangement, but not yet meet the criteria for a high homology to a RF CDR3 sequence, and additionally from a HCV-associated MALT lymphoma that harbours a novel IGHV4-59/IGHJ5 stereotypic rearrangement [42,63]. These findings indicate that the true frequency of MALT lymphomas that express BCR bearing RF activities is underestimated.…”

Biased IGH VDJ gene repertoire and clonal expansions in B cells of chronically hepatitis C virus–infected individuals

“…39,40,44,45 IGHV1-69 and IGHV4-59 genes are frequently expressed in HCVrelated B-cell disorders, namely MC B-cell clones producing rheumatoid factors and HCV-associated B-cell NHLs, and in other autoimmune diseases. 18,[20][21][22][23][24]46 Remarkably, these IGHV genes were more frequently used by NCS memory B cells of HCVinfected patients than those of healthy individuals (Figure 4). Thus, even in HCV patients without clinically detectable lymphoproliferation, there is a disease-associated disturbance of the BCR immunoglobulin gene repertoire, most pronounced in NCS memory B cells, with a significantly increased usage of those IGHV genes mainly involved in autoantibodies and pathological clonal B-cell expansions in HCV-infected patients.…”

Rheumatoid Factor Reactivity of Expanded CD21−/low B Cells in Patients With Sjögren's Syndrome: Comment on the Article by Glauzy et al

“…Based on these observations, we expect that the antibody from patient SS204, when expressed as IgM, will display in vitro RF activity. We and others have shown on several occasions that these stereotypic V1–69 RFs all exhibit RF activity when expressed as IgM antibodies . Thus, all clonally expanded CD21 −/low B cells from the 3 SS patients exhibit poly‐ and/or autoreactivity.…”

“…Previously, we identified 4 cases of HCV‐associated lymphomas, which were originally described by Ng et al , that also expressed stereotypic RFs, i.e., V4–59 RFs and V4–59/J H 5 RFs . From these lymphomas Ng and colleagues produced recombinant IgG antibodies, in the same system as that used by Glauzy et al , which were reported to have no in vitro RF activity.…”

“…We also produced these 4 HCV‐associated lymphoma‐derived antibodies recombinantly—but as IgM, instead of IgG, antibodies. These IgM antibodies were not polyreactive in vitro and displayed strong RF activity, with KD values ranging between 3.9 and 22.5 n M . Moreover, Charles and colleagues recombinantly produced both IgM and IgG of 3 stereotypic V1–69 RFs, which were isolated from single B cells of HCV‐infected patients with mixed cryoglobulinemia.…”