A mutated B cell chronic lymphocytic leukemia subset that recognizes and responds to fungi

Hoogeboom, Robbert; Kessel, Kok P. M. van; Hochstenbach, Frans; Wormhoudt, Thera A. M.; Reinten, Roy J.; Wagner, Kay Uwe; Kater, Arnon P.; Guikema, Jeroen E. J.; Bende, Richard J.; Noesel, Carel J. M. van

doi:10.1084/jem.20121801

Cited by 138 publications

(108 citation statements)

References 51 publications

(78 reference statements)

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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.…”

supporting

confidence: 72%

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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supporting

confidence: 72%

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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“…It was recently shown that a newly identified subset of CLL with mutated IgVH heavy chain, expresses stereotypic BCRs highly specific for β-(1,6)-glucan, a major antigenic determinant of yeast and molds. 60 The clonal B-cells of these patients were shown to proliferate in response to β-(1,6)-glucan, suggesting that the fungal microbiota can deliver functional ligands in the process of CLL.…”

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confidence: 93%

'Trained immunity: consequences for lymphoid malignancies

et al. 2016

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© Ferrata Storti Foundationhave no adaptive immune response, e.g., plants and invertebrates, but it also exists in humans, where it might be of special benefit in neonates that have yet to develop a mature adaptive immune repertoire.6 Importantly, 'training' of the innate immune system by the use of vaccination, resulting in increased immune activation, has been shown feasible. Hopefully these insights can be exploited in the near future for the design of new treatments for immunodeficiencies, infections and cancer.

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“…Furthermore, use of certain V genes (e.g., V1-69, V3-21) or even more specific restricted combinations of V(D)J and light chains are independent poor prognostic factors (16,17), with specific types having distinct gene expression patterns (18). It is postulated that this stereotypy results in surface BCR with specific affinity for immunogen capable of tonically stimulating the BCR, thereby promoting cancer cell survival 19,20). Additionally, there is evidence that certain stereotyped BCRs may be constitutively activated by self-self interaction (21).…”

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confidence: 99%

Immunoglobulin transcript sequence and somatic hypermutation computation from unselected RNA-seq reads in chronic lymphocytic leukemia

Blachly

Ruppert

Zhao

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Immunoglobulins (Ig) are produced by B lymphocytes as secreted antibodies or as part of the B-cell receptor. There is tremendous diversity of potential Ig transcripts (>1 × 10 12 ) as a result of hundreds of germ-line gene segments, random nucleotide incorporation during joining of gene segments into a complete transcript, and the process of somatic hypermutation at individual nucleotides. This recombination and mutation process takes place in the maturing B cell and is responsible for the diversity of potential epitope recognition. Cancers arising from mature B cells are characterized by clonal production of Ig heavy (IGH@) and light chain transcripts, although whether the sequence has undergone somatic hypermutation is dependent on the maturation stage at which the neoplastic clone arose. Chronic lymphocytic leukemia (CLL) is the most common leukemia in adults and arises from a mature B cell with either mutated or unmutated IGH@ transcripts, the latter having worse prognosis and the assessment of which is routinely performed in the clinic. Currently, IGHV mutation status is assessed by Sanger sequencing and comparing the transcript to known germ-line genes. In this paper, we demonstrate that complete IGH@ V-D-J sequences can be computed from unselected RNA-seq reads with results equal or superior to the clinical procedure: in the only discordant case, the clinical transcript was outof-frame. Therefore, a single RNA-seq assay can simultaneously yield gene expression profile, SNP and mutation information, as well as IGHV mutation status, and may one day be performed as a general test to capture multidimensional clinically relevant data in CLL.RNA sequencing | immunoglobulin | somatic hypermutation | B cells | CLL I mmunoglobulins (Igs) are proteins produced by mature B-lymphocytes that recognize foreign antigens, both as soluble antibody molecules and as part of the B-cell receptor. The generation of Ig diversity through gene recombination and hypermutation of the heavy chain (H) variable region (V) is essential to adaptive immunity. The extent of this process is strongly associated with both pathology and prognosis in chronic lymphocytic leukemia (CLL), wherein CLL that expresses an unmutated IGHV tends to be more aggressive than CLL using unmutated IGHV (1, 2). The accurate assessment of this IGHV mutation status is thus of a high clinical priority. As each patient's leukemia generally expresses only a single IGH@, the mutation status of IGHV is determined by amplifying the expressed transcript via RT-PCR, sequencing the gene via the Sanger technique, and then comparing this sequence with known inherited IGHV sequences. However, there are limitations to such methods, including variation in technique across institutions. RNA-sequencing is a powerful technology that can simultaneously yield information about gene and isoform expression as well as underlying DNA sequence (3, 4). Motivated by the notion that a single RNA sequencing experiment could replace many other discrete tests (qPCR, genotyping, microarray, I...

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A mutated B cell chronic lymphocytic leukemia subset that recognizes and responds to fungi

Abstract: A subset of chronic lymphocytic leukemia with mutated IGHV-genes express BCRs specific for an antigenic determinant of yeast and filamentous fungi, β-(1,6)-glucan.

Cited by 138 publications

References 51 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

'Trained immunity: consequences for lymphoid malignancies

Immunoglobulin transcript sequence and somatic hypermutation computation from unselected RNA-seq reads in chronic lymphocytic leukemia

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