Complementarity determining region-independent recognition of a superantigen by B-cell antigen receptors of mantle cell lymphoma

Fichtner, Michael; Spies, Elmar; Seismann, Henning; Riecken, Kristoffer; Engels, Niklas; Gösch, Barbara; Dierlamm, Judith; Gerull, Helwe; Nollau, Peter; Klapper, Wolfram; Dreyling, Martin; Binder, Mascha; Trepel, Martin

doi:10.3324/haematol.2016.141929

Cited by 11 publications

(11 citation statements)

References 18 publications

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“…Similar to findings from studies in small lymphocytic lymphoma/chronic lymphocytic leukemia (SLL/CLL), antigenic drive is hypothesized to have a role in the development of MCL. This is because of the finding of a biased and highly restricted immunoglobulin (IGHV) gene repertoire with stereotyped variable heavy chain (VH) complementary determining region (CDR3s) and recognition of superantigens by the B‐cell receptor (BCR) of MCL cells. The role of micro‐RNA and epigenetic factors in MCL etiology is also being explored.…”

Section: Introductionmentioning

confidence: 99%

Mantle cell lymphoma: 2019 update on the diagnosis, pathogenesis, prognostication, and management

2019

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Unprecedented advances in our understanding of the pathobiology, prognostication, and therapeutic options in mantle cell lymphoma (MCL) have taken place in the last few years. Heterogeneity in the clinical course of MCL—indolent vs aggressive—is further delineated by a correlation with the mutational status of the variable region of immunoglobulin heavy chain, methylation status, and SOX‐11 expression. Cyclin‐D1 negative MCL, in situ MCL neoplasia, and impact of the karyotype on prognosis are distinguished. Apart from Ki‐67% and morphology pattern (classic vs blastoid/pleomorphic), the proliferation gene signature has helped to further refine prognostication. Studies focusing on mutational dynamics and clonal evolution on Bruton's tyrosine kinase (BTK) inhibitors (ibrutinib, acalabrutinib) and/or Bcl2 antagonists (venetoclax) have further clarified the prognostic impact of somatic mutations in TP53, BIRC3, CDKN2A, MAP3K14, NOTCH2, NSD2, and SMARCA4 genes. In therapy, long‐term follow‐up on chemo‐immunotherapy studies has demonstrated durable remissions in some patients; however, long‐term toxicities, especially from second cancers, are a serious concern with chemotherapy. The therapeutic options in MCL are constantly evolving, with dramatic responses from nonchemotherapeutic agents (ibrutinib, acalabrutinib, and venetoclax). Chimeric antigen receptor therapy and combinations of nonchemotherapeutic agents are actively being studied and our focus is shifting toward making the treatment of MCL chemotherapy‐free. Still, MCL remains incurable. The following aspects of MCL continue to pose a challenge: disease transformation, role of the cytokine‐microenvironmental milieu, incorporation of positron emission tomography‐computerized tomography imaging, minimal residual disease in the prognosis, circulating tumor DNA testing for clonal evolution, predicting resistance to BTK inhibitors, and optimal management of patients who progress on BTK/Bcl2 inhibitors. Next‐generation clinical trials should incorporate nonchemotherapeutic agents and personalize the treatment based upon the genomic profile of individual patient. Recent advances in the field of MCL are reviewed.

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Section: Introductionmentioning

confidence: 99%

Mantle cell lymphoma: 2019 update on the diagnosis, pathogenesis, prognostication, and management

2019

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“…12 B-cell antigen capturing capability is partially preserved in B cell lymphomas. [13][14][15][16][17] To evaluate if this feature is also altered in EBV+ DLBCL, we analyzed the level of BCR signaling activity via IHC staining for pBTK.…”

Section: Antigen Capture Elements Were Deficient In Ebv+ Dlbclmentioning

confidence: 99%

Epstein–Barr virus-positive diffuse large B-cell lymphoma features disrupted antigen capture/presentation and hijacked T-cell suppression

Jiang

Yan

et al. 2019

OncoImmunology

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2020) Epstein-Barr virus-positive diffuse large B-cell lymphoma features disrupted antigen capture/presentation and hijacked T-cell suppression, ABSTRACT Background: B cells can function as antigen-presenting cells by presenting antigens captured by the B-cell receptor (BCR) on Class II Major Histocompatibility Complex (MHC II) to T cells. In addition, B-cells can also maintain immune homeostasis by expressing PD-L1 and suppressing T-cell activity. Epstein-Barr virus (EBV) infection can disrupt B-cell function and lead to B cell malignancies, including diffuse large B-cell lymphoma (DLBCL).Here we show that EBV-positive DLBCL (EBV+ DLBCL) has decreased expression of BCR and MHC II, but over-expressed PD-L1, which may lead to immune evasion. Methods: An EBV+ DLBCL cohort (n = 30) and an EBV-DLBCL control cohort (n = 83) were established. Immunostaining of PD-L1, MHC II, MHC II Transactivator (CIITA) and pBTK was performed on automated stainer. H-score was used to denote the results of staining of PD-L1 and pBTK. Break apart and deletion of CIITA locus was studied by fluorescent in situ hybridization. Surface immunoglobulin mean fluorescent insensitivity (MFI) was detected by flow cytometry to demonstrate the level BCR. Results: EBV+ DLBCL showed significantly lower expression of CIITA and MHC II compared to EBV-DLBCL. Genetic aberrations involving CIITA were also more common in EBV+ DLBCL, with 23% break apart events and 6% deletion events, comparted to 2% break apart and 0% deletion in EBV-DLBCL. In addition to the loss of antigen presentation molecule, the antigen capture receptor, BCR, was also downregulated in EBV+ DLBCL. Accordingly, BCR signaling was also significantly decreased in EBV+ DLBCL as denoted by the respective pBTK levels. Conclusions: EBV+ DLBCL shows over expression of the T-cell inhibitory ligand, PD-L1. Antigen capture and presentation system were disrupted, and T-cell inhibitory molecule was hijacked in EBV+ DLBCL, which may contribute to immune escape in this high risk disease. Therapies targeting these aberrations may improve the outcome of patients with EBV+ DLBCL. ARTICLE HISTORY

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“…Hadzidimitriou and colleagues proposed a more detailed differentiation. They showed that 29.5% of all MCL-derived Ig heavy chains are completely unmutated (which has not been described to this extent in any other lymphoma) and only 13.8% showed more than 3% deviation from the germline sequence [ 46 , 76 ]. The difference in the mutational load of the BCR has led to the assumption that MCL develops from two different pathways.…”

Section: Functional Involvement Of the B Cell Receptor In Mantle Cellmentioning

confidence: 99%

“…As an alternative to classical antigens which are bound by the antigen-binding site of the BCR, recent research proposed an involvement of superantigens in MCL development [ 76 ]. Superantigens were first described for T cell receptors and represent proteins which bind to the framework regions (FR) of TCRs and BCRs, instead of being bound by the complementarity determining regions (CDRs) [ 81 , 82 ].…”

Section: Superantigenic B Cell Receptor Interaction As a Potential Pamentioning

confidence: 99%

“…Importantly, the IGHV3-gene family is the most abundant IGHV-family and about half of all MCL- and CLL-cells express an IGHV3-gene. Nearly every MCL-BCR expressing an IGHV3 immunoglobulin also presents the SpA motif, and it was shown that these BCRs can be activated by SpA [ 76 ]. In healthy and matured B cells, the SpA motif is often mutated and the BCR cannot be activated by SpA anymore.…”

Section: Superantigenic B Cell Receptor Interaction As a Potential Pamentioning

confidence: 99%

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The role of B cell antigen receptors in mantle cell lymphoma

et al. 2017

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Mantle cell lymphoma (MCL) is characterized by an aggressive clinical course and secondary resistance to currently available therapies in most cases. Therefore, despite recent advances in the treatment of this disease, it is still considered to be incurable in the majority of cases. MCL B cells retain their B cell antigen receptor (BCR) expression during and after neoplastic transformation. BCRs in MCL show distinct patterns of antigen selection and ongoing BCR signaling. However, little is known about the involved antigens and the mechanisms leading to lymphomagenesis and lymphoma progression in MCL. Recent preclinical and clinical studies have established a crucial role of the BCR and the potential of inhibiting its signaling in this disease. This has established the B cell antigen receptor signaling cascade as a very promising therapeutic target to improve outcome in MCL alone or in combination with chemo-immunotherapy in recent years.

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Complementarity determining region-independent recognition of a superantigen by B-cell antigen receptors of mantle cell lymphoma

Cited by 11 publications

References 18 publications

Mantle cell lymphoma: 2019 update on the diagnosis, pathogenesis, prognostication, and management

Mantle cell lymphoma: 2019 update on the diagnosis, pathogenesis, prognostication, and management

Epstein–Barr virus-positive diffuse large B-cell lymphoma features disrupted antigen capture/presentation and hijacked T-cell suppression

The role of B cell antigen receptors in mantle cell lymphoma

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