CD137 deficiency causes immune dysregulation with predisposition to lymphomagenesis

Somekh, Ido; Thian, Marini; Medgyesi, Dávid; Gülez, Nesrin; Magg, Thomas; Duque, Alejandro Gallón; Stauber, Tali; Lev, Atar; Genel, Ferah; Ünal, Ekrem; Simon, Amos J.; Lee, Yu Nee; Kalinichenko, Artem; Dmytrus, Jasmin; Kraakman, Michael J; Schiby, Ginette; Rohlfs, Meino; Jacobson, Jeffrey M.; Özer, Erdener; Akçal, Ömer; Conca, Raffaele; Patıroğlu, Türkan; Karakükçü, Musa; Özcan, Alper; Shahin, Tala; Appella, Eliana; Tatematsu, Megumi; Martínez-Jaramillo, Catalina; Chinn, Iván K.; Orange, Jordan S.; Trujillo-Vargas, Claudia M.; Franco, José Luis; Hauck, Fabian; Somech, Raz; Klein, Christoph; Boztuğ, Kaan

doi:10.1182/blood.2019000644

Cited by 56 publications

(62 citation statements)

References 27 publications

(32 reference statements)

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“…Accordingly, all 4 patients analyzed by Somekh et al had increased proportions of immature B cells and decreased proportions of memory B cells and plasmablasts and abnormal immunoglobulin levels. 9 This phenotype was also observed in the two patients analyzed by Rodriguez et al, where memory B cell numbers were severely reduced. 10 Although B cell subsets were not analyzed by Alosaimi et al, low IgG and high IgM levels, and a poor antibody response to tetanus toxoid and an absent recall response to pneumococcal polysaccharide vaccine, in one of the two patients indicate a disturbance in B cell maturation.…”

supporting

confidence: 61%

“…Somekh et al also analyzed Tfh numbers and found reduced counts in 3 of the 4 patients. 9 These findings clearly document the importance of CD137 -CD137L interaction for the humoral immune response.…”

mentioning

confidence: 71%

“…27 Can the lack of CD137 on Treg be responsible for the observed phenotype of the patients? Although Somekh et al report lower Treg frequencies in the patients 9 it is unlikely that the observed EBV-associated lymphoma is due to fewer or less functional Treg.…”

mentioning

confidence: 89%

“…by transducing wild type CD137 into the patient T cells which restored activation-induced T cell proliferation. 9 Rodriguez et al identified two siblings with a homozygous mutation in CD137 that prevented CD137 protein expression. Both siblings suffered from a persistent high EBV viremia, with EBV mainly being present in T cells.…”

mentioning

confidence: 99%

“…10 Two of the four patients analyzed by Somekh et al suffered from an EBV-related B cell lymphoma, Hodgkin's lymphoma (HL) and Burkitt's lymphoma, respectively, and one patient described by Alosaimi et al presented with HL. 8,9 One patient analyzed by Rodriguez et al suffered from EBV-associated T cell lymphoproliferative disease, and finally succumbed to hemophagocytic lymphohistiocytosis (HLH). 10 Thus, a common denominator of the three studies is that mutations in CD137 facilitate EBV-associated diseases, implying that under normal conditions CD137 limits EBV in causing pathology.…”

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confidence: 99%

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Destroy, what destroys you

2019

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confidence: 61%

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confidence: 71%

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confidence: 89%

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confidence: 99%

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confidence: 99%

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Destroy, what destroys you

2019

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CD137 deficiency because of two novel biallelic TNFRSF9 mutations in a patient presenting with severe EBV‐associated lymphoproliferative disease

et al. 2023

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Objectives Increasing evidence indicates that some germline genetic mutations that impair pathways required for robust host immune surveillance against EBV infection may result in an extremely high susceptibility to EBV‐associated lymphoproliferative disease (EBV + LPD). TNFRSF9 encodes a vital costimulatory molecule that enhances CD8 + T‐cell proliferation, survival and cytolytic activity. To date, no relevant case resulting from TNFRSF9 heterozygous mutations has been identified. Methods Here, we report the first case of CD137 deficiency caused by two novel biallelic heterozygous TNFRSF9 mutations [NM_001561.5: c.208 + 1−>AT and c.452C>A (p.T151K)] in a patient presenting with severe EBV + LPD. Immunophenotyping and in vitro assays of lymphocyte function and NK cell activity were performed. Results Biallelic TNFRSF9 mutations resulted in markedly reduced or abrogated expression of CD137 on activated T, B and NK cells. CD8 + T cells from the patient had impaired activation, reduced expression/release of interferon‐γ (IFN‐γ), tumor necrosis factor‐α (TNF‐α), perforin and granzyme B, and diminished cytotoxic activity. Functional experiments identified both variations were hypomorphic mutations and played a contributing role in CD137 deficiency and the development of EBV + LPD. Conclusion Our study expands the genetic spectrum and clinical phenotype of patients with CD137 deficiency and provides additional evidence that the TNFRSF9 gene plays a critical role in host immune responses to EBV infection.

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Recombinant CD137‐Fc, its synthesis, and applications for improving the immune system functions, such as tumor immunotherapy and to reduce the inflammation due to the novel coronavirus

Ajami

Nazari

Mahmoodzadeh

et al. 2021

J of Cellular Biochemistry

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CD137 (ILA/4‐1BB), a member of tumor necrosis factor receptor superfamily, is one of the most important T cell costimulatory molecules. Interaction of this molecule with its ligand transmits a two‐way signal that activates both T lymphocyte and antigen presenting cells. The soluble form of CD137 (sCD137) reduces the activity of its membrane isoform and is associated with T lymphocyte activation‐induced cell death. Recombinant CD137‐Fc may be used to treat cancers, autoimmune disorders and viral infections. It may also be useful for management of coronavirus infection. The 1276 bp DNA sequence encoded CD137‐Fc recombinant protein was prepared and subcloned into lentiviral vector and expressed in transduced CHO‐K1 eukaryotic cells. The sodium dodecyl sulfate–polyacrylamide gel electrophoresis, Western blot analysis, and enzyme‐linked immunosorbent assay analysis results demonstrated that the expression of the 70‐kDa CD137‐Fc molecule was detectable without any degradation. This study helps to confirm previous research suggesting the use of this recombinant protein as a promising solution for the treatment of virus infections. CD137‐Fc fusion protein could also make immunotherapy more effective for some diseases. This product is widely used in novel medical treatments, including cell‐based immunotherapy such as dendritic cell, CAR T and CAR NK therapy. Its production and usage in research and treatment is noticeable also in current coronavirus disease 2019 pandemic.

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CD137 deficiency causes immune dysregulation with predisposition to lymphomagenesis

Abstract: Somekh and colleagues identify CD137, a member of the tumor necrosis factor superfamily, as a novel cause of immunodeficiency associated with a risk of autoimmunity and lymphoid malignancy.

Cited by 56 publications

References 27 publications

Destroy, what destroys you

Destroy, what destroys you

CD137 deficiency because of two novel biallelic TNFRSF9 mutations in a patient presenting with severe EBV‐associated lymphoproliferative disease

Recombinant CD137‐Fc, its synthesis, and applications for improving the immune system functions, such as tumor immunotherapy and to reduce the inflammation due to the novel coronavirus

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