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Immunodeficiency and EBV-induced lymphoproliferation caused by 4-1BB deficiency.

ABSTRACT: BACKGROUND:The tumor TNF receptor family member 4-1BB (CD137) is encoded by TNFRSF9 and expressed on activated T cells. 4-1BB provides a costimulatory signal that enhances CD8+ T-cell survival, cytotoxicity, and mitochondrial activity, thereby promoting immunity against viruses and tumors. The ligand for 4-1BB is expressed on antigen-presenting cells and EBV-transformed B cells. OBJECTIVE:We investigated the genetic basis of recurrent sinopulmonary infections, persistent EBV viremia, and EBV-induced lymphoproliferation in 2 unrelated patients. METHODS:Whole-exome sequencing, immunoblotting, immunophenotyping, and in vitro assays of lymphocyte and mitochondrial function were performed. RESULTS:The 2 patients shared a homozygous G109S missense mutation in 4-1BB that abolished protein expression and ligand binding. The patients' CD8+ T cells had reduced proliferation, impaired expression of IFN-? and perforin, and diminished cytotoxicity against allogeneic and HLA-matched EBV-B cells. Mitochondrial biogenesis, membrane potential, and function were significantly reduced in the patients' activated T cells. An inhibitory antibody against 4-1BB recapitulated the patients' defective CD8+ T-cell activation and cytotoxicity against EBV-infected B cells in vitro. CONCLUSION:This novel immunodeficiency demonstrates the critical role of 4-1BB costimulation in host immunity against EBV infection.

SUBMITTER: Alosaimi MF

PROVIDER: S-EPMC6688916 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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Immunodeficiency and EBV-induced lymphoproliferation caused by 4-1BB deficiency.

Alosaimi Mohammed F MF Hoenig Manfred M Jaber Faris F Platt Craig D CD Jones Jennifer J Wallace Jacqueline J Debatin Klaus-Michael KM Schulz Ansgar A Jacobsen Eva E Möller Peter P Shamseldin Hanan E HE Abdulwahab Ferdous F Ibrahim Niema N Alardati Hosam H Almuhizi Faisal F Abosoudah Ibraheem F IF Basha Talal A TA Chou Janet J Alkuraya Fowzan S FS Geha Raif S RS

The Journal of allergy and clinical immunology 20190311 2

<h4>Background</h4>The tumor TNF receptor family member 4-1BB (CD137) is encoded by TNFRSF9 and expressed on activated T cells. 4-1BB provides a costimulatory signal that enhances CD8<sup>+</sup> T-cell survival, cytotoxicity, and mitochondrial activity, thereby promoting immunity against viruses and tumors. The ligand for 4-1BB is expressed on antigen-presenting cells and EBV-transformed B cells.<h4>Objective</h4>We investigated the genetic basis of recurrent sinopulmonary infections, persisten ...[more]

PMID: 30872117

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Project description:Serine/threonine kinase 4 (STK4) deficiency is an autosomal recessive genetic condition that leads to primary immunodeficiency (PID) typically characterized by lymphopenia, recurrent infections and Epstein Barr Virus (EBV) induced lymphoproliferation and -lymphoma. State-of-the-art treatment regimens consist of prevention or treatment of infections, immunoglobulin substitution (IVIG) and restoration of the immune system by hematopoietic stem cell transplantation. Here, we report on two patients from two consanguineous families of Turkish (patient P1) and Moroccan (patient P2) decent, with PID due to homozygous STK4 mutations. P1 harbored a previously reported frameshift (c.1103 delT, p.M368RfsX2) and P2 a novel splice donor site mutation (P2; c.525+2 T>G). Both patients presented in childhood with recurrent infections, CD4 lymphopenia and dysregulated immunoglobulin levels. Patient P1 developed a highly malignant B cell lymphoma at the age of 10 years and a second, independent Hodgkin lymphoma 5 years later. To our knowledge she is the first STK4 deficient case reported who developed lymphoma in the absence of detectable EBV or other common viruses. Lymphoma development may be due to the lacking tumor suppressive function of STK4 or the perturbed immune surveillance due to the lack of CD4+ T cells. Our data should raise physicians' awareness of [1] lymphoma proneness of STK4 deficient patients even in the absence of EBV infection and [2] possibly underlying STK4 deficiency in pediatric patients with a history of recurrent infections, CD4 lymphopenia and lymphoma and unknown genetic make-up. Patient P2 experienced recurrent otitis in childhood, but when she presented at the age of 14, she showed clinical and immunological characteristics similar to patients suffering from Autoimmune Lymphoproliferative Syndrome (ALPS): elevated DNT cell number, non-malignant lymphadenopathy and hepatosplenomegaly, hematolytic anemia, hypergammaglobulinemia. Also patient P1 presented with ALPS-like features (lymphadenopathy, elevated DNT cell number and increased Vitamin B12 levels) and both were initially clinically diagnosed as ALPS-like. Closer examination of P2, however, revealed active EBV infection and genetic testing identified a novel STK4 mutation. None of the patients harbored typically ALPS-associated mutations of the Fas receptor mediated apoptotic pathway and Fas-mediated apoptosis was not affected. The presented case reports extend the clinical spectrum of STK4 deficiency.

Dataset Information

Immunodeficiency and EBV-induced lymphoproliferation caused by 4-1BB deficiency.

Publications

Immunodeficiency and EBV-induced lymphoproliferation caused by 4-1BB deficiency.

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