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Phenotype, penetrance, and treatment of 133 cytotoxic T-lymphocyte antigen 4-insufficient subjects.

ABSTRACT: BACKGROUND:Cytotoxic T-lymphocyte antigen 4 (CTLA-4) is a negative immune regulator. Heterozygous CTLA4 germline mutations can cause a complex immune dysregulation syndrome in human subjects. OBJECTIVE:We sought to characterize the penetrance, clinical features, and best treatment options in 133 CTLA4 mutation carriers. METHODS:Genetics, clinical features, laboratory values, and outcomes of treatment options were assessed in a worldwide cohort of CTLA4 mutation carriers. RESULTS:We identified 133 subjects from 54 unrelated families carrying 45 different heterozygous CTLA4 mutations, including 28 previously undescribed mutations. Ninety mutation carriers were considered affected, suggesting a clinical penetrance of at least 67%; median age of onset was 11 years, and the mortality rate within affected mutation carriers was 16% (n = 15). Main clinical manifestations included hypogammaglobulinemia (84%), lymphoproliferation (73%), autoimmune cytopenia (62%), and respiratory (68%), gastrointestinal (59%), or neurological features (29%). Eight affected mutation carriers had lymphoma, and 3 had gastric cancer. An EBV association was found in 6 patients with malignancies. CTLA4 mutations were associated with lymphopenia and decreased T-, B-, and natural killer (NK) cell counts. Successful targeted therapies included application of CTLA-4 fusion proteins, mechanistic target of rapamycin inhibitors, and hematopoietic stem cell transplantation. EBV reactivation occurred in 2 affected mutation carriers after immunosuppression. CONCLUSIONS:Affected mutation carriers with CTLA-4 insufficiency can present in any medical specialty. Family members should be counseled because disease manifestation can occur as late as 50 years of age. EBV- and cytomegalovirus-associated complications must be closely monitored. Treatment interventions should be coordinated in clinical trials.

SUBMITTER: Schwab C

PROVIDER: S-EPMC6215742 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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Phenotype, penetrance, and treatment of 133 cytotoxic T-lymphocyte antigen 4-insufficient subjects.

Schwab Charlotte C Gabrysch Annemarie A Olbrich Peter P Patiño Virginia V Warnatz Klaus K Wolff Daniel D Hoshino Akihiro A Kobayashi Masao M Imai Kohsuke K Takagi Masatoshi M Dybedal Ingunn I Haddock Jamanda A JA Sansom David M DM Lucena Jose M JM Seidl Maximilian M Schmitt-Graeff Annette A Reiser Veronika V Emmerich Florian F Frede Natalie N Bulashevska Alla A Salzer Ulrich U Schubert Desirée D Hayakawa Seiichi S Okada Satoshi S Kanariou Maria M Kucuk Zeynep Yesim ZY Chapdelaine Hugo H Petruzelkova Lenka L Sumnik Zdenek Z Sediva Anna A Slatter Mary M Arkwright Peter D PD Cant Andrew A Lorenz Hanns-Martin HM Giese Thomas T Lougaris Vassilios V Plebani Alessandro A Price Christina C Sullivan Kathleen E KE Moutschen Michel M Litzman Jiri J Freiberger Tomas T van de Veerdonk Frank L FL Recher Mike M Albert Michael H MH Hauck Fabian F Seneviratne Suranjith S Pachlopnik Schmid Jana J Kolios Antonios A Unglik Gary G Klemann Christian C Speckmann Carsten C Ehl Stephan S Leichtner Alan A Blumberg Richard R Franke Andre A Snapper Scott S Zeissig Sebastian S Cunningham-Rundles Charlotte C Giulino-Roth Lisa L Elemento Olivier O Dückers Gregor G Niehues Tim T Fronkova Eva E Kanderová Veronika V Platt Craig D CD Chou Janet J Chatila Talal A TA Geha Raif R McDermott Elizabeth E Bunn Su S Kurzai Monika M Schulz Ansgar A Alsina Laia L Casals Ferran F Deyà-Martinez Angela A Hambleton Sophie S Kanegane Hirokazu H Taskén Kjetil K Neth Olaf O Grimbacher Bodo B

The Journal of allergy and clinical immunology 20180504 6

<h4>Background</h4>Cytotoxic T-lymphocyte antigen 4 (CTLA-4) is a negative immune regulator. Heterozygous CTLA4 germline mutations can cause a complex immune dysregulation syndrome in human subjects.<h4>Objective</h4>We sought to characterize the penetrance, clinical features, and best treatment options in 133 CTLA4 mutation carriers.<h4>Methods</h4>Genetics, clinical features, laboratory values, and outcomes of treatment options were assessed in a worldwide cohort of CTLA4 mutation carriers.<h4 ...[more]

PMID: 29729943

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Project description:Myalgic encephalomyelitis or chronic fatigue syndrome (ME/CFS) is a debilitating disorder linked to diverse intracellular infections as well as physiological stress. Cytotoxic lymphocytes combat intracellular infections. Their function is attenuated by stress. Despite numerous studies, the role of cytotoxic lymphocytes in ME/CFS remains unclear. Prompted by advances in the understanding of defects in lymphocyte cytotoxicity, the discovery of adaptive natural killer (NK) cell subsets associated with certain viral infections, and compelling links between stress, adrenaline, and cytotoxic lymphocyte function, we reassessed the role of cytotoxic lymphocytes in ME/CFS. Forty-eight patients from two independent cohorts fulfilling the Canada 2003 criteria for ME/CFS were evaluated with respect to cytotoxic lymphocyte phenotype and function. Results were compared to values from matched healthy controls. Reproducible differences between patients and controls were not found in cytotoxic lymphocyte numbers, cytotoxic granule content, activation status, exocytotic capacity, target cell killing, or cytokine production. One patient expressed low levels of perforin, explained by homozygosity for the PRF1 p.A91V variant. However, overall, this variant was present in a heterozygous state at the expected population frequency among ME/CFS patients. No single patient displayed any pathological patterns of cellular responses. Increased expansions of adaptive NK cells or deviant cytotoxic lymphocyte adrenaline-mediated inhibition were not observed. In addition, supervised dimensionality reduction analyses of the full, multidimensional datasets did not reveal any reproducible patient/control discriminators. In summary, employing sensitive assays and analyses for quantification of cytotoxic lymphocyte differentiation and function, cytotoxicity lymphocyte aberrances were not found among ME/CFS patients. These assessments of cytotoxic lymphocytes therefore do not provide useful biomarkers for the diagnosis of ME/CFS.

Dataset Information

Phenotype, penetrance, and treatment of 133 cytotoxic T-lymphocyte antigen 4-insufficient subjects.

Publications

Phenotype, penetrance, and treatment of 133 cytotoxic T-lymphocyte antigen 4-insufficient subjects.

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