Phenotype, penetrance, and treatment of 133 cytotoxic T-lymphocyte antigen 4-insufficient subjects
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SCHWAB, Charlotte; Annemarie GABRYSCH; Peter OLBRICH; Virginia PATINO; Klaus WARNATZ; Daniel WOLFF; Akihiro HOSHINO; Masao KOBAYASHI; Kohsuke IMAI; Masatoshi TAKAGI; Ingunn DYBEDAL; Jamanda A. HADDOCK; David M. SANSOM; Jose M. LUCENA; Maximilian SEIDL; Annette SCHMITT-GRAEFF; Veronika REISER; Florian EMMERICH; Natalie FREDE; Alla BULASHEVSKA; Ulrich SALZER; Desiree SCHUBERT; Seiichi HAYAKAWA; Satoshi OKADA; Maria KANARIOU; Zeynep Yesim KUCUK; Hugo CHAPDELAINE; Lenka PETRUZELKOVA; Zdenek SUMNIK; Anna SEDIVA; Mary SLATTER; Peter D. ARKWRIGHT; Andrew CANT; Hanns-Martin LORENZ; Thomas GIESE; Vassilios LOUGARIS; Alessandro PLEBANI; Christina PRICE; Kathleen E. SULLIVAN; Michel MOUTSCHEN; Jiří LITZMAN; Tomáš FREIBERGER ORCID; Frank L. VAN DE VEERDONK; Mike RECHER; Michael H. ALBERT; Fabian HAUCK; Suranjith SENEVIRATNE; Jana Pachlopnik SCHMID; Antonios KOLIOS; Gary UNGLIK; Christian KLEMANN; Carsten SPECKMANN; Stephan EHL; Alan LEICHTNER; Richard BLUMBERG; Andre FRANKE; Scott SNAPPER; Sebastian ZEISSIG; Charlotte CUNNINGHAM-RUNDLES; Lisa GIULINO-ROTH; Oliver ELEMENTO; Gregor DUCKERS; Tim NIEHUES; Eva FRONKOVA; Veronika KANDEROVA; Craig D. PLATT; Janet CHOU; Talal A. CHATILA; Raif GEHA; Elizabeth MCDERMOTT; Su BUNN; Monika KURZAI; Ansgar SCHULZ; Laia ALSINA; Ferran CASALS; Angela DEYA-MARTINEZ; Sophie HAMBLETON; Hirokazu KANEGANE; Kjetil TASKEN; Olaf NETH a Bodo GRIMBACHER
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Journal of allergy and clinical immunology, New York, Mosby-Elsevier, 2018, 0091-6749
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 affectedmutation 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.
SCHWAB, Charlotte; Annemarie GABRYSCH; Peter OLBRICH; Virginia PATINO; Klaus WARNATZ; Daniel WOLFF; Akihiro HOSHINO; Masao KOBAYASHI; Kohsuke IMAI; Masatoshi TAKAGI; Ingunn DYBEDAL; Jamanda A. HADDOCK; David M. SANSOM; Jose M. LUCENA; Maximilian SEIDL; Annette SCHMITT-GRAEFF; Veronika REISER; Florian EMMERICH; Natalie FREDE; Alla BULASHEVSKA; Ulrich SALZER; Desiree SCHUBERT; Seiichi HAYAKAWA; Satoshi OKADA; Maria KANARIOU; Zeynep Yesim KUCUK; Hugo CHAPDELAINE; Lenka PETRUZELKOVA; Zdenek SUMNIK; Anna SEDIVA; Mary SLATTER; Peter D. ARKWRIGHT; Andrew CANT; Hanns-Martin LORENZ; Thomas GIESE; Vassilios LOUGARIS; Alessandro PLEBANI; Christina PRICE; Kathleen E. SULLIVAN; Michel MOUTSCHEN; Jiří LITZMAN; Tomáš FREIBERGER; Frank L. VAN DE VEERDONK; Mike RECHER; Michael H. ALBERT; Fabian HAUCK; Suranjith SENEVIRATNE; Jana Pachlopnik SCHMID; Antonios KOLIOS; Gary UNGLIK; Christian KLEMANN; Carsten SPECKMANN; Stephan EHL; Alan LEICHTNER; Richard BLUMBERG; Andre FRANKE; Scott SNAPPER; Sebastian ZEISSIG; Charlotte CUNNINGHAM-RUNDLES; Lisa GIULINO-ROTH; Oliver ELEMENTO; Gregor DUCKERS; Tim NIEHUES; Eva FRONKOVA; Veronika KANDEROVA; Craig D. PLATT; Janet CHOU; Talal A. CHATILA; Raif GEHA; Elizabeth MCDERMOTT; Su BUNN; Monika KURZAI; Ansgar SCHULZ; Laia ALSINA; Ferran CASALS; Angela DEYA-MARTINEZ; Sophie HAMBLETON; Hirokazu KANEGANE; Kjetil TASKEN; Olaf NETH a Bodo GRIMBACHER. Phenotype, penetrance, and treatment of 133 cytotoxic T-lymphocyte antigen 4-insufficient subjects. Journal of allergy and clinical immunology. New York: Mosby-Elsevier, 2018, roč. 142, č. 6, s. 1932-1946. ISSN 0091-6749. Dostupné z: https://doi.org/10.1016/j.jaci.2018.02.055.
@article{1482539, author = {Schwab, Charlotte and Gabrysch, Annemarie and Olbrich, Peter and Patino, Virginia and Warnatz, Klaus and Wolff, Daniel and Hoshino, Akihiro and Kobayashi, Masao and Imai, Kohsuke and Takagi, Masatoshi and Dybedal, Ingunn and Haddock, Jamanda A. and Sansom, David M. and Lucena, Jose M. and Seidl, Maximilian and SchmittandGraeff, Annette and Reiser, Veronika and Emmerich, Florian and Frede, Natalie and Bulashevska, Alla and Salzer, Ulrich and Schubert, Desiree and Hayakawa, Seiichi and Okada, Satoshi and Kanariou, Maria and Kucuk, Zeynep Yesim and Chapdelaine, Hugo and Petruzelkova, Lenka and Sumnik, Zdenek and Sediva, Anna and Slatter, Mary and Arkwright, Peter D. and Cant, Andrew and Lorenz, HannsandMartin and Giese, Thomas and Lougaris, Vassilios and Plebani, Alessandro and Price, Christina and Sullivan, Kathleen E. and Moutschen, Michel and Litzman, Jiří and Freiberger, Tomáš and van de Veerdonk, Frank L. and Recher, Mike and Albert, Michael H. and Hauck, Fabian and Seneviratne, Suranjith and Schmid, Jana Pachlopnik and Kolios, Antonios and Unglik, Gary and Klemann, Christian and Speckmann, Carsten and Ehl, Stephan and Leichtner, Alan and Blumberg, Richard and Franke, Andre and Snapper, Scott and Zeissig, Sebastian and CunninghamandRundles, Charlotte and GiulinoandRoth, Lisa and Elemento, Oliver and Duckers, Gregor and Niehues, Tim and Fronkova, Eva and Kanderova, Veronika and Platt, Craig D. and Chou, Janet and Chatila, Talal A. and Geha, Raif and McDermott, Elizabeth and Bunn, Su and Kurzai, Monika and Schulz, Ansgar and Alsina, Laia and Casals, Ferran and DeyaandMartinez, Angela and Hambleton, Sophie and Kanegane, Hirokazu and Tasken, Kjetil and Neth, Olaf and Grimbacher, Bodo}, article_location = {New York}, article_number = {6}, doi = {https://doi.org/10.1016/j.jaci.2018.02.055}, keywords = {Cytotoxic T-lymphocyte antigen 4; primary immunodeficiency; autoimmunity; hypogammaglobulinemia; hematopoietic stem cell transplantation; abatacept; sirolimus; immune dysregulation; common variable immunodeficiency}, language = {eng}, issn = {0091-6749}, journal = {Journal of allergy and clinical immunology}, title = {Phenotype, penetrance, and treatment of 133 cytotoxic T-lymphocyte antigen 4-insufficient subjects}, volume = {142}, year = {2018} }
TY - JOUR ID - 1482539 AU - Schwab, Charlotte - Gabrysch, Annemarie - Olbrich, Peter - Patino, Virginia - Warnatz, Klaus - Wolff, Daniel - Hoshino, Akihiro - Kobayashi, Masao - Imai, Kohsuke - Takagi, Masatoshi - Dybedal, Ingunn - Haddock, Jamanda A. - Sansom, David M. - Lucena, Jose M. - Seidl, Maximilian - Schmitt-Graeff, Annette - Reiser, Veronika - Emmerich, Florian - Frede, Natalie - Bulashevska, Alla - Salzer, Ulrich - Schubert, Desiree - Hayakawa, Seiichi - Okada, Satoshi - Kanariou, Maria - Kucuk, Zeynep Yesim - Chapdelaine, Hugo - Petruzelkova, Lenka - Sumnik, Zdenek - Sediva, Anna - Slatter, Mary - Arkwright, Peter D. - Cant, Andrew - Lorenz, Hanns-Martin - Giese, Thomas - Lougaris, Vassilios - Plebani, Alessandro - Price, Christina - Sullivan, Kathleen E. - Moutschen, Michel - Litzman, Jiří - Freiberger, Tomáš - van de Veerdonk, Frank L. - Recher, Mike - Albert, Michael H. - Hauck, Fabian - Seneviratne, Suranjith - Schmid, Jana Pachlopnik - Kolios, Antonios - Unglik, Gary - Klemann, Christian - Speckmann, Carsten - Ehl, Stephan - Leichtner, Alan - Blumberg, Richard - Franke, Andre - Snapper, Scott - Zeissig, Sebastian - Cunningham-Rundles, Charlotte - Giulino-Roth, Lisa - Elemento, Oliver - Duckers, Gregor - Niehues, Tim - Fronkova, Eva - Kanderova, Veronika - Platt, Craig D. - Chou, Janet - Chatila, Talal A. - Geha, Raif - McDermott, Elizabeth - Bunn, Su - Kurzai, Monika - Schulz, Ansgar - Alsina, Laia - Casals, Ferran - Deya-Martinez, Angela - Hambleton, Sophie - Kanegane, Hirokazu - Tasken, Kjetil - Neth, Olaf - Grimbacher, Bodo PY - 2018 TI - Phenotype, penetrance, and treatment of 133 cytotoxic T-lymphocyte antigen 4-insufficient subjects JF - Journal of allergy and clinical immunology VL - 142 IS - 6 SP - 1932-1946 EP - 1932-1946 PB - Mosby-Elsevier SN - 00916749 KW - Cytotoxic T-lymphocyte antigen 4 KW - primary immunodeficiency KW - autoimmunity KW - hypogammaglobulinemia KW - hematopoietic stem cell transplantation KW - abatacept KW - sirolimus KW - immune dysregulation KW - common variable immunodeficiency N2 - 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 affectedmutation 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. ER -
SCHWAB, Charlotte; Annemarie GABRYSCH; Peter OLBRICH; Virginia PATINO; Klaus WARNATZ; Daniel WOLFF; Akihiro HOSHINO; Masao KOBAYASHI; Kohsuke IMAI; Masatoshi TAKAGI; Ingunn DYBEDAL; Jamanda A. HADDOCK; David M. SANSOM; Jose M. LUCENA; Maximilian SEIDL; Annette SCHMITT-GRAEFF; Veronika REISER; Florian EMMERICH; Natalie FREDE; Alla BULASHEVSKA; Ulrich SALZER; Desiree SCHUBERT; Seiichi HAYAKAWA; Satoshi OKADA; Maria KANARIOU; Zeynep Yesim KUCUK; Hugo CHAPDELAINE; Lenka PETRUZELKOVA; Zdenek SUMNIK; Anna SEDIVA; Mary SLATTER; Peter D. ARKWRIGHT; Andrew CANT; Hanns-Martin LORENZ; Thomas GIESE; Vassilios LOUGARIS; Alessandro PLEBANI; Christina PRICE; Kathleen E. SULLIVAN; Michel MOUTSCHEN; Jiří LITZMAN; Tomáš FREIBERGER; Frank L. VAN DE VEERDONK; Mike RECHER; Michael H. ALBERT; Fabian HAUCK; Suranjith SENEVIRATNE; Jana Pachlopnik SCHMID; Antonios KOLIOS; Gary UNGLIK; Christian KLEMANN; Carsten SPECKMANN; Stephan EHL; Alan LEICHTNER; Richard BLUMBERG; Andre FRANKE; Scott SNAPPER; Sebastian ZEISSIG; Charlotte CUNNINGHAM-RUNDLES; Lisa GIULINO-ROTH; Oliver ELEMENTO; Gregor DUCKERS; Tim NIEHUES; Eva FRONKOVA; Veronika KANDEROVA; Craig D. PLATT; Janet CHOU; Talal A. CHATILA; Raif GEHA; Elizabeth MCDERMOTT; Su BUNN; Monika KURZAI; Ansgar SCHULZ; Laia ALSINA; Ferran CASALS; Angela DEYA-MARTINEZ; Sophie HAMBLETON; Hirokazu KANEGANE; Kjetil TASKEN; Olaf NETH a Bodo GRIMBACHER. Phenotype, penetrance, and treatment of 133 cytotoxic T-lymphocyte antigen 4-insufficient subjects. \textit{Journal of allergy and clinical immunology}. New York: Mosby-Elsevier, 2018, roč.~142, č.~6, s.~1932-1946. ISSN~0091-6749. Dostupné z: https://doi.org/10.1016/j.jaci.2018.02.055.