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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, 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 and 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, vol. 142, No 6, p. 1932-1946. ISSN 0091-6749. Available from: https://dx.doi.org/10.1016/j.jaci.2018.02.055.

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@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 = {http://dx.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  -

Basic information
Original name	Phenotype, penetrance, and treatment of 133 cytotoxic T-lymphocyte antigen 4-insufficient subjects
Authors	SCHWAB, Charlotte (276 Germany), Annemarie GABRYSCH (276 Germany), Peter OLBRICH (724 Spain), Virginia PATINO (858 Uruguay), Klaus WARNATZ (276 Germany), Daniel WOLFF (276 Germany), Akihiro HOSHINO (392 Japan), Masao KOBAYASHI (392 Japan), Kohsuke IMAI (392 Japan), Masatoshi TAKAGI (392 Japan), Ingunn DYBEDAL (578 Norway), Jamanda A. HADDOCK (826 United Kingdom of Great Britain and Northern Ireland), David M. SANSOM (826 United Kingdom of Great Britain and Northern Ireland), Jose M. LUCENA (724 Spain), Maximilian SEIDL (276 Germany), Annette SCHMITT-GRAEFF (276 Germany), Veronika REISER (276 Germany), Florian EMMERICH (276 Germany), Natalie FREDE (276 Germany), Alla BULASHEVSKA (276 Germany), Ulrich SALZER (276 Germany), Desiree SCHUBERT (276 Germany), Seiichi HAYAKAWA (392 Japan), Satoshi OKADA (392 Japan), Maria KANARIOU (300 Greece), Zeynep Yesim KUCUK (840 United States of America), Hugo CHAPDELAINE (124 Canada), Lenka PETRUZELKOVA (203 Czech Republic), Zdenek SUMNIK (203 Czech Republic), Anna SEDIVA (203 Czech Republic), Mary SLATTER (826 United Kingdom of Great Britain and Northern Ireland), Peter D. ARKWRIGHT (826 United Kingdom of Great Britain and Northern Ireland), Andrew CANT (826 United Kingdom of Great Britain and Northern Ireland), Hanns-Martin LORENZ (276 Germany), Thomas GIESE (276 Germany), Vassilios LOUGARIS (380 Italy), Alessandro PLEBANI (380 Italy), Christina PRICE (840 United States of America), Kathleen E. SULLIVAN (840 United States of America), Michel MOUTSCHEN (56 Belgium), Jiří LITZMAN (203 Czech Republic, belonging to the institution), Tomáš FREIBERGER (203 Czech Republic, belonging to the institution), Frank L. VAN DE VEERDONK (528 Netherlands), Mike RECHER (756 Switzerland), Michael H. ALBERT (276 Germany), Fabian HAUCK (276 Germany), Suranjith SENEVIRATNE (826 United Kingdom of Great Britain and Northern Ireland), Jana Pachlopnik SCHMID (756 Switzerland), Antonios KOLIOS (756 Switzerland), Gary UNGLIK (36 Australia), Christian KLEMANN (276 Germany), Carsten SPECKMANN (276 Germany), Stephan EHL (276 Germany), Alan LEICHTNER (840 United States of America), Richard BLUMBERG (840 United States of America), Andre FRANKE (276 Germany), Scott SNAPPER (840 United States of America), Sebastian ZEISSIG (276 Germany), Charlotte CUNNINGHAM-RUNDLES (840 United States of America), Lisa GIULINO-ROTH (840 United States of America), Oliver ELEMENTO (840 United States of America), Gregor DUCKERS (276 Germany), Tim NIEHUES (276 Germany), Eva FRONKOVA (203 Czech Republic), Veronika KANDEROVA (203 Czech Republic), Craig D. PLATT (840 United States of America), Janet CHOU (840 United States of America), Talal A. CHATILA (840 United States of America), Raif GEHA (840 United States of America), Elizabeth MCDERMOTT (826 United Kingdom of Great Britain and Northern Ireland), Su BUNN (826 United Kingdom of Great Britain and Northern Ireland), Monika KURZAI (276 Germany), Ansgar SCHULZ (276 Germany), Laia ALSINA (724 Spain), Ferran CASALS (724 Spain), Angela DEYA-MARTINEZ (724 Spain), Sophie HAMBLETON (826 United Kingdom of Great Britain and Northern Ireland), Hirokazu KANEGANE (392 Japan), Kjetil TASKEN (578 Norway), Olaf NETH (724 Spain) and Bodo GRIMBACHER (276 Germany, guarantor).
Edition	Journal of allergy and clinical immunology, New York, Mosby-Elsevier, 2018, 0091-6749.

Other information
Original language	English
Type of outcome	Article in a journal
Field of Study	30225 Allergy
Country of publisher	United States of America
Confidentiality degree	is not subject to a state or trade secret
Impact factor	Impact factor: 14.110
RIV identification code	RIV/00216224:14110/18:00105160
Organization unit	Faculty of Medicine
Doi	http://dx.doi.org/10.1016/j.jaci.2018.02.055
UT WoS	000452315800026
Keywords in English	Cytotoxic T-lymphocyte antigen 4; primary immunodeficiency; autoimmunity; hypogammaglobulinemia; hematopoietic stem cell transplantation; abatacept; sirolimus; immune dysregulation; common variable immunodeficiency
Tags	14110114, podil, rivok
Tags	International impact, Reviewed
Changed by	Changed by: Mgr. Pavla Foltynová, Ph.D., učo 106624. Changed: 12/3/2019 15:48.

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 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.

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 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.