Natural Killer Cells from Patients with Recombinase-Activating Gene and Non-Homologous End Joining Gene Defects Comprise a Higher Frequency of CD56(bright) NKG2A+++ Cells, and Yet Display Increased Degranulation and Higher Perforin Content
Mutations of the recombinase-activating genes 1 and 2 (RAG1 and RAG2) in humans are associated with a broad range of phenotypes. For patients with severe clinical presentation, hematopoietic stem cell transplantation (HSCT) represents the only curative treatment; however, high rates of graft failure...
| Authors: | ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; |
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| Format: | Article |
| Publication date: | 2017 |
| Country: | España |
| Institution: | Conselleria de Salut i Consum del Govern de les Illes Balears |
| Repository: | Docusalut |
| Language: | English |
| OAI Identifier: | oai:docusalut.com:20.500.13003/9743 |
| Online Access: | https://hdl.handle.net/20.500.13003/9743 |
| Access Level: | Open access |
| Keyword: | natural killer cells recombinase-activating genes non-homologous end joining immunodeficiency CD56 interferon-gamma degranulation |
| _version_ | 1878739967597871104 |
|---|---|
| author | Dobbs, Kerry |
| author2 | Tabellini, Giovanna Calzoni, Enrica Patrizi, Ornella Martinez, Paula Giliani, Silvia Clara Moratto, Daniele Al-Herz, Waleed Cancrini, Caterina Cowan, Morton Bleesing, Jacob Booth, Claire Buchbinder, David Burns, Siobhan O. Chatila, Talal A. Chou, Janet Daza-Cajigal, Vanessa de Bruin, Lisa M. Ott de la Morena, Maite Di Matteo, Gigliola Finocchi, Andrea Geha, Raif Goyal, Rakesh K. Hayward, Anthony Holland, Steven Huang, Chiung-Hui Kanariou, Maria G. King, Alejandra Kaplan, Blanka Kleva, Anastasiya Kuijpers, Taco W. Lee, Bee Wah Lougaris, Vassilios Massaad, Michel Meyts, Isabelle Morsheimer, Megan Neven, Benedicte Pai, Sung-Yun Plebani, Alessandro Prockop, Susan Reisli, Ismail Soh, Jian Yi Somech, Raz Torgerson, Troy R. Kim, Yae-Jaen Walter, Jolan E. Gennery, Andrew R. Keles, Sevgi Manis, John P. Marcenaro, Emanuela Moretta, Alessandro Parolini, Silvia Notarangelo, Luigi D. |
| author2_role | author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author |
| author_browse | Al-Herz, Waleed Bleesing, Jacob Booth, Claire Buchbinder, David Burns, Siobhan O. Calzoni, Enrica Cancrini, Caterina Chatila, Talal A. Chou, Janet Cowan, Morton Daza-Cajigal, Vanessa Di Matteo, Gigliola Dobbs, Kerry Finocchi, Andrea Geha, Raif Gennery, Andrew R. Giliani, Silvia Clara Goyal, Rakesh K. Hayward, Anthony Holland, Steven Huang, Chiung-Hui Kanariou, Maria G. Kaplan, Blanka Keles, Sevgi Kim, Yae-Jaen King, Alejandra Kleva, Anastasiya Kuijpers, Taco W. Lee, Bee Wah Lougaris, Vassilios Manis, John P. Marcenaro, Emanuela Martinez, Paula Massaad, Michel Meyts, Isabelle Moratto, Daniele Moretta, Alessandro Morsheimer, Megan Neven, Benedicte Notarangelo, Luigi D. Pai, Sung-Yun Parolini, Silvia Patrizi, Ornella Plebani, Alessandro Prockop, Susan Reisli, Ismail Soh, Jian Yi Somech, Raz Tabellini, Giovanna Torgerson, Troy R. Walter, Jolan E. de Bruin, Lisa M. Ott de la Morena, Maite |
| author_facet | Dobbs, Kerry Tabellini, Giovanna Calzoni, Enrica Patrizi, Ornella Martinez, Paula Giliani, Silvia Clara Moratto, Daniele Al-Herz, Waleed Cancrini, Caterina Cowan, Morton Bleesing, Jacob Booth, Claire Buchbinder, David Burns, Siobhan O. Chatila, Talal A. Chou, Janet Daza-Cajigal, Vanessa de Bruin, Lisa M. Ott de la Morena, Maite Di Matteo, Gigliola Finocchi, Andrea Geha, Raif Goyal, Rakesh K. Hayward, Anthony Holland, Steven Huang, Chiung-Hui Kanariou, Maria G. King, Alejandra Kaplan, Blanka Kleva, Anastasiya Kuijpers, Taco W. Lee, Bee Wah Lougaris, Vassilios Massaad, Michel Meyts, Isabelle Morsheimer, Megan Neven, Benedicte Pai, Sung-Yun Plebani, Alessandro Prockop, Susan Reisli, Ismail Soh, Jian Yi Somech, Raz Torgerson, Troy R. Kim, Yae-Jaen Walter, Jolan E. Gennery, Andrew R. Keles, Sevgi Manis, John P. Marcenaro, Emanuela Moretta, Alessandro Parolini, Silvia Notarangelo, Luigi D. |
| author_role | author |
| collection | Docusalut |
| description | Mutations of the recombinase-activating genes 1 and 2 (RAG1 and RAG2) in humans are associated with a broad range of phenotypes. For patients with severe clinical presentation, hematopoietic stem cell transplantation (HSCT) represents the only curative treatment; however, high rates of graft failure and incomplete immune reconstitution have been observed, especially after unconditioned haploidentical transplantation. Studies in mice have shown that Rag-/-natural killer (NK) cells have a mature phenotype, reduced fitness, and increased cytotoxicity. We aimed to analyze NK cell phenotype and function in patients with mutations in RAG and in non-homologous end joining (NHEJ) genes. Here, we provide evidence that NK cells from these patients have an immature phenotype, with significant expansion of CD56(bright) CD16(-/int) CD57(-cells), yet increased degranulation and high perforin content. Correlation was observed between in vitro recombinase activity of the mutant proteins, NK cell abnormalities, and in vivo clinical phenotype. Addition of serotherapy in the conditioning regimen, with the aim of depleting the autologous NK cell compartment, may be important to facilitate engraftment and immune reconstitution in patients with RAG and NHEJ defects treated by HSCT. |
| eu_rights_str_mv | openAccess |
| format | article |
| id | ES_cb4e1f7eb34c9c60dc5f3ee733fa8b7f |
| institution | Conselleria de Salut i Consum del Govern de les Illes Balears |
| instname_str | Conselleria de Salut i Consum del Govern de les Illes Balears |
| language | eng |
| network_acronym_str | ES |
| network_name_str | España |
| oai_identifier_str | oai:docusalut.com:20.500.13003/9743 |
| publishDate | 2017 |
| publishDateSort | 2017 |
| publisher | Frontiers Media Sa |
| publisherStr | Frontiers Media Sa |
| reponame_str | Docusalut |
| spelling | Natural Killer Cells from Patients with Recombinase-Activating Gene and Non-Homologous End Joining Gene Defects Comprise a Higher Frequency of CD56(bright) NKG2A+++ Cells, and Yet Display Increased Degranulation and Higher Perforin Content Dobbs, Kerry Tabellini, Giovanna Calzoni, Enrica Patrizi, Ornella Martinez, Paula Giliani, Silvia Clara Moratto, Daniele Al-Herz, Waleed Cancrini, Caterina Cowan, Morton Bleesing, Jacob Booth, Claire Buchbinder, David Burns, Siobhan O. Chatila, Talal A. Chou, Janet Daza-Cajigal, Vanessa de Bruin, Lisa M. Ott de la Morena, Maite Di Matteo, Gigliola Finocchi, Andrea Geha, Raif Goyal, Rakesh K. Hayward, Anthony Holland, Steven Huang, Chiung-Hui Kanariou, Maria G. King, Alejandra Kaplan, Blanka Kleva, Anastasiya Kuijpers, Taco W. Lee, Bee Wah Lougaris, Vassilios Massaad, Michel Meyts, Isabelle Morsheimer, Megan Neven, Benedicte Pai, Sung-Yun Plebani, Alessandro Prockop, Susan Reisli, Ismail Soh, Jian Yi Somech, Raz Torgerson, Troy R. Kim, Yae-Jaen Walter, Jolan E. Gennery, Andrew R. Keles, Sevgi Manis, John P. Marcenaro, Emanuela Moretta, Alessandro Parolini, Silvia Notarangelo, Luigi D. natural killer cells recombinase-activating genes non-homologous end joining immunodeficiency CD56 interferon-gamma degranulation Mutations of the recombinase-activating genes 1 and 2 (RAG1 and RAG2) in humans are associated with a broad range of phenotypes. For patients with severe clinical presentation, hematopoietic stem cell transplantation (HSCT) represents the only curative treatment; however, high rates of graft failure and incomplete immune reconstitution have been observed, especially after unconditioned haploidentical transplantation. Studies in mice have shown that Rag-/-natural killer (NK) cells have a mature phenotype, reduced fitness, and increased cytotoxicity. We aimed to analyze NK cell phenotype and function in patients with mutations in RAG and in non-homologous end joining (NHEJ) genes. Here, we provide evidence that NK cells from these patients have an immature phenotype, with significant expansion of CD56(bright) CD16(-/int) CD57(-cells), yet increased degranulation and high perforin content. Correlation was observed between in vitro recombinase activity of the mutant proteins, NK cell abnormalities, and in vivo clinical phenotype. Addition of serotherapy in the conditioning regimen, with the aim of depleting the autologous NK cell compartment, may be important to facilitate engraftment and immune reconstitution in patients with RAG and NHEJ defects treated by HSCT. Frontiers Media Sa https://hdl.handle.net/20.500.13003/9743 |
| spellingShingle | Natural Killer Cells from Patients with Recombinase-Activating Gene and Non-Homologous End Joining Gene Defects Comprise a Higher Frequency of CD56(bright) NKG2A+++ Cells, and Yet Display Increased Degranulation and Higher Perforin Content Dobbs, Kerry natural killer cells recombinase-activating genes non-homologous end joining immunodeficiency CD56 interferon-gamma degranulation |
| title | Natural Killer Cells from Patients with Recombinase-Activating Gene and Non-Homologous End Joining Gene Defects Comprise a Higher Frequency of CD56(bright) NKG2A+++ Cells, and Yet Display Increased Degranulation and Higher Perforin Content |
| title_full | Natural Killer Cells from Patients with Recombinase-Activating Gene and Non-Homologous End Joining Gene Defects Comprise a Higher Frequency of CD56(bright) NKG2A+++ Cells, and Yet Display Increased Degranulation and Higher Perforin Content |
| title_fullStr | Natural Killer Cells from Patients with Recombinase-Activating Gene and Non-Homologous End Joining Gene Defects Comprise a Higher Frequency of CD56(bright) NKG2A+++ Cells, and Yet Display Increased Degranulation and Higher Perforin Content |
| title_full_unstemmed | Natural Killer Cells from Patients with Recombinase-Activating Gene and Non-Homologous End Joining Gene Defects Comprise a Higher Frequency of CD56(bright) NKG2A+++ Cells, and Yet Display Increased Degranulation and Higher Perforin Content |
| title_short | Natural Killer Cells from Patients with Recombinase-Activating Gene and Non-Homologous End Joining Gene Defects Comprise a Higher Frequency of CD56(bright) NKG2A+++ Cells, and Yet Display Increased Degranulation and Higher Perforin Content |
| title_sort | Natural Killer Cells from Patients with Recombinase-Activating Gene and Non-Homologous End Joining Gene Defects Comprise a Higher Frequency of CD56(bright) NKG2A+++ Cells, and Yet Display Increased Degranulation and Higher Perforin Content |
| topic | natural killer cells recombinase-activating genes non-homologous end joining immunodeficiency CD56 interferon-gamma degranulation |
| topic_facet | natural killer cells recombinase-activating genes non-homologous end joining immunodeficiency CD56 interferon-gamma degranulation |
| url | https://hdl.handle.net/20.500.13003/9743 |