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IL-17 protects T cells from apoptosis and contributes to development of ALPS-like phenotypes

Boggio, E.; Clemente, N.; Mondino, A.; Cappellano, G.; Orilieri, E.; Gigliotti, C.L.; Toth, E. LU ; Ramenghi, Ugo; Dianzani, U. and Chiocchetti, Andreas (2014) In Blood 123(8). p.1178-1186
Abstract
In autoimmune/lymphoproliferative syndrome (ALPS), defective Fas death receptor function causes lymphadenomegaly/splenomegaly, the expansion of T-cell receptor αβ+ CD4/CD8 double-negative T cells, and frequent development of hematologic autoimmunity. Dianzani autoimmune lymphoproliferative disease (DALD) has a similar phenotype but lacks the expansion of double-negative T cells. This work shows that patients with ALPS and DALD have high serum levels of interleukin 17A (IL-17A), IL-17F, and IL-17AF, which are involved in several autoimmune diseases, and that their T cells show increased secretion of these cytokines upon activation in vitro. The following data indicate that these cytokines may contribute to ALPS and DALD: (1) recombinant... (More)
In autoimmune/lymphoproliferative syndrome (ALPS), defective Fas death receptor function causes lymphadenomegaly/splenomegaly, the expansion of T-cell receptor αβ+ CD4/CD8 double-negative T cells, and frequent development of hematologic autoimmunity. Dianzani autoimmune lymphoproliferative disease (DALD) has a similar phenotype but lacks the expansion of double-negative T cells. This work shows that patients with ALPS and DALD have high serum levels of interleukin 17A (IL-17A), IL-17F, and IL-17AF, which are involved in several autoimmune diseases, and that their T cells show increased secretion of these cytokines upon activation in vitro. The following data indicate that these cytokines may contribute to ALPS and DALD: (1) recombinant IL-17A and IL-17F significantly inhibit Fas-induced cell death in Fas-sensitive T cells from healthy donors; (2) this inhibitory effect is also induced by the patients' serum and is reversed by anti-IL-17A antibodies; (3) IL-17A neutralization substantially increases Fas-induced cell death in T cells from ALPS and DALD patients in vitro; and (4) treatment with anti-IL-17A antibodies ameliorates the autoimmune manifestations and, at a lesser extent, the lymphoproliferative phenotype and prolongs survival in MRLlpr/lpr mice, which are an animal model of ALPS. These data suggest that IL-17A and IL-17F could be targeted therapeutically to improve Fas function in ALPS and DALD. © 2014 by The American Society of Hematology. (Less)
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keywords
CD4 antigen, chemokine receptor CCR6, Fas antigen, interleukin 17, interleukin 17 antibody, interleukin 17AF, interleukin 17F, T lymphocyte receptor alpha chain, T lymphocyte receptor beta chain, unclassified drug, IL17A protein, human, IL17F protein, human, lymphocyte antigen receptor, neutralizing antibody, animal cell, animal experiment, animal model, animal tissue, apoptosis, article, autoimmune lymphoproliferative syndrome, autoimmunity, cell death, clinical article, controlled study, cytokine release, Dianzani autoimmune lymphoproliferative disease, enzyme linked immunosorbent assay, female, human, human cell, in vitro study, nonhuman, passive immunization, phenotype, priority journal, protein blood level, survival time, T lymphocyte, T lymphocyte activation, Th17 cell, animal, blood, cell culture, child, cytology, genetics, immunology, immunophenotyping, male, mouse, Murphy Roths large lymphoproliferative mouse, pathology, preschool child, young adult, Animals, Antibodies, Neutralizing, Apoptosis, Autoimmune Lymphoproliferative Syndrome, Cells, Cultured, Child, Child, Preschool, Female, Humans, Immunization, Passive, Immunophenotyping, Interleukin-17, Male, Mice, Mice, Inbred MRL lpr, Phenotype, Receptors, Antigen, T-Cell, alpha-beta, T-Lymphocytes, Young Adult
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Blood
volume
123
issue
8
pages
9 pages
publisher
American Society of Hematology
external identifiers
  • scopus:84897900832
ISSN
1528-0020
DOI
10.1182/blood-2013-07-518167
language
English
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433a34d1-007c-4596-99f3-3a996d8fff0c
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https://www.scopus.com/inward/record.uri?eid=2-s2.0-84897900832&doi=10.1182%2fblood-2013-07-518167&partnerID=40&md5=40a8122a9b8394e07feb11a8e7bfb550
date added to LUP
2017-04-18 11:20:29
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2017-08-13 05:06:40
@article{433a34d1-007c-4596-99f3-3a996d8fff0c,
  abstract     = {In autoimmune/lymphoproliferative syndrome (ALPS), defective Fas death receptor function causes lymphadenomegaly/splenomegaly, the expansion of T-cell receptor αβ+ CD4/CD8 double-negative T cells, and frequent development of hematologic autoimmunity. Dianzani autoimmune lymphoproliferative disease (DALD) has a similar phenotype but lacks the expansion of double-negative T cells. This work shows that patients with ALPS and DALD have high serum levels of interleukin 17A (IL-17A), IL-17F, and IL-17AF, which are involved in several autoimmune diseases, and that their T cells show increased secretion of these cytokines upon activation in vitro. The following data indicate that these cytokines may contribute to ALPS and DALD: (1) recombinant IL-17A and IL-17F significantly inhibit Fas-induced cell death in Fas-sensitive T cells from healthy donors; (2) this inhibitory effect is also induced by the patients' serum and is reversed by anti-IL-17A antibodies; (3) IL-17A neutralization substantially increases Fas-induced cell death in T cells from ALPS and DALD patients in vitro; and (4) treatment with anti-IL-17A antibodies ameliorates the autoimmune manifestations and, at a lesser extent, the lymphoproliferative phenotype and prolongs survival in MRLlpr/lpr mice, which are an animal model of ALPS. These data suggest that IL-17A and IL-17F could be targeted therapeutically to improve Fas function in ALPS and DALD. © 2014 by The American Society of Hematology.},
  author       = {Boggio, E. and Clemente, N. and Mondino, A. and Cappellano, G. and Orilieri, E. and Gigliotti, C.L. and Toth, E. and Ramenghi, Ugo and Dianzani, U. and Chiocchetti, Andreas},
  issn         = {1528-0020},
  keyword      = {CD4 antigen,chemokine receptor CCR6,Fas antigen,interleukin 17,interleukin 17 antibody,interleukin 17AF,interleukin 17F,T lymphocyte receptor alpha chain,T lymphocyte receptor beta chain,unclassified drug,IL17A protein, human,IL17F protein, human,lymphocyte antigen receptor,neutralizing antibody, animal cell,animal experiment,animal model,animal tissue,apoptosis,article,autoimmune lymphoproliferative syndrome,autoimmunity,cell death,clinical article,controlled study,cytokine release,Dianzani autoimmune lymphoproliferative disease,enzyme linked immunosorbent assay,female,human,human cell,in vitro study,nonhuman,passive immunization,phenotype,priority journal,protein blood level,survival time,T lymphocyte,T lymphocyte activation,Th17 cell,animal,blood,cell culture,child,cytology,genetics,immunology,immunophenotyping,male,mouse,Murphy Roths large lymphoproliferative mouse,pathology,preschool child,young adult, Animals,Antibodies, Neutralizing,Apoptosis,Autoimmune Lymphoproliferative Syndrome,Cells, Cultured,Child,Child, Preschool,Female,Humans,Immunization, Passive,Immunophenotyping,Interleukin-17,Male,Mice,Mice, Inbred MRL lpr,Phenotype,Receptors, Antigen, T-Cell, alpha-beta,T-Lymphocytes,Young Adult},
  language     = {eng},
  number       = {8},
  pages        = {1178--1186},
  publisher    = {American Society of Hematology},
  series       = {Blood},
  title        = {IL-17 protects T cells from apoptosis and contributes to development of ALPS-like phenotypes},
  url          = {http://dx.doi.org/10.1182/blood-2013-07-518167},
  volume       = {123},
  year         = {2014},
}