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.
| Original language | English |
|---|---|
| Pages (from-to) | 1178-1186 |
| Number of pages | 9 |
| Journal | Blood |
| Volume | 123 |
| Issue number | 8 |
| DOIs | |
| Publication status | Published - Feb 20 2014 |
Fingerprint
ASJC Scopus subject areas
- Hematology
- Biochemistry
- Cell Biology
- Immunology
Cite this
IL-17 protects T cells from apoptosis and contributes to development of ALPS-like phenotypes. / Boggio, Elena; Clemente, Nausicaa; Mondino, Anna; Cappellano, Giuseppe; Orilieri, Elisabetta; Gigliotti, Casimiro L.; Toth, Erika; Ramenghi, Ugo; Dianzani, Umberto; Chiocchetti, Annalisa.
In: Blood, Vol. 123, No. 8, 20.02.2014, p. 1178-1186.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - IL-17 protects T cells from apoptosis and contributes to development of ALPS-like phenotypes
AU - Boggio, Elena
AU - Clemente, Nausicaa
AU - Mondino, Anna
AU - Cappellano, Giuseppe
AU - Orilieri, Elisabetta
AU - Gigliotti, Casimiro L.
AU - Toth, Erika
AU - Ramenghi, Ugo
AU - Dianzani, Umberto
AU - Chiocchetti, Annalisa
PY - 2014/2/20
Y1 - 2014/2/20
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84897900832&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84897900832&partnerID=8YFLogxK
U2 - 10.1182/blood-2013-07-518167
DO - 10.1182/blood-2013-07-518167
M3 - Article
C2 - 24363402
AN - SCOPUS:84897900832
VL - 123
SP - 1178
EP - 1186
JO - Blood
JF - Blood
SN - 0006-4971
IS - 8
ER -