title: IL-17 protects T cells from apoptosis and contributes to development of ALPS-like phenotypes.
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.
authors.affiliation: Interdisciplinary Research Center of Autoimmune Diseases, Department of Health Sciences "A. Avogadro" University of Eastern Piedmont, Novara, Italy; and.
authors.forename: Elena
authors.initials: E
authors.lastname: Boggio
authors.forename: Nausicaa
authors.initials: N
authors.lastname: Clemente
authors.forename: Anna
authors.initials: A
authors.lastname: Mondino
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Cappellano
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Orilieri
authors.forename: Casimiro L
authors.initials: CL
authors.lastname: Gigliotti
authors.forename: Erika
authors.initials: E
authors.lastname: Toth
authors.forename: Ugo
authors.initials: U
authors.lastname: Ramenghi
authors.forename: Umberto
authors.initials: U
authors.lastname: Dianzani
authors.forename: Annalisa
authors.initials: A
authors.lastname: Chiocchetti
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000276:immunology; D017209:Apoptosis / Q000276:immunology*; D056735:Autoimmune Lymphoproliferative Syndrome / Q000276:immunology* / Q000473:pathology; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D007116:Immunization, Passive; D016130:Immunophenotyping; D020381:Interleukin-17 / Q000097:blood / Q000276:immunology*; D008297:Male; D051379:Mice; D019463:Mice, Inbred MRL lpr; D010641:Phenotype; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics / Q000276:immunology; D013601:T-Lymphocytes / Q000166:cytology* / Q000276:immunology; D055815:Young Adult
chemical_list: D057134:Antibodies, Neutralizing; C508717:IL17A protein, human; C440021:IL17F protein, human; D020381:Interleukin-17; D016693:Receptors, Antigen, T-Cell, alpha-beta