Germline TIM-3 Mutations Characterize Sub-Cutaneous Panniculitis T-Cell Lymphomas with Hemophagocytic Lymphohistiocytic Syndrome
Rattachement africain : au, ca, fr, br, us. Niveau de preuve : code pays fourni par la source.
Le résumé fourni par la source
Abstract Introduction Sub-cutaneous panniculitis T-cell lymphomas (SPTCL), a rare non-Hodgkin lymphoma, can be associated with hemophagocytic lymphohistiocytosis (HLH), a life-threatening activation of the immune system which adversely impacts survival. T-cell immunoglobulin mucin 3 (TIM-3) is a modulator of immune responses expressed on subgroups of T- and innate immune cells. In this work we describe the first germline variants associated with SPTCL, which are in the TIM-3 gene. Methods We sequenced 27 SPTCL cases to identify gene variants. We performed TIM-3 functional analysis on immune cells from patients and HEK293 cells engineered to overexpress wild-type or mutant TIM-3. Results We identified homozygous, germline, loss-of-function, missense variants in highly conserved residues of TIM-3, namely p.Y82C and p.I97M in about 60% (16/27) of SPTCL cases. These samples were drawn from cases series across 3 continents. Patients with bi-allelic TIM-3 mutations were younger at diagnosis, and several had life-threatening HLH and severe disease course. TIM-3 mutations show specific geographic distribution. Y82C TIM-3 mutations occur on a founder chromosome in patients with East-Asian and Polynesian ancestry, while I97M TIM-3 is observed in Caucasians. Both variants induce protein misfolding and cytoplasmic retention of TIM-3. Loss of TIM-3 membrane expression in TIM-3 mutants abrogates the PD-1/PDL-1 checkpoint and prevents the termination of a Th1-immune response. In HEK293 cells, mutant TIM-3 was not expressed on the cell surface. Defective TIM-3 expression leads to persistent immune activation with increased production of inflammatory cytokines including TNF-alpha and IL-1beta by innate immune cells. Conclusion Our findings highlight HLH/SPTCL as a new genetic entity where loss of the TIM-3 immune checkpoint is associated with T-cell infiltration of adipose tissue and inflammasome activation. This is the first causative germline defect identified in SPTCL. While our findings indicate that TIM-3-mutant HLH/SPTCL benefit from immunomodulation, therapeutic repression of the TIM-3 checkpoint could have serious adverse consequences. Disclosures Prince: Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees.
Ce résumé expose les affirmations des auteurs. BNTIC ne l’interprète pas comme une validation indépendante des résultats.
Le contrôle bibliographique ouvert
DOI retrouvé dans Crossref DOI retrouvé ; titre concordant.
- Titre Crossref
- Germline TIM-3 Mutations Characterize Sub-Cutaneous Panniculitis T-Cell Lymphomas with Hemophagocytic Lymphohistiocytic Syndrome
- Date Crossref
- 29/11/2018
- Éditeur
- American Society of Hematology
- Type
- journal-article
Ce recoupement confirme des métadonnées liées au DOI. Il ne confirme ni la méthode ni les conclusions de l’étude, et il ne compte pas comme une seconde source scientifique indépendante.
Où se fait cette recherche
-
The University of Melbourne pays non établi dans la noticeUniversité ou école supérieure
-
McGill University pays non établi dans la noticeUniversité ou école supérieure
-
Délégation Paris 5 pays non établi dans la noticeOrganisme public
-
Université Paris Cité pays non établi dans la noticeUniversité ou école supérieure
-
Universidade de São Paulo pays non établi dans la noticeUniversité ou école supérieure
-
University of Toronto pays non établi dans la noticeUniversité ou école supérieure
-
Ontario Genomics pays non établi dans la noticeOrganisation à but non lucratif
-
Sinai Health System pays non établi dans la noticeÉtablissement de santé
-
McGill University Health Centre pays non établi dans la noticeÉtablissement de santé
-
Montreal Children's Hospital pays non établi dans la noticeÉtablissement de santé
-
Institut des Maladies Génétiques Imagine pays non établi dans la noticeStructure de recherche
-
Hôpital Necker-Enfants Malades pays non établi dans la noticeÉtablissement de santé
The University of Melbourne, McGill University et Délégation Paris 5, avec 9 autres affiliations.
Une affiliation ne permet pas de déduire la nationalité d’un auteur.