| Literature DB >> 25213377 |
Hye Sun Kuehn1, Weiming Ouyang2, Bernice Lo3,4, Elissa K Deenick5,6, Julie E Niemela1, Danielle T Avery5, Jean-Nicolas Schickel7, Dat Q Tran8, Jennifer Stoddard1, Yu Zhang4,9, David M Frucht2, Bogdan Dumitriu10, Phillip Scheinberg10, Les R Folio11, Cathleen A Frein12, Susan Price3,4, Christopher Koh13, Theo Heller13, Christine M Seroogy14, Anna Huttenlocher14,15, V Koneti Rao3,4, Helen C Su4,9, David Kleiner16, Luigi D Notarangelo17, Yajesh Rampertaap18, Kenneth N Olivier18, Joshua McElwee19, Jason Hughes19, Stefania Pittaluga16, Joao B Oliveira20, Eric Meffre7, Thomas A Fleisher1, Steven M Holland4,18, Michael J Lenardo3,4, Stuart G Tangye5,6, Gulbu Uzel18.
Abstract
Cytotoxic T lymphocyte antigen-4 (CTLA-4) is an inhibitory receptor found on immune cells. The consequences of mutations in CTLA4 in humans are unknown. We identified germline heterozygous mutations in CTLA4 in subjects with severe immune dysregulation from four unrelated families. Whereas Ctla4 heterozygous mice have no obvious phenotype, human CTLA4 haploinsufficiency caused dysregulation of FoxP3(+) regulatory T (Treg) cells, hyperactivation of effector T cells, and lymphocytic infiltration of target organs. Patients also exhibited progressive loss of circulating B cells, associated with an increase of predominantly autoreactive CD21(lo) B cells and accumulation of B cells in nonlymphoid organs. Inherited human CTLA4 haploinsufficiency demonstrates a critical quantitative role for CTLA-4 in governing T and B lymphocyte homeostasis.Entities:
Mesh：
Substances：
Year: 2014 PMID： 25213377 PMCID： PMC4371526 DOI： 10.1126/science.1255904
Source DB: PubMed Journal: Science ISSN： 0036-8075 Impact factor: 47.728