Jak3 and the pathogenesis of severe combined immunodeficiency.
The discovery that Jak3 mutations are a significant cause of severe combined immunodeficiency (SCID), a rare inherited defect characterized by lymphopenia, has provided valuable insights into the functions of Jak3 in lymphoid development and function. The current therapy for patients suffering from Jak3 SCID is hematopoetic stem cell transplantation, although gene therapy trials have also been performed. In lieu of crystal structure data, these patient-derived mutations have aided in the elucidation of the functions of various structural components of Jak3. By virtue of its requirement for lymphoid functions, Jak3 makes a tantalizing target for immunosuppression and anti-cancer therapy. Herein, we discuss the normal actions of the gammac cytokines, the pathogenesis and treatment protocols for SCID, and finally, the production of a new, selective Jak3 inhibitor capable of preventing transplant rejection in two animal models. Further study of Jak3 will hopefully provide insights into the clinical treatment of patients suffering from immune-mediated diseases.
O'Shea
John J
JJ
Molecular Immunology and Inflammation Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, MSC 1820, 10 Center Drive, Bethesda, MD 20892, USA.
Husa
Matthew
M
Li
Denise
D
Hofmann
Sigrun R
SR
Watford
Wendy
W
Roberts
Joseph L
JL
Buckley
Rebecca H
RH
Changelian
Paul
P
Candotti
Fabio
F
D000818:Animals; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D006801:Humans; D053616:Janus Kinase 3; D009154:Mutation; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000172:deficiency* / Q000235:genetics; D020395:Receptors, Interleukin-7 / Q000235:genetics / Q000378:metabolism; D016511:Severe Combined Immunodeficiency / Q000201:enzymology / Q000235:genetics* / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology / Q000502:physiology*; D013329:Structure-Activity Relationship
D016207:Cytokines; D020395:Receptors, Interleukin-7; D011505:Protein-Tyrosine Kinases; C507933:JAK3 protein, human; D053616:Janus Kinase 3