Area: Pediatrics and Rheumatology
Chief, Immunology, Allergy and Rheumatology | Director, Center for Human Immunobiology | Texas Children's Hospital
Professor of Pediatrics, Pathology and Immunology | Vice Chair for Research | Department of Pediatrics
Director, Pediatrician Scientist Training and Development Program | Baylor College of Medicine
Dr. Jordan Orange, professor of pediatrics and rheumatology, has concentrated his research on the study of primary immunodeficiency, and on the cell biology and deficiencies of natural killer (NK) cell defenses, a major player in the rejection of tumors and viral infections. His work has improved our understanding of the genetic bases and mechanisms of immunodeficiencies, underscoring the importance of NK cells defenses. Recent work, reported in Nature Genetics, applied cell biology, genomic and microscopy techniques, and revealed an unexpected molecular link between a vesicular transport protein and a hereditary autoimmune-mediated lung disease and arthritis. In 2016, a paper in the Journal of Clinical Investigation was the culmination of a 12 year study to determine the cause of an NK deficiency that makes patients susceptible to severe viral infections. Their investigation pinpointed two rare variants of the gene IRF8; one of them had not been reported before. The individuals carrying two defective IRF8 variants have fewer mature NK cells than those with the normal gene, and these fewer cells do not work properly. On another study, Dr. Orange has moved forward our understanding of how NK cells kill their targets. He had previously described that NK cells concentrate their lytic granules on the area of contact with the diseased cell, but why this concentration occurred was not clear. His paper published in the Journal of Cell Biology this year showed that by converging their lytic granules, NK cells improved the killing efficiency of their targets while preventing collateral damage to neighboring healthy cells.
Dr. Orange's nomination was based on the following publications:
Hsu HT, Mace EM, Carisey AF, Viswanath DI, Christakou AE, Wiklund M, Önfelt B, Orange JS. NK cells converge lytic granules to promote cytotoxicity and prevent bystander killing. J Cell Biol. 2016 Dec 19;215(6):875-889. Epub 2016 Nov 30.
Watkin LB, Jessen B, Wiszniewski W, Vece TJ, Jan M, Sha Y, Thamsen M, Santos-Cortez RL, Lee K, Gambin T, Forbes LR, Law CS, Stray-Pedersen A, Cheng MH, Mace EM, Anderson MS, Liu D, Tang LF, Nicholas SK, Nahmod K, Makedonas G, Canter DL, Kwok PY, Hicks J, Jones KD, Penney S, Jhangiani SN, Rosenblum MD, Dell SD, Waterfield MR, Papa FR, Muzny DM, Zaitlen N, Leal SM, Gonzaga-Jauregui C; Baylor-Hopkins Center for Mendelian Genomics., Boerwinkle E, Eissa NT, Gibbs RA, Lupski JR, Orange JS, Shum AK. COPA mutations impair ER-Golgi transport and cause hereditary autoimmune-mediated lung disease and arthritis. Nat Genet. 2015 Jun;47(6):654-60. doi: 10.1038/ng.3279. Epub 2015 Apr 20.
Mace EM, Bigley V, Gunesch JT, Chinn IK, Angelo LS, Care MA, Maisuria S, Keller MD, Togi S, Watkin LB, LaRosa DF, Jhangiani SN, Muzny DM, Stray-Pedersen A, Coban Akdemir Z, Smith JB, Hernández-Sanabria M, Le DT, Hogg GD, Cao TN, Freud AG, Szymanski EP, Savic S, Collin M, Cant AJ, Gibbs RA, Holland SM, Caligiuri MA, Ozato K, Paust S, Doody GM, Lupski JR, Orange JS. Biallelic mutations in IRF8 impair human NK cell maturation and function. J Clin Invest. 2017 Jan 3;127(1):306-320. doi: 10.1172/JCI86276. Epub 2016 Nov 28.