Department of Immunology

David J. Rawlings, M.D.

PROFESSOR, PEDIATRICS; DIRECTOR, CENTER FOR IMMUNITY AND IMMUNOTHERAPIES, SEATTLE CHILDREN’S RESEARCH INSTITUTE; CHIEF, DIVISION OF IMMUNOLOGY, SEATTLE CHILDREN’S HOSPITAL; AND ADJUNCT PROFESSOR, IMMUNOLOGY

Dr. Rawlings graduated Magna Cum Laude in Biological Sciences from Davidson College, and received his M.D. from the University of North Carolina. He completed residency and chief residency in pediatrics at UCSF, and Pediatric Rheumatology/Immunology subspecialty training at Children’s Hospital Los Angeles. He pursued post-doctoral research as an intramural fellow at the NIH and in the HHMI, UCLA. Formerly a member of the UCLA faculty, Dr. Rawlings joined the University of Washington in 2001. He directs the Center for Immunity and Immunotherapies at Seattle Children’s Research Institute and is also chief of the Division of Immunology overseeing the immunodeficiency clinic at Seattle Children’s Hospital. Dr. Rawlings has received numerous awards and was elected to the American Society for Clinical Investigation in 2001 and the Association of American Physicians in 2007.

CONTACT INFO

drawling@uw.edu
Seattle Children’s Research Institute
M/S JMB-6, PO Box 5371
1900 9th Avenue
Seattle WA 98101
Phone: 206-987-7319
Fax: 206-884-1016
Assistant Contact:
Jennifer Haddock, Executive Assistant
206-884-3903
jennifer.haddock@seattlechildrens.org

RESEARCH AREAS

Tolerance & Autoimmunity
Molecular Immunology
Developmental Immunology
Cancer Immunology

LAB MEMBERS

Graduate Students
Fahd Alquershah, fahd.alquershah@seattlechildrens.org
Malika Hale, malika.hale@seattlechildrens.org
Ragan Pitner, ragan.pitner@seattlechildrens.org
Kerri Thomas, kerri.thomas@seattlechildrens.org

Postdoctoral Fellows
Jacquelyn Gorman, jacquelyn.gorman@seattlechildrens.org
Michelle Wray-Dutra, michelle.dutra@seattlechildrens.org
Warren Anderson, warren.anderson@seattlechildrens.org

Laboratory Members
Mason Berger, mason.berger@seattlechildrens.org
Ahmad Boukhris, ahmad.boukhris@seattlechildrens.org
Yu Chen, yu.chen@seattlechildrens.org
Michelle Christian, michelle.christian@seattlechildrens.org
Peter Cook, peter.cook@seattlechildrens.org
Noelle Dahl, noelle.dahl@seattlechildrens.org
Tony Dai, xuezhi.dai@seattlechildrens.org
Samuel Du, samuel.du@seattlechildrens.org
Matthew Garling, matthew.garling@seattlechildrens.org
Claire Gendrin, claire.gendrin@seattlechildrens.org
David Gruber, david.gruber@seattlechildrens.org
Gene Hess, gene.hess@seattlechildrens.org
Yuchi Honaker, yuchi.honaker@seattlechildrens.org
Amalia Icreverzi, amalia.icreverzi@seattlechildrens.org
Hank Jones, harold.jones@seattlechildrens.org
Iram Khan, iram.khan@seattlechildrens.org
Jit Khim, socheath.khim@seattlechildrens.org
Stefan Lachkar, stefan.lachkar@seattlechildrens.org
Christina Lopez, christina.lopez@seattlechildrens.org
Ezra Lopez, ezra.lopez@seattlechildrens.org
Samantha Lotti, samantha.lotti@seattlechildrens.org
Shivani Patel, shivani.patel@seattlechildrens.org
Sowmya Pattabhi, sowmya.pattabhi@seattlechildrens.org
Andrea Repele, andrea.repele@seattlechildrens.org
Samuel Scharffenberger, samuel.scharffenberger@seattlechildrens.org
Akhilesh Singh, akhilesh.singh@seattlechildrens.org
Swati Singh, swati.singh@seattchildrens.org
Jessica Smith, jessica.smith@seattlechildrens.org
Karen Sommer, karen.sommer@seattlechildrens.org
Yumei Song, yumei.song@seattlechildrens.org
Claire Stoffers, claire.stoffers@seattlechildrens.org
Christopher Thouvenel, christopher.thouvenel@seattlechildrens.org
Yupeng Wang, yupeng.wang@seattlechildrens.org
Su Yang, SuJung.Yang@seattlechildrens.org
Christopher Zavala, christopher.zavalagalvan@seattlechildrens.org

RESEARCH

Dr. Rawlings’ primary research interests include dysregulated lymphoid development and signaling leading to immunodeficiency, autoimmunity and/or lymphoid malignancies, and the development of gene therapy for immune diseases. His laboratory uses expertise in basic and clinical immunology, signal transduction and developmental biology to understand how altered signals can lead to immunologic disease, with the goal of developing translational therapies that specifically modulate key pathways. Dr. Rawlings is a member of multiple regional and national organizations, participates in various NIH study sections, and ad hoc reviewer for international grant programs and immunology journals. He also co-directs the Seattle Children’s Program for Cell and Gene Therapy, a focused on clinical application of both viral gene therapy and designer nuclease-mediated gene editing in hematopoietic cells for treatment of immune diseases.

Current work in the Rawlings laboratory is focused in 3 major areas:

  1. Lymphocyte signal transduction. B cell antigen receptor (BCR) engagement generates a multi-component complex of signaling effectors, or “signalosome”, that simultaneously trigger both positive and negative signals. The response to receptor engagement depends on the convergence of these signals. Two critical signals regulated by this “signalosome” include: a.) the sustained intracellular calcium signal; and b.) activation of NFκB-mediated survival signals. Our work has focused on the biochemical events regulating these signals. Our current studies include biochemical analysis of tyrosine kinases, adapter proteins, and lipid enzymes; and use of various animal models to evaluate the developmental consequences of altered expression of these proteins.
  2. Gene Therapy for primary immunodeficiency disorders. The past decade has witnessed tremendous progress in linking deficient function of signaling effectors with specific primary immunodeficiency disorders (PIDD). The non-receptor tyrosine kinase, Btk, is mutated in the primary B lineage immunodeficiency disease X-linked agammaglobulinemia (XLA in humans and in X-linked immunodeficiency, XID in mice). Similarly, mutation of the Wiskott-Aldrich Syndrome protein (WASp) leads to a multilineage immunodeficiency in humans and mice. Because of the selective advantage for gene corrected cells, these disorders represent excellent targets for stem cell-based gene therapy. We have developed lineage specific viral systems for use in hematopoietic stem cells. We are also evaluating the capacity of Homing endonucleases (HEs) to facilitate genetic repair of mutant loci in animal models of immunodeficiency. Our ongoing includes analysis of reconstitution function in mutant mice, and human multipotent stem cells in vitro and in vivo. The laboratory is strongly committed to moving from preclinical studies into translational trials of clinical gene therapy for patients with primary immunodeficiency disorders.
  3. Modeling normal and altered lymphopoiesis. We utilize unique (human and murine) in vitro B lineage culture models and murine knock-in /knock out models to study the signals that regulate B lymphopoiesis, B cell activation and B lineage Function in autoimmunity and malignancies. Current studies include analysis of Toll like receptor, Notch, and BAFF-receptor signaling cascades in the generation of peripheral B cell subsets and B cell tolerance; and analysis of the PKCβ/NFκB/PKD pathways in the development or progression of lymphoma.

PUBLICATIONS

  1. Rawlings DJ, Saffran DC, Tsukada S, Largaespada DA, Grimaldi JC, Cohen L, Mohr RN, Bazan JF, Howard M, Copeland NG, Jenkins NA and Witte ON. Mutation of unique region of Bruton’s tyrosine kinase in immunodeficient XID mice. (1993) Science 261:358-361.
  2. Rawlings DJ, Scharenberg AM, Park H, Wahl MI, Lin S, Kato RM, Fluckiger AC, Witte ON, Kinet JP. Activation of Btk by a phosphorylation mechanism initiated by src family kinases. (1996) Science 271:822- 825.
  3. Fluckiger AC, Li Z, Kato RM, Wahl MI, Ochs HD, Longnecker R, Kinet JP, Witte ON, Scharenberg, Rawlings DJ. Btk/Tec kinases regulate sustained increases in intracellular Ca2+ following B-cell receptor activation. (1998) EMBO 17:1973-1985. PMCID: PMC1170543
  4. Humphries LA, Dangelmaier C, Sommer K, Kipp K, Kato RM, Griffith N, Bakman I, Turk CW, Daniel JL, Rawlings DJ. Tec kinases mediate sustained calcium influx via site-specific tyrosine phosphorylation of the phospholipase Cgamma Src homology 2-Src homology 3 linker. (2004) J Biol Chem 279(36):37651-37661.
  5. Su TT, Guo B, Kawakami Y, Sommer K, Chae K, Humphries LA, Kato RM, Kang S, Patrone L, Wall R, Teitell M, Leitges M, Kawakami T, Rawlings DJ. PKCb controls IkB kinase lipid raft recruitment and activation in response to BCR signaling. (2002) Nature Immunol 3:780-786.
  6. Sommer K, Guo B, Pomerantz JL, Bandaranayake AD, Moreno-Garcia ME, Ovechkina YL, Rawlings DJ. Phosphorylation of the CARMA1 Linker Controls NF-κB Activation. (2005) Immunity 23 (6): 561-574.
  7. Rawlings DJ, Sommer K, Moreno-García ME. The CARMA1 signalosome links the signalling machinery of adaptive and innate immunity in lymphocytes. (2006) Nat Rev Immunol 6(11):799-812.
  8. Moreno-García ME, Sommer K, Shinohara H, Bandaranayake AD, Kurosaki T, Rawlings DJ. MAGUK-controlled ubiquitination of CARMA1 modulates lymphocyte NF-κB activity. (2010) Mol Cell Biol. 30(4):922-934. PMCID: PMC2815576
  9. Humblet-Baron S, Sather B, Anover S, Becker-Herman S, Kasprowicz DJ, Khim S, Nguyen T, Hudkins- Loya K, Alpers CE, Ziegler SF, Ochs H, Torgerson T, Campbell DJ, Rawlings DJ. Wiskott-Aldrich syndrome protein is required for regulatory T cell homeostasis. (2007) J Clin Invest. 1;117(2):407-418. PMCID: PMC1764857
  10. Becker-Herman S, Meyer-Bahlburg A, Schwartz M, Jackson S, Hudkins K, Chaohong L, Sather B, Socheath K, Liggitt D, Song W, Silverman G, Alpers C, Rawlings DJ. WASp Deficient B Cells Play a Critical, Cell Intrinsic Role in Triggering Autoimmunity. (2011) J Exp Med. 208(10): 2033-42. PMCID: PMC3182055
  11. Jackson S, Jacobs HM, Arkatkar T, Dam E, Scharping NE, Kolhatkar NS, Hou B, Buckner J, Rawlings DJ. B cell IFN-γ receptor signaling promotes autoimmune germinal centers via cell-intrinsic induction of BCL-6. (2016) J Exp Med. 213(5): 733-50. PMCID: PMC4854732
  12. Gorman JA, Hundhausen C, Kingman M, Arkatkar T, Allenspach EJ, Clough C, West SE, Thomas K, Eken A, Khim S, Hale M, Oukka M, Jackson S, Cerosaletti K, Buckner JH, Rawlings DJ. The TYK2-P1104A autoimmune protective variant limits coordinate signals required to generate specialized T cell subsets. (2018) Frontiers of Immunology, 10, 44.
  13. Kerns HM, Ryu BY, Stirling BV, Sather BD, Astrakhan A, Humblet-Baron S, Liggitt D, and Rawlings DJ. B- cell–specific lentiviral gene therapy leads to sustained B-cell functional recovery in a murine model of X-linked agammaglobulinemia. (2010) Blood, 115(11):2146-2155. PMCID: PMC2844021
  14. Astrakhan A, Sather BD, Ryu BY, Khim S, Singh S, Humblet-Baron, Ochs HD, Miao CH, Rawlings DJ. Ubiquitous high-level gene expression in hematopoietic lineages provides effective lentiviral gene therapy of murine Wiskott-Aldrich Syndrome. (2012) Blood. 119(19):4395-407. PMCID: PMC3362358
  15. Singh S, Khan I, Khim S, Seymour B, Sommer K, Wielgosz M, Norgaard Z, Kiem HP, Adair J, Liggitt D, Nienhuis A, Rawlings DJ. (2017). Safe and Effective Gene Therapy for Murine Wiskott-Aldrich Syndrome Using an Insulated Lentiviral Vector. Mol Ther Meth & Clin Dev, 4:1-16. PMCID: PMC5363182
  16. Wang CX, Sather BD, Wang X, Adair J, Khan I, Singh S, Lang S, Adams A, Curinga G, Kiem HP, Miao CH, Rawlings DJ*, Torbett BE*. Rapamycin Relieves Lentiviral Vector Transduction Resistance in Human and Mouse Hematopoietic Stem Cells. (2014) Blood. 124(6):913-23. PMCID: PMC4126331 *co-corresponding author
  17. Certo MT, Ryu BY, Annis JE, Garibov M, Jarjour J, Rawlings DJ*, Scharenberg AM. Tracking genome engineering outcome at individual DNA breakpoints. (2011) Nat Methods. 8(8):671-6. *co-corresponding author. PMCID: PMC3415300
  18. Sather BD, Romano Ibarra GS, Sommer K, Curinga G, Hale M, Khan IF, Singh S, Song Y, Gwiazda K, Sahni J, Jarjour J, Astrakhan A, Wagner TA, Scharenberg AM, Rawlings DJ. Efficient Modification of CCR5 in Primary Human Hematopoietic Cells using a megaTAL Nuclease and AAV Donor Template. (2015) Sci Trans Med. 7(307) ra156. PMCID: PMC4790757
  19. Hubbard N, Hagin D, Sommer K, Song Y, Khan I, Clough C, Ochs HD, Rawlings DJ*, Scharenberg AM, Torgerson TR. Targeted Gene Editing Restores Regulated CD40L Expression and Function in X-HIGM T Cells. *co-corresponding author. (2016) Blood. 127(21):2513-522. PMID: 26903548
  20. Hung K, Meitlis I, Hale M, Chen CY, Singh S, Jackson SW, Miao CH, Khan IF, Rawlings DJ*, James RG. Engineering protein-secreting plasma cells by homology-directed repair in primary human B cells. *co-corresponding author. (2017) Mol Ther. 26(2):456-67. PMCID: PMC5835153