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.
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 directs the Seattle Children’s Program for Cell and Gene Therapy, 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:
- 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.
- 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.
- 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
See Complete List of Published Work in My Bibliography
- Whaley RE, Ameny S, Arkatkar T, Seese A, Wall A, Khan I, Carter JJ, Scherer EM, Rawlings DJ, Galloway DA, McElrath JM, Cohen KW, McGuire AT. Generation of a cost-effective cell line for support of high-throughput isolation of primary human B cells and monoclonal neutralizing antibodies. J Immunol Methods. 2021 Jan;488:112901. doi: 10.1016/j.jim.2020.112901. PMCID: PMC7560121.
- Rodda LB, Netland J, Shehata L, Pruner KB, Morawski PA, Thouvenel CD, Takehara KK, Eggenberger J, Hemann EA, Waterman HR, Fahning ML, Chen Y, Hale M, Rathe J, Stokes C, Wrenn S, Fiala B, Carter L, Hamerman JA, King NP, Gale Jr M, Campbell DJ, Rawlings DJ, Pepper M. Functional SARS-CoV-2-Specific Immune Memory Persists after Mild COVID-19. Cell. 2021 Jan 7;184(1):169-183. doi: 10.1016/j.cell.2020.11.029. PMCID: PMC7682481.
- O’Donoghue GP, Bugaj LJ, Anderson W, Daniels KG, Rawlings DJ, Lim WA. T cells selectively filter oscillatory signals on the minutes timescale. Proc Natl Acad Sci U S A. 2021 Mar 2;118(9):e2019285118. doi: 10.1073/pnas.2019285118. PMCID: PMC7936380.
- Seymour BJ, Singh S, Kerns HM, Sommer K, Sather BD, Khim S, Clough C, Hale M, Pangello J, Ryu BY, Khan IF, Adair JE, Rawlings DJ. Effective, safe, and sustained correction of murine XLA using a UCOE-BTK promoter-based lentiviral vector. Mol Ther Methods Clin Dev. 2021 Jan 20;20:635-651. doi: 10.1016/j.omtm.2021.01.007. PMCID: PMC7907679.
- Thouvenel CD, Fontana MF, Netland J, Krishnamurty AT, Takehara KK, Chen Y, Singh S, Miura K, Keitany GJ, Lynch EM, Portugal S, Miranda MC, King NP, Kollman JM, Crompton PD, Long CA, Pancera M, Rawlings DJ*, Pepper M (*co-corresponding author). Multimeric antibodies from antigen-specific human IgM+ memory B cells restrict Plasmodium parasites. J Exp Med. 2021 Apr 5;218(4):e20200942. doi: 10.1084/jem.20200942. PMCID: PMC7938364.
- Allenspach EJ, Soveg F, Finn LS, So L, Gorman JA, Rosen ABI, Skoda-Smith S, Wheeler MM, Barrow KA, Rich LM, Debley JS, Bamshad MJ, Nickerson DA, Savan R, Torgerson TR, Rawlings DJ. Germline SAMD9L truncation variants trigger global translational repression. J Exp Med. 2021 May 3;218(5):e20201195. doi: 10.1084/jem.20201195. PMCID: PMC7970252.
- Jacobs HM, Arkatkar T, Du SW, Scharping NE, Woods J, Li QZ, Hudkins KL, Alpers CE, Rawlings DJ, Jackson SW. TACI haploinsufficiency protects against BAFF-driven humoral autoimmunity in mice. Eur J Immunol. 2021 Jun 19. doi: 10.1002/eji.202149244. Epub ahead of print. PMID: 34146342.
- Thomas KR, Allenspach EJ, Camp ND, Wray-Dutra MN, Khim S, Zielinska-Kwiatkowska A, Timms AE, Loftus JP, Liggitt HD, Georgopoulos K, Tasian SK, James RG, Rawlings DJ. Activated interleukin-7 receptor signaling drives B-cell acute lymphoblastic leukemia in mice. Leukemia. 2021 Jun 30. doi: 10.1038/s41375-021-01326-x. Epub ahead of print. PMID: 34193976.
- Chiang K, Largent AD, Arkatkar T, Thouvenel CD, Du SW, Shumlak N, Woods J, Li QZ, Liu Y, Hou B, Rawlings DJ, Jackson SW. Cutting Edge: A Threshold of B Cell Costimulatory Signals Is Required for Spontaneous Germinal Center Formation in Autoimmunity. J Immunol. 2021 Sep 29:ji2100548. doi: 10.4049/jimmunol.2100548. Epub ahead of print. PMID: 34588220.
- Al Qureshah F, Sagadiev S, Thouvenel CD, Liu S, Hua Z, Hou B, Acharya M, James RG, Rawlings DJ. Activated PI3Kδ signals compromise plasma cell survival via limiting autophagy and increasing ER stress. J Exp Med. 2021 Dec 6;218(12):e20211035. doi: 10.1084/jem.20211035. Epub 2021 Sep 29. PMID: 34586341.
