Profile

David J. Rawlings, MD

On staff since October 2001

Children's Title: Division Chief, Immunology; Director, Center for Immunity and Immunotherapies

Research Center: Center for Immunity and Immunotherapies

"As a parent and a physician, I am continually amazed by the capacity of our patients and their families to adapt to the challenges of living with a chronic immune-system disease. As a physician-scientist, I am driven by the challenge to make this battle less difficult by whatever means possible — now and in the future. And as a graying athlete, I see medical care as the ultimate team sport. Each day, I do my best to build and lead stronger teams — teams that more quickly identify a diagnosis and the impact of immune disease and, most importantly, teams that build better and safer treatments and cures for these conditions."

David J. Rawlings, MD, is chief in the Division of Immunology, overseeing the immunodeficiency clinic at Seattle Children’s Hospital. He is also director of the Center for Immunity and Immunotherapies leading the immunology research programs at Seattle Children’s Research Institute. Dr. Rawlings is professor of pediatrics and adjunct professor in the Department of Immunology at the University of Washington School of Medicine.

He earned his MD with honors from the University of North Carolina School of Medicine and completed a residency and chief residency in pediatrics at the University of California, San Francisco. He was an intramural research fellow at the NIH and a senior fellow at the Howard Hughes Medical Institute, UCLA. He completed specialty training in pediatric rheumatology and immunology at Children’s Hospital Los Angeles and directed the pediatric rheumatology program at UCLA. Dr. Rawlings has been the recipient of many awards including election to the American Society for Clinical Investigation, Association of American Physicians, and the Children’s Hospital Guild Association Endowed Chair in Pediatric Immunology Research. Dr. Rawlings also co-directs the Northwest Genome Engineering Consortium, a research program funded as part of the NIH Roadmap for Medical Research and focused on developing enzymatic reagents and delivery methods for site specific gene repair in hematopoietic stem cells. His publications include more than 90 peer-reviewed papers and many invited reviews. His primary research interests include dysregulated B cell development and signaling leading to immunodeficiency, autoimmunity or lymphoid malignancies, and the development of gene therapy for primary immune deficiency diseases. His laboratory uses expertise in basic and clinical immunology, signal transduction and lymphocyte developmental biology to understand how altered signals can lead to immunologic disease, with the ultimate goal of developing translational therapies capable of specifically modulating these disorders. He is also actively involved in collaborative studies with the bone marrow transplant team to design and test of new protocols for stem cell transplant in non-malignant disorders. Dr. Rawlings is a member of multiple regional and national organizations, an NIH study section member, and ad hoc reviewer for various grant programs and immunology journals.

Making a Difference

Improving Tools for Gene Repair
Innovations in enzyme development move researchers in Seattle closer to making precision gene manipulation a therapeutic reality.
... cont.

A Thriving Biomedical Community

Partnering with UW and the Hutchinson Center for world-class science.... cont.

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Overview
Awards and Honors
Publications
Presentations

Overview

Board Certification(s): Pediatric Rheumatology
Medical/Professional School: University of North Carolina at Chapel Hill School of Medicine, Chapel Hill
Residency: Pediatrics, University of California - San Francisco, San Francisco
Pediatrics, University of California - San Francisco, San Francisco
Fellowship: Pediatric Rheumatology, Children's Hospital of Los Angeles - Pediatric Residency, Los Angeles
Infectious Disease, National Institute of Health, Rockville
UCLA School of Medicine, Los Angeles
Research Description: My primary research interests include altered lymphoid B cell development and signaling leading to immunodeficiency, autoimmunity or lymphoid malignancies, and the development of gene therapy for primary immune deficiency diseases. My laboratory uses expertise in basic and clinical immunology, signal transduction and lymphocyte developmental biology to understand how altered signals can lead to immunologic disease, with the ultimate goal of developing translational therapies capable of specifically modulating these disorders.

I am a member of multiple regional and national organizations, an NIH study section member, chairman for the USIDNET XLA patient registry, and ad hoc reviewer for various grant programs and immunology journals. I also co-direct the Northwest Genome Engineering Consortium, a research program funded as part of the NIH Roadmap focused on developing enzymatic reagents and delivery methods for site specific gene repair in hematopoietic stem cells. Northwest Genome Engineering Consortium (NGEC), http://research.seattlechildrens.org/ngec.

The Immunology research laboratories carry out basic, pre-clinical and clinical research. Primary immunodeficiency disorders (PIDD) represent some of the best candidate disorders for treatment via hematopoietic stem cell gene therapy, and our translational research programs include modeling of novel gene and cellular therapies. Our clinical program also participates in novel clinical trials for non myeloablative hematopoietic stem cell transplant in PIDD.
Lab URL: http://depts.washington.edu/immunweb/faculty/profiles/rawlings.html
Research Focus Area: Immunology

Awards and Honors

Award Name	Award Description	Awarded By	Award Date
Ellis Dresner Reserach Award		Southern California Rheumatology Society	1993
Merle Carson Research Award		Southwestern Pediatric Society	1992

Publications

Heterozygous signal transducer and activator of transcription 3 mutations in hyper-IgE syndrome result in altered B-cell maturation.
The Journal of allergy and clinical immunology , 2011 Oct 24

WASp-deficient B cells play a critical, cell-intrinsic role in triggering autoimmunity.
The Journal of experimental medicine , 2011 Sep 26: 2033-42

Daedalus: a robust, turnkey platform for rapid production of decigram quantities of active recombinant proteins in human cell lines using novel lentiviral vectors.
Nucleic acids research , 2011 Sep 12

Tracking genome engineering outcome at individual DNA breakpoints.
Nature methods , 2011 Jul 10: 671-6

Development of B-lineage predominant lentiviral vectors for use in genetic therapies for B cell disorders.
Molecular therapy : the journal of the American Society of Gene Therapy , 2011 Mar: 515-25

Successful targeting and disruption of an integrated reporter lentivirus using the engineered homing endonuclease Y2 I-AniI.
PloS one , 2011 Feb 9: e16825

Stable hematopoietic cell engraftment after low-intensity nonmyeloablative conditioning in patients with immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome.
The Journal of allergy and clinical immunology , 2010 Nov: 1000-5

G alpha q-containing G proteins regulate B cell selection and survival and are required to prevent B cell-dependent autoimmunity.
The Journal of experimental medicine , 2010 Aug 2: 1775-89

Galphaq-containing G proteins regulate B cell selection and survival and are required to prevent B cell-dependent autoimmunity.
The Journal of experimental medicine , 2010 Aug 2: 1775-89

B cell-specific lentiviral gene therapy leads to sustained B-cell functional recovery in a murine model of X-linked agammaglobulinemia.
Blood , 2010 Mar 18: 2146-55

MAGUK-controlled ubiquitination of CARMA1 modulates lymphocyte NF-kappaB activity.
Molecular and cellular biology , 2010 Feb: 922-34

CD19(+)CD24(hi)CD38(hi) B cells exhibit regulatory capacity in healthy individuals but are functionally impaired in systemic Lupus Erythematosus patients.
Immunity , 2010 Jan 29: 129-40

Serine 649 phosphorylation within the protein kinase C-regulated domain down-regulates CARMA1 activity in lymphocytes.
Journal of immunology (Baltimore, Md. : 1950) , 2009 Dec 1: 7362-70

Improving cellular therapy for primary immune deficiency diseases: recognition, diagnosis, and management.
The Journal of allergy and clinical immunology , 2009 Dec: 1152-60.e12

Serine 649 phosphorylation within the protein kinase C-regulated domain down-regulates CARMA1 activity in lymphocytes.
Journal of immunology (Baltimore, Md. : 1950) , 2009 Dec 1: 7362-70

Improving cellular therapy for primary immune deficiency diseases: recognition, diagnosis, and management.
The Journal of allergy and clinical immunology , 2009 Dec: 1152-60.e12

Anti-CD3 antibodies modulate anti-factor VIII immune responses in hemophilia A mice after factor VIII plasmid-mediated gene therapy.
Blood , 2009 Nov 12: 4373-82

CD4+FOXP3+ regulatory T cells confer long-term regulation of factor VIII-specific immune responses in plasmid-mediated gene therapy-treated hemophilia mice.
Blood , 2009 Nov 5: 4034-44

Antiplatelet antibodies in WASP(-) mice correlate with evidence of increased in vivo platelet consumption.
Experimental hematology , 2009 Nov: 1353-63

Wiskott-Aldrich syndrome protein is required for homeostasis and function of invariant NKT cells.
Journal of immunology (Baltimore, Md. : 1950) , 2009 Jun 15: 7370-80

Bruton's tyrosine kinase revealed as a negative regulator of Wnt-beta-catenin signaling.
Science signaling , 2009 May 26: ra25

Reduced c-myc expression levels limit follicular mature B cell cycling in response to TLR signals.
Journal of immunology (Baltimore, Md. : 1950) , 2009 Apr 1: 4065-75

Transitional B cells exhibit a B cell receptor-specific nuclear defect in gene transcription.
Journal of immunology (Baltimore, Md. : 1950) , 2009 Mar 1: 2868-78

Immunologic reconstitution during PEG-ADA therapy in an unusual mosaic ADA deficient patient.
Clinical immunology (Orlando, Fla.) , 2009 Feb: 162-74

Imatinib suppresses cryoglobulinemia and secondary membranoproliferative glomerulonephritis.
Journal of the American Society of Nephrology : JASN , 2009 Jan: 68-77

Resident enteric microbiota and CD8+ T cells shape the abundance of marginal zone B cells.
European journal of immunology , 2008 Dec: 3411-25

Wiskott-Aldrich syndrome protein deficiency in B cells results in impaired peripheral homeostasis.
Blood , 2008 Nov 15: 4158-69

Transient blockade of the inducible costimulator pathway generates long-term tolerance to factor VIII after nonviral gene transfer into hemophilia A mice.
Blood , 2008 Sep 1: 1662-72

An exemplum of XLA.
Clinical immunology (Orlando, Fla.) , 2008 Feb: 137-9

B cell autonomous TLR signaling and autoimmunity.
Autoimmunity reviews , 2008 Feb: 313-6

An exemplum of XLA.
Clinical immunology (Orlando, Fla.) , 2008 Feb: 137-9

B cell autonomous TLR signaling and autoimmunity.
Autoimmunity reviews , 2008 Feb: 313-6

Characterization of a late transitional B cell population highly sensitive to BAFF-mediated homeostatic proliferation.
The Journal of experimental medicine , 2008 Jan 21: 155-68

B cell intrinsic TLR signals amplify but are not required for humoral immunity.
The Journal of experimental medicine , 2007 Dec 24: 3095-101

Myc stimulates B lymphocyte differentiation and amplifies calcium signaling.
The Journal of cell biology , 2007 Nov 19: 717-31

Calcium signalling and cell-fate choice in B cells.
Nature reviews. Immunology , 2007 Oct: 778-89

Novel suppressive function of transitional 2 B cells in experimental arthritis.
Journal of immunology (Baltimore, Md. : 1950) , 2007 Jun 15: 7868-78

Local increase in thymic stromal lymphopoietin induces systemic alterations in B cell development.
Nature immunology , 2007 May: 522-31

Wiskott-Aldrich syndrome protein is required for regulatory T cell homeostasis.
The Journal of clinical investigation , 2007 Feb: 407-18

The CARMA1 signalosome links the signalling machinery of adaptive and innate immunity in lymphocytes.
Nature reviews. Immunology , 2006 Nov: 799-812

Mutifactorial analysis of risk factors for reduced bone mineral density in patients with Crohn's disease.
World journal of gastroenterology : WJG , 2006 Sep 21: 5680-6

Immunomodulation of transgene responses following naked DNA transfer of human factor VIII into hemophilia A mice.
Blood , 2006 Jul 1: 19-27

HS1 functions as an essential actin-regulatory adaptor protein at the immune synapse.
Immunity , 2006 Jun: 741-52

Proximal signals controlling B-cell antigen receptor (BCR) mediated NF-kappaB activation.
Advances in experimental medicine and biology , 2006: : 89-106

The biology and biochemistry of inflammatory signalosomes. Meeting on signaling networks in immunity and inflammation.
EMBO reports , 2006 Jan: 25-30

Proximal signals controlling B-cell antigen receptor (BCR) mediated NF-kappaB activation.
Advances in experimental medicine and biology , 2006: 89-106

Low bone mineral density measurements in care home residents--a treatable cause of fractures.
Age and ageing , 2006 Jan: 37-41

The biology and biochemistry of inflammatory signalosomes. Meeting on signaling networks in immunity and inflammation.
EMBO reports , 2006 Jan: 25-30

Phosphorylation of the CARMA1 linker controls NF-kappaB activation.
Immunity , 2005 Dec: 561-74

Lifecourse study of bone health at age 49-51 years: the Newcastle thousand families cohort study.
Journal of epidemiology and community health , 2005 Jun: 475-80

Bruton's tyrosine kinase regulates immunoglobulin promoter activation in association with the transcription factor Bright.
Molecular and cellular biology , 2005 Mar: 2073-84

CD38 signaling regulates B lymphocyte activation via a phospholipase C (PLC)-gamma 2-independent, protein kinase C, phosphatidylcholine-PLC, and phospholipase D-dependent signaling cascade.
Journal of immunology (Baltimore, Md. : 1950) , 2005 Mar 1: 2687-95

Bruton's tyrosine kinase regulates immunoglobulin promoter activation in association with the transcription factor Bright.
Molecular and cellular biology , 2005 Mar: 2073-84

TSLP (Thymic stromal lymphopoietin)
Enclyclopedia of Hormones , 2005

B-Cell Development
Hematology: Basic Principles and Practice , 2005: 119-133

Integration with the human genome of peptide sequences obtained by high-throughput mass spectrometry.
Genome biology , 2005: R9

Protein kinase C betaII regulates Akt phosphorylation on Ser-473 in a cell type- and stimulus-specific fashion.
The Journal of biological chemistry , 2004 Nov 12: 47720-5

ATM protein purified from vaccinia virus expression system: DNA binding requirements for kinase activation.
Biochemical and biophysical research communications , 2004 Sep 10: 74-81

Tec kinases mediate sustained calcium influx via site-specific tyrosine phosphorylation of the phospholipase Cgamma Src homology 2-Src homology 3 linker.
The Journal of biological chemistry , 2004 Sep 3: 37651-61

Sustained correction of B-cell development and function in a murine model of X-linked agammaglobulinemia (XLA) using retroviral-mediated gene transfer.
Blood , 2004 Sep 1: 1281-90

Naked DNA transfer of Factor VIII induced transgene-specific, species-independent immune response in hemophilia A mice.
Molecular therapy : the journal of the American Society of Gene Therapy , 2004 Jul: 117-26

Protein kinase C family functions in B-cell activation.
Current opinion in immunology , 2004 Jun: 367-73

Signaling in transitional type 2 B cells is critical for peripheral B-cell development.
Immunological reviews , 2004 Feb: 161-78

Predominant Antibody Deficiencies: X-linked Agammaglobulinemia
Immunologic Disorders of Infants and Children , 2004: 357-373

Signaling in transitional type 2 B cells is critical for peripheral B-cell development.
Immunological reviews , 2004 Feb: 161-78

BTK regulates PtdIns-4,5-P2 synthesis: importance for calcium signaling and PI3K activity.
Immunity , 2003 Nov: 669-78

A Ras activation pathway dependent on Syk phosphorylation of protein kinase C.
Proceedings of the National Academy of Sciences of the United States of America , 2003 Aug 5: 9470-5

B cell developmental requirement for the G alpha i2 gene.
Journal of immunology (Baltimore, Md. : 1950) , 2003 Feb 15: 1707-15

Dysregulated TCL1 promotes multiple classes of mature B cell lymphoma.
Proceedings of the National Academy of Sciences of the United States of America , 2002 Oct 29: 14392-7

SHP-1 regulates Fcgamma receptor-mediated phagocytosis and the activation of RAC.
Blood , Sept. 2002: : 1852-9

SHP-1 regulates Fcgamma receptor-mediated phagocytosis and the activation of RAC.
Blood , 2002 Sep 1: 1852-9

PKC-beta controls I kappa B kinase lipid raft recruitment and activation in response to BCR signaling.
Nature immunology , 2002 Aug: 780-6

Emerging roles for PKC isoforms in immune cell function.
Molecular interventions , 2002 Jun: 141-4

Transitional B lymphocyte subsets operate as distinct checkpoints in murine splenic B cell development.
Journal of immunology (Baltimore, Md. : 1950) , 2002 Mar 1: 2101-10

PKCbeta modulates antigen receptor signaling via regulation of Btk membrane localization.
The EMBO journal , 2001 Oct 15: 5692-702

TCL1 oncogene expression in B cell subsets from lymphoid hyperplasia and distinct classes of B cell lymphoma.
Laboratory investigation; a journal of technical methods and pathology , 2001 Apr: 555-64

Unrelated umbilical cord stem cell transplantation for X-linked immunodeficiencies.
The Journal of pediatrics , 2001 Apr: 570-3

Primary angiitis of the central nervous system in children: 5 cases.
The Journal of rheumatology , 2001 Mar: 616-23

Redundant and opposing functions of two tyrosine kinases, Btk and Lyn, in mast cell activation.
Journal of immunology (Baltimore, Md. : 1950) , 2000 Aug 1: 1210-9

Engagement of the human pre-B cell receptor generates a lipid raft-dependent calcium signaling complex.
Immunity , 2000 Aug: 243-53

Hydroxychloroquine inhibits calcium signals in T cells: a new mechanism to explain its immunomodulatory properties.
Blood , 2000 Jun 1: 3460-6

Aberrant B cell receptor signaling from B29 (Igbeta, CD79b) gene mutations of chronic lymphocytic leukemia B cells.
Proceedings of the National Academy of Sciences of the United States of America , 2000 May 9: 5504-9

Bruton's tyrosine kinase controls a sustained calcium signal essential for B lineage development and function.
Clinical immunology (Orlando, Fla.) , 1999 Jun: 243-53

In situ detection of activated Bruton's tyrosine kinase in the Ig signaling complex by phosphopeptide-specific monoclonal antibodies.
Proceedings of the National Academy of Sciences of the United States of America , 1999 Mar 2: 2221-6

In vitro reconstitution of human B-cell ontogeny: from CD34(+) multipotent progenitors to Ig-secreting cells.
Blood , 1998 Dec 15: 4509-20

DSHP: a "power bar" for sustained immune responses?
Proceedings of the National Academy of Sciences of the United States of America , 1998 Nov 10: 13355-7

Btk/Tec kinases regulate sustained increases in intracellular Ca2+ following B-cell receptor activation.
The EMBO journal , 1998 Apr 1: 1973-85

Preliminary evidence for cyclosporin A as an alternative in the treatment of recalcitrant juvenile rheumatoid arthritis and juvenile dermatomyositis.
The Journal of rheumatology , 1997 Dec: 2436-43

Phosphorylation of two regulatory tyrosine residues in the activation of Bruton's tyrosine kinase via alternative receptors.
Proceedings of the National Academy of Sciences of the United States of America , 1997 Oct 14: 11526-33

Constitutive membrane association potentiates activation of Bruton tyrosine kinase.
Oncogene , 1997 Sep 18: 1375-83

Differentiation of human CD34+CD38- cord blood stem cells into B cell progenitors in vitro.
Experimental hematology , 1997 Jan: 66-72

Regulation of Btk by Src family tyrosine kinases.
Molecular and cellular biology , 1996 Jul: 3465-71

Regulation of Btk function by a major autophosphorylation site within the SH3 domain.
Immunity , 1996 May: 515-25

Activation of BTK by a phosphorylation mechanism initiated by SRC family kinases.
Science (New York, N.Y.) , 1996 Feb 9: 822-5

Impaired expansion of mouse B cell progenitors lacking Btk.
Immunity , 1995 Sep: 301-12

The Btk subfamily of cytoplasmic tyrosine kinases: structure, regulation and function.
Seminars in immunology , 1995 Aug: 237-46

Long-term culture system for selective growth of human B-cell progenitors.
Proceedings of the National Academy of Sciences of the United States of America , 1995 Feb 28: 1570-4

Development of btk transgenic mice.
Current topics in microbiology and immunology , 1995: 363-70

A novel glucose-6-phosphate dehydrogenase in Plasmodium falciparum: cDNA and primary protein structure.
Biochimica et biophysica acta , 1994 Sep 13: 191-4

Deletion within the Src homology domain 3 of Bruton's tyrosine kinase resulting in X-linked agammaglobulinemia (XLA).
The Journal of experimental medicine , 1994 Aug 1: 461-70

Role of Bruton's tyrosine kinase in immunodeficiency.
Current opinion in immunology , 1994 Aug: 623-30

Brief report: a point mutation in the SH2 domain of Bruton's tyrosine kinase in atypical X-linked agammaglobulinemia.
The New England journal of medicine , 1994 May 26: 1488-91

Bruton's tyrosine kinase is a key regulator in B-cell development.
Immunological reviews , 1994 Apr: 105-19

Prolonged course of illness in a child with malignant lymphoma mimicking sarcoidosis.
The Journal of rheumatology , 1993 Sep: 1583-7

Mutation of unique region of Bruton's tyrosine kinase in immunodeficient XID mice.
Science (New York, N.Y.) , 1993 Jul 16: 358-61

Deficient expression of a B cell cytoplasmic tyrosine kinase in human X-linked agammaglobulinemia.
Cell , 1993 Jan 29: 279-90

Introducing restriction sites into double-stranded plasmid DNA.
Methods in enzymology , 1993: 295-301

Common Variable Immune Deficiency Overview
, 1993

Alpha-tubulin II is a male-specific protein in Plasmodium falciparum.
Molecular and biochemical parasitology , 1992 Dec: 239-50

Adjuvant-dependent immune response to malarial transmission-blocking vaccine candidate antigens.
The Journal of experimental medicine , 1992 Nov 1: 1483-7

A novel 40-kDa membrane-associated EF-hand calcium-binding protein in Plasmodium falciparum.
The Journal of biological chemistry , 1992 Feb 25: 3976-82

Rapid method for introducing restriction sites into double stranded plasmid DNA.
Nucleic acids research , 1989 Dec 11: 10135

Immunologic Basics of Hematology Part 2: B-Cell Immunity
Hematology: Basic Principles and Practice. 5th Edition ,

Presentations

Presentations Title	Event	Location	Date
B Cell homeostatis and activiation	53. IUIS Expert Meeting on Primary Immunodeficiencies	Dublin, Ireland	June 3, 2009
Improving Cellular Therapy for Primary Immune Deficiency Diseases - Recognition, Diagnosis and Management	NIH Workshop	Bethesda, MD	May 20, 2009

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David J. Rawlings, MD

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