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Division of Rheumatology
1959 NE Pacific St
Health Science Bldg BB561
Campus Box 356428
Seattle, WA 98195

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Phone: 206-543-3414
 

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Research

Basic and Applied Research

 

Basic: Dr. Elkon | Dr. Hughes | Dr. Nelson | Dr. Peng | Dr. Simkin | Dr. Giltiay

Clinical & Translational: Dr. Dugowson | Dr. Gardner | Dr. Ng

Adjunct Faculty: Dr. Clark | Dr. Wener | Dr. Stetson

 

 

Research Labs

 


* Click to enlarge

 

Elkon Lab    |    Hughes Lab

 


 

Basic Research

 

Dr. Keith Elkon's research objective is to better define the molecular and genetic basis for autoimmune diseases such as lupus and arthritis. Current areas of investigation include the following:

 

Apoptosis and the Immune Response – Loss of tolerance leads to autoantibody production in systemic autoimmune disorders such as systemic lupus erythematosus (SLE). There is considerable evidence to support the concept that autoantibodies are generated in response to impaired clearance of dead and dying cells. Dr. Elkon's laboratory has identified novel pathways that involve opsonization of dying cells by serum factors (complement, CRP and natural antibodies) thereby promoting the phagocytosis of apoptotic cells. One hypothesis currently being explored is that deficiencies of these serum opsonins leads to delayed clearance of dying cells sequentially facilitating necrosis, an inflammatory response to self antigens and loss of tolerance. Current studies explore the how self antigens (e.g. nucleoprotein particles such as nucleosomes, spliceosomes and ribosomes) are processed and activate the innate immune system, especially plasmacytoid dendritic cells (pDCs) to induce IFN-a. In addition, the molecular signals whereby apoptotic cells turn off inflammatory cytokines such as IL-12 in DCs and anergize T cells under homeostatic conditions, are also being investigated.

 

Removal of inflammatory nucleoprotein complexes. A related line of investigation explores how the debris derived from apoptotic cells, nucleoprotein particles, can be rendered less immunogenic. The research involves the creation of transgenic mice expressing "cleanup: molecules as well as biologics that have nuclease activity and that can be administered exogenously.

 

Neuropsychiatric Lupus (NPSLE). The pathogenesis of NPSLE is poorly understood. This laboratory has had a longstanding interest in NPSLE. We are currently examining the role of type 1 interferons in the induction of certain clinical manifestations of NPSLE. Regulation of inflammation by serologic factors is also under investigation.

 

Recent Publications

 

Wiedeman A, Santer DM, Yan W, Miescher S, Kaisermann F, Elkon KB. Contrasting mechanisms of interferon-α inhibition by intravenous immunoglobulin after stimulation with immune complexes versus toll like receptor agonists. Arthritis Rheum, Jul 9. doi: 10.1002/art.38082. [Epub ahead of print], 2013. Commentary Arthritis Rheum, same issue and Nature Rev Rheum, September, 2013.

Giltiay NV, Chappell CP, Sun X, Kolhatkar N, Teal T, Wiedeman A, Kim J, Tanaka L, Buechler MB, Hamerman JA, Imanishi-Kari T, Clark EA, Elkon KB. Overexpression of TLR7 promotes cell-intrinsic expansion and autoantibody production by transitional T1 B cells. J Exp Med, in press, 2013.

Sun XZ, Wiedeman A, Agrawal N, Teal TH, Tanaka L, Hudkins KL, Alpers CE, Bolland S, Buechler M, Hamerman JA, Ledbetter JA, Liggitt D, Elkon KB. Increased RNase expression reduces inflammation and prolongs survival in TLR7 transgenic mice. J Immunol, 190:2536-2543, 2013.

Elkon KB, Wiedeman A. Type I IFN system in the development and manifestations of SLE. Current Opinion Rheumatol, 24:499-505, 2012.

Peng Y-F, Elkon KB. Autoimmunity in MFG-E8-deficient mice is associated with altered trafficking and enhanced cross-presentation of apoptotic cell antigens. J Clin Invest, 121:2221-2241, 2011.

Briggs TA, Rice GI, Daly S et al. Tartrate-resistant acid phosphatase deficiency causes a bone dysplasia with autoimmunity and a type I interferon expression signature. Nature Genetics, 43: 127-131, 2011.

Santer DM, Hall BE, George TC, Tangsombatvisit S, Liu CL, Arkwright PD, Elkon KB. C1q deficiency leads to the defective suppression of IFN-alpha in response to nucleoprotein containing immune complexes. J Immunol. 185:4738-49, 2010.Elkon KB, Rönnblom L. Cytokines as therapeutic targets in SLE. Nat Reviews Rheumatol, 2010.

Elkon, KB. News and Views. Autoimmunity: apoptotic fats grease transcription. Nature Medicine, 15:1246-8, 2009.

Peng YF, Latchman Y, Elkon KB. Monocytes differentiate into dendritic cells and cross-tolerize T cells through PDL-1, J Immunol, 182: 2777-2785, 2009.

Elkon KB. Cell Survival and Death in Rheumatic Diseases.. In: Kelley’s Textbook of Rheumatology. Ruddy S, Harris ED, Sledge CB, Budd RC, Sergent JS (eds). W.B. Saunders Company, Philadelphia, 8th edition, pp.379-396, 2009.

Santer DM, Yoshio T, Minota S, Möeller T, Elkon KB. Potent induction of interferon-a and chemokines by autoantibodies in the cerebrospinal fluid of patients with neuropsychiatric lupus. J Immunol, 182:1192-1201. 2009.

Okamoto A, Fujio K, van Rooijen N, Tsuno NH, Takahashi K, Tsurui H, Hirose S, Elkon KB, Yamamoto K. Splenic phagocytes promote responses to nucleosomes in (NZB x NZW) F1 mice. J Immunol, 181:5264-5271, 2008.

Duan H, Fleming J, Pritchard DK, Amon LM, Xue J, Arnett HA, Chen G, Breen P, Buckner JH, Molitor JA, Elkon KB, Schwartz S. Combined analysis of monocyte and lymphocyte mRNA expression with serum protein profiles in patients with scleroderma. Arthritis Rheum, 58:1465-1474, 2008.

Martin DM, Zhang K, Kenkel J, Hughes G, Clark E, Davidson A, Elkon KB. Autoimmunity stimulated by adoptively transferred dendritic cells is initiated by both a/b and g/d T-cells but does not require MyD88 signaling. J Immunol, 179: 5819-5828, 2007.

Martin, DA, Elkon, KB. Intracellular mammalian DNA stimulates myeloid dendritic cells to produce Type I interferons independently of MyD88 or TLR9. Arthritis Rheum, 54:951-962., 2006.

Martin, DA and Elkon, KB. 2005. Autoantibodies make a U-turn: the toll hypothesis for autoantibody specificity. J Exp Med 202:1465-1469, 2005.

 

 


 

Dr. Grant C. Hughes studies the relationship between female reproduction and lupus autoimmunity. The discovery of specific sex steroid receptors in immune cells has sparked renewed interest in understanding the interplay between reproduction and immunity. This area of investigation is particularly relevant to understanding the biology of systemic lupus erythematosus (SLE), a disease that most often strikes women of childbearing age. Dr. Hughes’s lab is now studying how estrogen and progesterone control pathways of inflammation and immunity important in SLE disease development and activity. Estrogen is believed to increase the risk of lupus in genetically susceptible women by favoring production of auto-antibodies. However, Dr. Hughes’s lab discovered that progesterone, another chief female reproductive hormone, suppresses interferon-alpha, an inflammatory mediator important to both the development of auto-antibodies and SLE disease activity. Moreover, progesterone may counteract estrogen’s tendency to worsen one of the most serious complications of SLE, lupus nephritis. Thus, the balance of estrogen vs. progesterone may influence SLE disease development and outcomes. The Hughes lab also is determining which receptors on immune cells are required for hormone effects and what controls their expression – an important step in predicting how natural and synthetic hormones could be manipulated to treat SLE patients.

 

Recent Publications

 

Hughes GC, Clark EA, Wong AH. The intracellular progesterone receptor regulates CD4+ T cells and T cell-dependent antibody responses. J Leukoc Biol. 2013 Mar;93(3):369-75. doi: 10.1189/ jlb.1012491.

Hughes GC. Progesterone and autoimmune disease. Autoimmun Rev. 2012 May;11(6-7): A502-14. Epub 2011 Dec 13.

Hughes GC, Martin D, Zhang K, Hudkins KL, Alpers CE, Clark EA, Elkon KB. Decrease in glomerulonephritis and Th1-associated autoantibody production after progesterone treatment in NZB/NZW mice. Arthritis Rheum. 2009 Jun;60(6):1775-84.

Hughes GC, Thomas S, Li C, Kaja M, Clark EA. Progesterone regulates interferon-alpha production by plasmacytoid dendritic cells. J Immunol 2008;180:2029-2033.

Martin DA, Zhang K, Kenkel J, Hughes G, Clark E, Davidson A, Elkon KB. Autoimmunity stimulated by adoptively transferred dendritic cells is initiated by both ab and gd T-cells but does not require MyD88 signaling. J Immunol 2007;179:5819-5828.

Hughes GC, Clark EA. Regulation of dendritic cells by female sex steroids: relevance to immunity and autoimmunity. Autoimmunity 2007;40:470-481.

Koh P, Hughes GC, Faulkner G, Keeble W, Bagby G. The Fanconi anemia group C gene product modulates apoptotic responses to tumor necrosis factor- and Fas ligand but does not suppress expression of receptors of the tumor necrosis factor receptor subfamily. Experimental Hematology 1999;27:1-8.

Rathbun R, Faulkner G, Ostroski M, Christianson T, Hughes GC, Jones G, Cahn R, Maziarz R, Royle G, Keeble W, Heinrich M, Grompe M, Tower A, Bagby G. Inactivation of the Fanconi anemia group C gene augments interferon-gamma-induced apoptotic responses in hematopoietic cells. Blood 1997;90:974-85.

 

 


 

Dr. J. Lee Nelson's research includes:

  1. Microchimerism (Mc) in health and autoimmune disease. Mc refers to harboring a small population of genetically disparate cells, usually acquired from maternal-fetal cell transfer during pregnancy. Maternal and fetal Mc are being investigated in the pathogenesis of selected autoimmune diseases with a primary focus on systemic sclerosis (SSc) and rheumatoid arthritis (RA). Prior work included studies of type 1 diabetes and neonatal and systemic lupus.
  2. Pregnancy in RA susceptibility and prognosis. Pregnancy and HLA alleles are being examined in RA and evaluated for correlation with susceptibility and long-term outcome in women with RA from a prospective population-based case-control study.
  3. Familial HLA-relationships in autoimmune disease risk. Familial HLA studies are being conducted and analyzed for patients with RA and SSc.
  4. Pregnancy-induced amelioration of RA. Studies are investigating the molecular mechanism(s) behind our prior observation that the pregnancy-induced amelioration of RA is associated with fetal-maternal disparity for HLA class II alleles.
  5. Fetal microchimerism in breast cancer. FMc is being investigated in protection from breast cancer.
  6. Donor DNA quantification in islet transplantation. A panel of HLA-sequence specific real-time quantitative PCR assays is being employed to quantify donor DNA and to assess the utility for predicting engraftment and early rejection.
  7. Immunological and immunogenetic investigations of preeclampsia. Maternal-fetal cell transfer, familial immunogenetic relationships and regulatory mechanisms are being investigated in pregnancies complicated by preeclampsia and normal pregnancies.

 

Recent Publications

 

Gammill, HG, Nelson JL. Naturally acquired microchimerism. Int J Dev Bio, 54:531-43, 2010. PMCID: In process.

Guthrie KA, Gammill HS, Madeleine MM, Dugowson CE, Nelson JL. Parity and HLA alleles in risk of rheumatoid arthritis. Chimerism. 2011 Jan;2(1):11-15.

Adams-Waldorf K, Gammill HS, Lucas J, Aydelotte TM, Leisenring W, Lambert NC, Nelson JL. Dynamic changes in fetal microchimerism in maternal peripheral blood mononuclear cells, CD4+ and CD8+ cells in normal pregnancy. Placenta, May 31, 2010. [Epub ahead of print.]

Radstake TRDJ, Gorlova O, Rueda B, Martin JE, Alizadeh B, Palomino-Morales R, Coenen M, Vonk M, Voskuyl A, Scheurweg A, Broen J, van Riel PLCM, Riemekasten G, Gay G, Gonzalez-Escribano M, Spanish Scleroderma Group, Gregersen P, Lee A, Wigley F, Hummers L, Nelson JL, Agarwal S, Assassi S, Gourh P, Tan F, Koeleman B, Arnett F, Martin J, Mayes M. Genome-wide association study in systemic sclerosis identifies novel susceptibility loci. Nature Genetics, Apr 11 2010. [Epub ahead of print].

Guthrie KA, Dugowson C, Voigt LF, Koepsell TD, Nelson JL. Does pregnancy provide vaccine-like protection against rheumatoid arthritis? Arthritis Rheum, Mar 22 2010. [Epub ahead of print.]

Nelson JL. Naturally acquired microchimerism: For better or for worse. Arthritis Rheum 60:5-7, 2009. PMCID: PMC2693961.

Stevens, AM, Hermes HM, Kiefer MM, Rutledge JC, Nelson JL. Chimeric Maternal cells with tissue-specific antigen expression and morphology are common in infant tissues. Pediatr Dev Pathol 12:337-46, 2009. PMCID: PMC2783488.

Adams KA, Nelson JL. Autoimmune disease during pregnancy and the microchimerism legacy of pregnancy. Immunol Invest 37:631-44, 2008. PMCID: PMC2709983.

Guthrie KG, Tishkevich NR, Nelson JL. Non-inherited maternal HLA alleles in susceptibility to familial rheumatoid arthritis. Ann Rheum Dis 68:107-9, 2009. PMCID: PMC2760537.

Nelson JL. Your cells are my cells. Scientific American 298:72-76, 2008. PMCID: PMC2693961.

Gadi VK, Malone KE, Guthrie KA, Porter PL. Nelson JL. Case-Control study of fetal microchimerism and breast Cancer. PLoS One 3:1706-10, 2008. PMCID: PMC2248618.

Nelson JL, Gillespie KM, Lambert NC, Stevens AM, Loubiere LS, Rutledge JC, Leisenring WM, Erickson TD, Yan Z, Mullarkey ME, Boespflug ND, Bingley PJ, Gale EAM. Maternal microchimerism in peripheral blood in type 1 diabetes and pancreatic islet  cell microchimerism. Proc Natl Acad Sci 104:1637-42, 2007.

Adams K, Yan Z, Stevens AM, Nelson JL. The changing maternal “self” hypothesis: A mechanism for maternal tolerance of the fetus. Placenta 28:378-82, 2007.

Yan Z, Ostensen M, Lambert NC, Guthrie KA, Nelson JL. Prospective study of cell-free fetal DNA and disease activity during pregnancy in women with inflammatory arthritis.

 

 


 

Dr. Yufeng Peng studies autoimmune diseases. Failure to clear apoptotic cell contributes to autoimmune diseases, such as SLE. However, the cellular and molecular defects caused the failure need to be defined. Mice deficient in MFG-E8 can not cleared in a timely fashion. His main interest is to examine how MFG-E8 deficiency affects both innate and adaptive immunity, including: monocyte/dendritic cell differentiation, cross-presentation of apoptotic cell to T cells and B cell response to apoptotic cell associated antigen.

 

Recent Publications

 

Becker L, Liu NC, Averill MM, Yuan W, Pamir N, Peng Y, Irwin AD, Fu X, Bornfeldt KE, Heinecke JW. Unique proteomic signatures distinguish macrophages and dendritic cells. PLoS One. 2012;7(3):e33297. Epub 2012 Mar 12.

Peng YF, Elkon KB. Autoimmunity in MFG-E8-deficient mice is associated with altered trafficking and enhanced cross-presentation of apoptotic cell antigens. J Clin Invest. 2011 Jun 1;121(6):2221-41. doi: 10.1172/JCI43254. Epub 2011 May 2.

Peng, YF, Latchman Y, Elkon KB. Ly6C low monocytes differentiate into dendritic cells and cross-tolerize T cells through PDL-1. J Immunol Mar 1, 182 (5) 2009: 2777-2785.

Peng YF, Elkon KB.Peripheral CD8 T-cell responses to apoptotic cell proteins and peptides. Crit Rev Immunol. 2007;27(4):357-65. Review.

Peng Y, Martin DA, Kenkel J, Zhang K, Ogden CA, Elkon KB.Innate and adaptive immune response to apoptotic cells. J Autoimmun. 2007 Dec;29(4):303-9.

Ogden CA, Kowalewski R, Peng Y, Montenegro V, Elkon KB. IGM is required for efficient complement mediated phagocytosis of apoptotic cells in vivo. Autoimmunity. 2005 Jun;38(4):259-64.

Peng Y, Kowalewski R, Kim S, Elkon KB. The role of IgM antibodies in the recognition and clearance of apoptotic cells. Mol Immunol. 2005 May;42(7):781-7. Epub 2005 Jan 16. Review.

Peng Y, Gorelik L, Laouar Y, Li MO, Flavell RA. TGFbeta-mediated immunoregulation. Ernst Schering Res Found Workshop. 2006;(56):155-60.

Peng Y, Laouar Y, Li MO, Green EA, Flavell RA. TGF-beta regulates in vivo expansion of Foxp3-expressing CD4+CD25+ regulatory T cells responsible for protection against diabetes. Proc Natl Acad Sci U S A. 2004 Mar 30;101(13):4572-7. Epub 2004 Mar 18.

 

 


 

Dr. Peter Simkin studies the pathophysiology and management of gouty arthritis as well as the structure and function of the synorium, cartilage and bone in healthy and diseased joints. He recognized, quantified, and explained striking structural differences in the bony architecture of convex and concave joint members. The concave side has a thick subchondral plate, is stiff, and is vulnerable to "blow out" fracture during impact loading. The convex side has a thin subchondral plate, is both flexible and hydraulically supported, and is vulnerable to avascular necrosis secondary to retrograde embolization by marrow fat. Another area of investigation involves use of a simple loading device to show that the interface between articular cartilage and underlying bone is consistently permeable to saline under hydrostatic pressures analagous to those experienced by normal joints in vivo. In contrast, larger molecules appear to be retained. This selectivity implies that  molecules released from apoptotic chondrocytes may form an extracellular deposit at the site of the semipermeable barrier. This mechanism is offered to explain the histologic feature known as the "tidemark" which lies between uncalcified and calcified cartilage. In susceptible, autoimmune individuals this deposit could provide the antigenic stimulus for invasion by inflammatory tissues - a plausible explanation for apparent tidemark-targeting by rheumatoid pannus.

 

Additional past and present interests have included: developing techniques to measure blood flow and lymphatic drainage in joints of people and animals, quantifying the dimensions as well as the number of microvascular pores in normal and inflamed human knees, developing a simpler technique for quantifying uric acid excretion, devising a systematic nomenclature for the microcrystaline arthritides, postulating a plausible mechanism for the gouty predilection for the base of the great toe, describing two new forms of urate crystals (spherulites and nonbirefringent needles) in gouty synovial fluids, devising a novel technique (tetracycline binding) for recognition of basic calcium phosphate crystals. Testing the possibility that an acquired zinc deficiency may lead to more active rheumatoid disease, describing a "simian stance" as the now classic sign of spinal stenosis, introducing continuous passive motion as a possible therapeutic measure for osteoarthritis of the hips and knees, taking advantage of the known depth of MRI images to measure the volume of dead bone in the femoral heads of patients with osteonecrosis, and suggesting that antigenicity of fibrillin (or a related protein) may underlie the tendency of ankylosing spondylitis to attack fibrocartilage from underlying bone.

 

Recent Publications

 

Simkin PA. Consider the Tidemark. J Rheumatol. 2012 May; 39(5): 890-2.

Simkin PA, Bassett JE. Pathways of Microvascular Permeability in the Synovium of Normal and Diseased Human Knees. J Rheumatol. 2011 Dec; 38(12): 2635-42. Epub 2011 Nov 1.

Mandell BF, Edwards NL, Pile JC, Simkin, PA, Sunday JS: Preventing and Treating Acute Gout Attacks Across the Clinical Spectrum: A Roundtable Discussion. Cleveland Clinic Journal of Medicine. 2010 Jun; 77(2): S2-S25.

Simkin, PA: Rethinking the physiology of articular cartilage. J Clin Rheum. 2009 Aug;15(5): 260-3.

Simkin PA: Pressure-driven intravasation of osseous fat. Pain in Osteoarthritis. Felson D, Schaible H (Ed), pp 175-183, 2009.

Simkin, PA: A biography of the chondrocyte. Ann Rheum Dis 2008; 67:1064-1068.

Rosenthal AR, Fahey M, Gohr G, Burner T, Konon I, Daft L, Mattson E, Hirschmugl C, Ryan LM, Simkin P: Feasibility of a tetracycline-binding method for detecting synovial fluid basic calcium phosphate crystals. Arthritis Rheum 58: 3270-3274. 2008.

Simkin PA, Gardner GC. Musculoskeletal System and Joint Physiology. In: Rheumatology. Hochberg M et al Ed, 4th Edition, London, Elsevier, pp 33-43, 2008.

Simkin PA: Fluid dynamics of the joint space and trafficking of matrix products. In: Dynamics of Bone and Cartilage Metabolism, 2nd ed. Seibel MJ, Robbins SP, & Bilezekian JP (eds). San Diego, Academic Press, pp 451-456, 2006.

Simkin PA: Physiologic Aspects of Urate Homeostasis. In: Cyrstal-Induced Arthropathies, R. Wortmann, H.R. Schumacher, Jr., M. Becker, L. Ryans (eds.), Taylor and Francis, pp 255-277, 2006.

 

 


 

Dr. Natalia Giltiay studies the role of B cell in immunopathology of autoimmune diseases. A hallmark of SLE, SjS, and other autoimmune diseases is the production of auto-antibodies (auto-Abs), directed against ubiquitous cellular components, such as DNA, RNA, and other nuclear antigens. Genetic data have supported a strong link between genetic variations of TLR7 and SLE susceptibility. Still, very little has been done to define how dysregulation of TLR7 expression might affect human B cells and contribute to the development of SLE. Current projects in the lab are focused on identifying new signaling mechanisms involved in the regulation of TLR7 expression, specifically in B cells. We are also exploring the effects of TLR7 over-expression in different B cell subsets in human and mice with respect to cell activation, auto-Ab production and cytokine production. We are currently testing how genetic variations of TLR7 affect B cells in SLE patients. 


In collaboration with Dr. Clark’s Lab, we are also studying the effects of Epratuzumab (Emab), a humanized anti-CD22 mAb currently in clinical trials for treatment of SLE, on B cell responses, in an effort to explain how Emab might function to suppress B cell activation in SLE.
Other areas of research have been focused on the role of plasmacytoid DCs (pDCs) in regulating T- and B- cell responses and how antigen-targeting to pDCs via pDC-specific C-type lectin receptor BDCA2, can be used to promote immune tolerance.

 

Recent Publications (12 of 22)

 

Chappell CP*, Giltiay NV*, Draves KE, Chen C, Hayden-Ledbetter MS, Shlomchik MJ, Kaplan DH, Clark EA. Antigen delivery to pDCs through hBDCA2 leads to reduction of effector T-cell activation and Ag-specific Ab responses. J Immunol. 2014 Jun 15; 192 (12):5789-801. (*equal contribution)

 

Chappell CP, Giltiay NV, Dresch C, Clark EA. Controlling immune responses by targeting antigens to dendritic cell subsets and B cells. Int Immunol. 2014 Jan; 26 (1):3-11.

 

Giltiay NV, Chappell CP, Sun X, Kolhatkar N, Teal TH, Kim J, Tanka L, Buechler MB, Hamerman JA, Imanishi-Kari T, Clark EA, Elkon KB. Overexpression of toll-like receptor 7 promotes cell-intrinsic expansion and autoantibody production by transitional T1 B cells, J Exp Med. 2013 Nov 18; 210 (12):2773-89.

 

Giltiay NV, Lu Y, Cullen JL, Jørgensen TN, Shlomchik MJ, Li X. Spontaneous loss of tolerance of autoreactive B cells in Act1-deficient rheumatoid factor transgenic mice. J Immunol. 2013. 191:2155-63.

 

Giltiay NV, Chappell CP, Clark EA. B-cell selection and the development of autoantibodies. Arthritis Res Ther. 2012;14 Suppl 4:S1

 

Chappell CP, Draves KE, Giltiay NV, Clark EA. Extrafollicular B cell activation by marginal zone dendritic cells drives T cell-dependent antibody responses. J Exp Med. 2012. 209:1825-40.

 

Johnson AC, Davison LM, Giltiay NV, Vareechon C, Li X, Jørgensen TN. Lack of T cells in Act1-deficient mice results in elevated IgM-specific autoantibodies but reduced lupus-like disease. Eur J Immunol. 2012. 42:1695-705.

 

Giltiay NV, Lu Y, Allman D, Jørgensen TN, Li X. The adaptor molecule Act1 regulates BAFF responsiveness and self-reactive B cell selection during transitional B cell maturation. J Immunol. 2010. 185:99-109.

 

Kang Z, Altuntas CZ, Gulen MF, Liu C, Giltiay N, Qin H, Liu L, Qian W, Ransohoff RM, Bergmann C, Stohlman S, Tuohy VK, Li X. Astrocyte-restricted ablation of IL-17-induced Act1-mediated signaling ameliorates autoimmune encephalomyelitis. Immunity. 2010. 32:414-25.

 

Liu C, Qian W, Qian Y, Giltiay NV, Lu Y, Swaidani S, Misra S, Deng L, Chen ZJ, Li X. Act1, a novel U-box E3 ubiquitin ligase for IL-17R-mediated signaling. Science Signaling. 2009. 2: ra 63.

 

Trine N. Jørgensen, Natalia V. Giltiay, Angela Johnson and Xiaoxia Li. The role of Act1 in the control of autoimmunity. Chapter 4 in The Epigenetics of Autoimmune Disease (Wiley Publishing Group, 2009), edited by Moncef Zouali.

 

Qian* Y, Giltiay* N, Xiao J, Wang Y, Tian J, Han S, Scott M, Carter R, Jorgensen TN, Li X. Deficiency of Act1, a critical modulator of B cell function, leads to development of Sjögren's Syndrome. (* equal contribution) Eur J Immunol. 2008. 38: 2219-28.

 


 

 

Clinical Research

 

Dr. Carin Dugowson's investigations focus on the epidemiology of musculoskeletal diseases.

 

 


 

Dr. Gregory Gardner's research interests include MRI evaluation of RA patients under treatment with biologic agents and teaching rheumatology to medical residents.

 

 

Translational Research


 

Dr. Bernard Ng has held several research grants in the past, the most recent was a grant for “Evaluating the Optimal Use of Traditional Disease-Modifying Drugs of Rheumatic Diseases (DMARDS) in the Biologic Era” which was funded by South Central VA Health Care Network Research Grants Program. Currently, Dr. Ng has two grants administered by SIBCR – one from DoD and the other is an investigator-initiated grant sponsored by Antares Pharma.


Dr. Ng has research interests pertaining to areas of health services research and his current research focuses on pharmacoepidemiology of anti-rheumatic agents. In addition, he is also interested in long term disease outcomes of various musculoskeletal diseases, in particular, gout and rheumatoid arthritis. Between 2009 and 2012, Dr. Ng has received Veteran Affair’s local and VISN grants to support his research which resulted in the publication of three original papers and the completion of a master thesis on this subject. 

 

Recent Publications

Ng SKB: Intravenous immunoglobulin infusion causing pseudohyponatremia. Lupus 8(6):488-90, 1999.

 

Ng B, Litin Sc: 49-year-old woman with acute abdominal pain and nausea. Mayo Clin Proc 76 (6):649-52, 2001

 

Ng B, U Specks, KP Offord, EL Matteson: A population based study of epidemiology and clinical features of Wegener’s granulamatosis since introduction of ANCA testing. J Clin Rheumatol 9(6):387-388, 2003.

 

Ng B, U Specks, KP Offord, EL Matteson: A population based study of epidemiology and clinical features of Wegener’s granulamatosis since introduction of anca testing. Revista Colombiana De Rheumatologia  10(3):213-217, 2003.

 

Yan Y, Phan L, Yang F, Talpaz M, Yang Y, Xiong Z, Ng B, Timchenko NA, Wu CJ, Ritz J, Wang H, Yang XF.  A novel mechanism of alternative promoter and splicing regulates the epitope generation of tumor antigen CML66-L.  J Immunol. 172(1): 651-60, 2004.

 

Ng B, F Yang, DP Huston, Y Yan, Y Yang, Z Xiong, LE Peterson, H Wang and XF Yang. Increseasd non-canonical splicing of autoantigen transcripts provides the structural basis for expression of untolerized epitopes. J Allergy Clin Immunol. 2004 Dec;114(6):1463-70

 

Yang Y, Xiong Z, Zhang S, Yan Y, Nguyen J, Ng B, Lu H, Brendese J, Yang F, Wang H, Yang XF. Bcl-xL inhibits T-cell apoptosis induced by expression of SARS coronavirus E protein in the absence of growth factors. Biochemical Journal 392(1), 135-143, Nov. 15, 2005

 

Garcia-Gonzalez A, Richardson M, Garcia Popa-Lisseanu M, Cox V, Kallen MA, Janssen N, Ng B, Marcus DM, Reveille JD, Suarez-Almazor ME. Treatment adherence in patients with rheumatoid arthritis and systemic lupus erythematosus. Clin Rheumatol. 2008 Jul;27(7):883-9.

 

Aslam F, Ng B. "You never asked doc., I do fish". Clin Rheumatol. 2010;29(6):691-3.

Gonzalez-Fuentes AM, Green DM, Rossen RD, Ng B. Intra-articular hyaluronic acid increases cartilage breakdown biomarker in patients with knee osteoarthritis. Clin Rheumatol. 2010;29(6):619-24.

 

B. Ng, Qurat Ul-Ain Kamili. Current Perspectives on Rheumatic Laboratory Tests. Federal Practitioner 28(4), 2011.

 


 

 

Adjunct Faculty Research

 

Dr. Edward Clark: A major goal of Dr. Clark's lab has been to define receptors and ligands regulating B cells and dendritic cells (DCs) and to help translate findings for use in clinical immunology. His lab helped discover and characterize human B cell/DC-associated surface molecules like CD20, CD22, CD40, CD80 (B7.1), CD150 (SLAM) and CD180 (RP105). Recently, the lab has focused on defining C-type lectin receptors (CLRs) on DCs including DCAL1, which binds to a ligand on CD4 T cells and promotes IL-4 production, and DCAL2, which is a useful marker to identify and isolate mouse DC subsets. In order to assess the function of CLRs and their possible use for vaccine development, Dr. Clark’s lab has coupled antigens (Ags) to monoclonal antibodies (mAbs) specific for CLRs expressed on DC subsets. The Ag-mAb conjugates are inoculated into mice as a kind of ‘antigen-delivery system’, which enables Ags to be selectively targeted to a particular DC subset, which then responses and programs an appropriate, protective immune response. Transgenic mice expressing human CLRs such as DCAL1 or BDCA2 have been made and are being used as preclinical vaccine models for assessing Ag-anti-human CLR conjugates in vivo.

 

B cells are very social cells; their behavior is influenced not only by T cells, but also by Ag presented in different forms including in association with DCs or macrophages. DCs and macrophages also produce cytokines like BAFF, which are essential for B cell survival and maturation. The Clark lab investigates how DCs regulate B cell responses. Current projects in this area include: 1) defining the role CD22 and other B cell/DC-associated receptors play in protective immune responses to West Nile virus; 2) characterizing how TLR7 regulates and dysregulates B cell development and antibody production; 3) defining how DCs program B cells to develop extrafollicular Ab responses or germinal centers and long-lived humoral immunity; 4) investigating how BAFF from different cell sources regulates B cell responses to Ag. You can find more information on his research at his Department of Immunology website.

 

Recent Publications

 

Hughes GC, Thomas S, Li C, Kaja MK, Clark EA. Progesterone regulates IFN-α production by plasmacytoid dendritic cells, J Immunol Cutting Edge, 180:2029-2033, 2008.

Hughes GC, Martin DA, Zhang K, Alpers CE, Clark EA, Elkon KB. Progesterone treatment of lupus-prone NZB/W mice decreases glomerulonephritis and TH1-associated autoantibody production, Arthritis Rheum 60:1775-1784, 2009.

Ma D, Clark EA. Role of CD40 and CD40L in dendritic cells, Seminars Immunol 21:265-272, 2009.
Suthar MS, Ma D, Thomas S, Daffis S, Lund J, Zhang N, Rudensky AY, Bevan MJ, Clark EA, Krisha-Kaja M, Diamond MS, Gale Jr M. IPS-1 is essential for the control of West Nile virus infection and immunity, PLos Pathogens, 6:e1000757, 2010.

Yurchenko MY, Kovalevska LM, Shlapatska LM, Berdova GG, Clark EA, Sidorenko SP. CD150 regulates JNK1/2 activation in normal and Hodgkin’s lymphoma B cells, Immunol Cell Biol, 88:565-74, 2010.

Yin L, Chino T, Horst OV, Hacker BM, Clark EA, Dale BA, Chung WO. Differential and coordinated expression of defensins and cytokines by gingival epithelial cells and dendritic cells in response to oral bacteria, BMC Immunology 11:37, 2010.

Giordano D, Li C, Suthar MS, Draves KE, Ma DY, Gale MG Jr, Clark EA. Role of nitric oxide in dendritic cell survival, cytokine production and induction of Th17 and Th1 T cell responses, J Leukocyte Biol, 89: 443-455, 2011.

Porakishvili N, Memon A, Vispute K, Kulikova N, Clark EA, Rai K, Nathwani A, Damle RN, Chiorazzi N, Lydyard PM. CD180 functions in activation, survival and cycling of B chronic lymphocytic leukaemia cells, Bri J Hematol 153:486-498, 2011.

Chaplin JW, Kasahara S, Clark EA, Ledbetter JA. Anti-CD180 (RP105) activates B cells to rapidly produce polyclonal Ig via a T cell and MyD88-independent pathway, J Immunol 187:4199-4209, 2011.

Richards SM, Li C, Draves KE, Niiro H, Dinauer MC, Clark EA. The adaptor protein Bam32 regulates G1 cycle progression downstream of B cell receptor signaling, Europ J Immunol, submitted, 2011.

Watanabe C, Shu GL, Clark EA. Caspase 6 regulates early B cell differentiation, Europ J Immunol, submitted 2011.

Kasahara S, Clark EA. Dendritic cell-associated lectin 2 (DCAL2) defines a distinct CD8α- dendritic cell subset, J Leukocyte Biol, 91:437-448, 2012.

 

 


 

Dr. Mark Wener studies antibodies that contribute to kidney disease in lupus and is involved in diagnostic testing for rheumatoid arthritis and other autoimmune disorders. You can find more information on his research at his Department of Laboratory Medicine website.

 

Recent Publications

 

Toriola AT, Cheng TY, Neuhouser ML, Wener MH, Zheng Y, Brown E, Miller JW, Song X, Beresford SA, Gunter MJ, Caudill MA, Ulrich CM. Biomarkers of inflammation are associated with colorectal cancer risk in women but are not suitable as early detection markers. Int J Cancer. 2012 Nov 15. doi: 10.1002/ijc.27942. [Epub ahead of print] PubMed PMID: 23161620. 

 

Imayama I, Ulrich CM, Alfano CM, Wang C, Xiao L, Wener MH, Campbell KL, Duggan C, Foster-Schubert KE, Kong A, Mason CE, Wang CY, Blackburn GL, Bain CE, Thompson HJ, McTiernan A. Effects of a caloric restriction weight loss diet and exercise on inflammatory biomarkers in overweight/obese postmenopausal women: a randomized controlled trial. Cancer Res. 2012 May 1;72(9):2314-26. PubMed PMID: 22549948; PubMed Central PMCID: PMC3342840. 

 

Wener MH. Multiplex, megaplex, index and complex: the present and future of laboratory diagnostics in rheumatology. Arthritis Res Ther. 2011 Nov 24;13(6):134. PubMed PMID: 22129036.

 

Williams L, Ulrich CM, Larson T, Wener MH, Wood B, Chen-Levy Z, Campbell PT, Potter J, McTiernan A, De Roos AJ. Fine Particulate Matter (PM2·5) Air Pollution and Immune Status Among Women in the Seattle Area. Arch Environ Occup Health. 2011 Jul-Sep;66(3):155-65. PubMed PMID: 21864104.

 

Dillon SR, Harder B, Lewis KB, Moore MD, Liu H, Bukowski TR, Hamacher NB, Lantry MM, Maurer M, Krejsa CM, Ellsworth JL, Pederson S, Elkon KB, Wener MH, Dall'era M, Gross JA. B-lymphocyte stimulator/a proliferation-inducing ligand heterotrimer's are elevated in the sera of patients with autoimmune disease and are neutralized by atacicept and B-cell maturation antigen-immunoglobulin. Arthritis Res Ther; 2010; 12(2):R48. PMID: 20302641.

 

 


 

Dr. Daniel Stetson focuses on mechanisms by which cells detect and respond to viral infection. All organisms have viral pathogens, and an ancient and fundamental mechanism for detecting viral infection makes use of sensors that recognize viral nucleic acids. In vertebrates, these sensors coordinate an inducible antiviral response by activating the production of type I interferons (IFNs). You can find more information on his research at his Department of Immunology website.

 

Recent Publications

 

Eckard SC, Rice GI, Fabre A, Badens C, Gray EE, Hartley JL, Crow YJ, Stetson DB. 2014. The SKIV2L RNA exosome limits activation of the RIG-I-like receptors. Nature Immunology, 15(9):839-845. NIHMS ID: 609228.

 

Volkman HE, Stetson DB. 2014. The enemy within: endogenous retroelements and autoimmune disease. Nature Immunology 15(5):415-422. PMID 24747712.

 

Stetson DB. 2012. Endogenous retroelements and autoimmune disease. Current Opinion in Immunology, 24(6):692-697.

 

Brunette RL, Young JA, Whitley DG, Brodsky IE, Malik HS, Stetson DB. 2012. Extensive evolutionary and functional diversity among mammalian AIM2-like receptors. Journal of Experimental Medicine, 209(11):1969-1883. PMCID: PM3478938.

 

Gall A., Treuting P., Elkon KB, Loo YM, Gale M Jr., Barber GN, Stetson, DB. 2012. Autoimmunity Initiates in Nonhematopoietic Cells and Progresses via Lymphocytes in an Interferon-Dependent Autoimmune Disease. Immunity. 2012 Jan 27; 36(1):120-31. PMID 22284419.

 

Stetson DB. 2009. Connections between antiviral defense and autoimmunity. Current Opinion in Immunology 21(3):244-250.

 

Rice GI, Bond J, Asipu A, Brunette RL, Manfield IW, Carr IM, Lamb T, Briggs TA, Ali M, Couthard LR, Aeby A, Attard-Montalto S, Bertini E, Bodemer C, Brockmann K, Brueton LA, Corry PC, Desguerre I, Fazzi E, Fuller J, Garcia Cazorla A, Gener B, Hamel BCJ, Heiberg A, Hunter M, Jackson R, van der Knaap M, Kumar R, Lagae L, Landrieu PG, Lourenco CM, Marom D, McDermott M, van der Merwe W, Orcesi S, Prendiville J, Rasmussen M, Shalev SA, Soler D, Shinawi M, Spiegel R, Tan T, Vanderver A, Wakeling E, Wassmer E, Whittaker E, Lebon P, Stetson DB, Bonthron DT, Crow YJ.  2009.  Mutations in Aicardi-Goutières syndrome implicate SAMHD1 as a novel regulator of the innate immune response.  Nature Genetics 41(7):829-832.

 

Stetson DB*, Ko JS, Heidmann T, Medzhitov R*. 2008. Trex1 prevents cell-intrinsic initiation of autoimmunity. Cell 134:587-598. *Corresponding authors PMCID: PMC2626626.

 

Stetson DB and Medzhitov R. 2006. Recognition of cytosolic DNA activates in IRF3-dependent innate immune response.  Immunity 24(1):93-103.

 

 

 



 

 

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