Division of Rheumatology
1959 NE Pacific St
Health Science Bldg BB561
Campus Box 356428
Seattle, WA 98195
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.
Lood C, Blanco LP, Purmalek MM, Carmona-Rivera C , De Ravin SS, Smith CK, Malech HL, Ledbetter JA, Elkon KB, Kaplan MJ (co-last authors). Mitochondrial ROS generate NETs enriched in oxidized interferogenic mitochondrial DNA and contribute to lupus-like disease. Nature Medicine, 22:146-53, 2016. PMID: 26779811.
Sisirak V, Sally B, D'Agati V, Martinez-Ortiz W, Özçakar ZB, David J, Rashidfarrokhi A, Yeste A, Panea C, Chida AS, Bogunovic M, Ivanov II, Quintana FJ, Sanz I, Elkon KB, Tekin M, Yalçınkaya F, Cardozo TJ, Clancy RM, Buyon JP, Reizis B. Digestion of Chromatin in Apoptotic Cell Microparticles Prevents Autoimmunity. Cell. 2016 Jun 9. pii: S0092-8674(16)30585-2. doi: 10.1016/j.cell.2016.05.034. [Epub ahead of print]. PMID: 27293190
Barrat FJ, Elkon KB, Fitzgerald KA. Importance of nucleic acid recognition in inflammation and autoimmunity, Ann Rev Med, Ann Rev Med, 67:323-336, 2016 PMID: 26526766.
Han CY, Tang C, Guevara ME, Wei H, Wietecha T, Shao B, Subramanian S, Omer M, Wang S, O’Brien KD, Wight TN, Vaisar T, de Beer MC, de Beer FC, Osborne WR, Elkon KB, Chait A Serum Amyloid A contributes to inflammation-induced impairment in HDL function. J Clin Invest, 126:796, 2016.
An J, Woodward JJ, Sasaki T, Minie M, Elkon KB. Cutting Edge: Antimalarial Drugs Inhibit IFN-β Production through Blockade of Cyclic GMP-AMP Synthase-DNA Interaction. J Immunol. 194:4089-93, 2015.
Sisirak V, Ganguly D, Lewis KL, Couillault C, Tanaka L, Bolland S, D’Agati V, Elkon KB, Reizis B. Genetic evidence for the role of plasmacytoid dendritic cells in systemic lupus erythematosus. J Exp Med, 2011:1969-1976, 2014.
Colonna L, Lood C, Elkon KB. Beyond apoptosis in lupus. Curr Opin Rheumatol. 26:459-466, 2014.
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, 65:2713-23, 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, 210:2713-23, 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.
Santer DM, Wiedeman AE, Teal T, Ghosh P, Elkon KB. Plasmacytoid dendritic cells and C1q differentially regulate inflammatory gene induction by lupus immune complexes. J Immunol, 188:902-15, 2012. PMCID: 22147767. PMC3238790
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.
Elkon KB, Rönnblom L. Cytokines as therapeutic targets in SLE. Nat Reviews Rheumatol, 2010.
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.
Lood C, Hughes GC. Neutrophil extracellular traps as a potential source of autoantigen in cocaine-associated autoimmunity. Rheumatology (Oxford). 2016 Jun 27. pii.kew256.
Gazitt T, Thomason J, Hughes GC. The Reply. Am J Med. 2016 Jan;129(1):e19. doi: 10.1016/j.amjmed.2015.09.003. No abstract available. PMID: 26703010
Tsur A, Hughes GC, Schoenfeld Y. Interdisciplinary exchange of ideas: progestagens for autoimmunity, biologics for pregnancy complications. Immunol Res 2015;61:31-4.
Wong A, Agrawal N, Hughes GC. The nuclear progesterone receptor regulates IgG2c autoantibodies, T follicular helper and regulator T cells in lupus-prone Nba2 mice. Autoimmunity 2015;10:1-13.
*Hughes GC, Choubey D. Modulation of autoimmune rheumatic diseases by oestrogen and progesterone. Nat Rev Rheumatol 2014 Aug 26. doi: 10.1038/nrrheum.2014.144. [Epub ahead of print]
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.
Dr. J. Lee Nelson's research includes:
Kanaan SB, Onat OE, Balandraud N, Martin GV, Nelson JL, Azzouz DF, Auger I, Arnoux F, Martin M, Roudier J, Ozcelik T, Lambert NC. Evaluation of X Chromosome Inactivation with Respect to HLA Genetic Susceptibility in Rheumatoid Arthritis and Systemic Sclerosis.PLoS One. 2016 Jun 29;11(6):e0158550. doi: 10.1371/journal.pone.0158550. eCollection 2016.
Stevens AM, Kanaan SB, Torok KS, Medsger TA, Mayes MD, Reveille JD, Klein-Gitelman M, Reed AM, Lee T, Li SC, Henstorf G, Luu C, Aydelotte T, Nelson JL. HLA DRB1, DQA1 and DQB1 in Juvenile Onset Systemic Sclerosis. Arthritis Rheumatol. 2016 May 23. doi: 10.1002/art.39765.
Deutz NE, Matheson EM, Matarese LE, Baggs GE, Nelson JL, Hegazi RA, Luo M, Tappenden KA, Ziegler TR; NOURISH Study Group. Reply, Letter to the Editor - Supplemental and energy likely account for multi-ingredient supplementation in mitigating morbidity and mortality in compromised elderly malnourished patients. Clin Nutr. 2016 Aug;35(4):977-8. doi: 10.1016/j.clnu.2016.03.027. Epub 2016 Apr 6. No abstract available.
Mittal A, Pachter L, Nelson JL, Kjærgaard H, Smed MK, Gildengorin VL, Zoffmann V, Hetland ML, Jewell NP, Olsen J, Jawaheer D. Pregnancy-Induced Changes in Systemic Gene Expression among Healthy Women and Women with Rheumatoid Arthritis. PLoS One. 2015 Dec 18;10(12):e0145204. doi: 10.1371/journal.pone.0145204. eCollection 2015. PMID: 26683605
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. 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.
Simkin PA, Snitily BK. Impact-driven, pulmonary emboli of osseous fat in exercise-induced bronchospasm. Med Hypotheses. 2015 Nov;85(5):694-8. doi: 10.1016/j.mehy.2015.08.014. Epub 2015 Aug 28.PMID: 26328480
Simkin PA. Response to 'interspinous bursitis is common in polymyalgia rheumatica, but is not associated with spinal pain'.Arthritis Res Ther. 2015 Apr 28;17:111. doi: 10.1186/s13075-015-0620-7. No abstract available. PMID: 25927338
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.
Chappell CP, Giltiay NV, Draves KE, Chen C, Hayden-Ledbetter MS, Shlomchik MJ, Kaplan DH, Clark EA.Targeting antigens through blood dendritic cell antigen 2 on plasmacytoid dendritic cells promotes immunologic tolerance. J Immunol. 2014 Jun 15;192(12):5789-801. doi: 10.4049/jimmunol.1303259. Epub 2014 May 14. PMID: 24829416
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.
Dr. Erika Noss investigates how fibroblast hyperplasia defines rheumatoid arthritis, there is little understanding about how fibroblasts accumulate in the synovium. Currently fibroblasts are defined mainly by what they are not – not immune, epithelial, endothelial, nerve, muscle or bone cells. Her work and other reseach has suggested that fibroblast populations are not homogeneous and that different fibroblast subpopulations may have unique functions in disease. Dr. Noss's research interests are to use both human tissues and mouse models to better define synovial fibroblast function in rheumatoid arthritis. The Nosslaboratory is working to define pathways that promote synovial fibroblast accumulation in rheumatoid arthritis and examine mechanisms regulating IL-6 production in fibroblast subpopulations. Dr. Noss has extensive experience examining synovial fibroblast function in vitro and ex vivo and is proficient with several mouse arthritis models
Noss EH, Nguyen HN, Chang SK, Watts GFM. Genetic polymorphism directs IL‐6 expression in fibroblasts but not selected other cell types. 2015;112(48):14948-53. *co-first authors
Noss EH, Watts GFM, Zocco D, Keller TL, Whitman M, Blobel CP, Lee DM, Brenner MB. Evidence for cadherin‐11 cleavage in the synovium and partial characterization of its mechanism. Arth Res Ther 2015;17:126-37.
Lee YC, Padera RR, Noss EH, Fossel AH, Bienfang D, Liang MH, Docken WP. Clinical course and management of a consecutive series of patients with “healed temporal arteritis”. J Rheum 2012;39(2):295‐302.
Noss EH, Chang SK, Watts GFM, Brenner MB. Modulation of matrix metalloproteinase production by rheumatoid arthritis synovial fibroblasts after cadherin 11 engagement. Arthritis Rheum 2011;63(12):3768‐78.
Chang SK, Noss EH, Chen M, Gu Z, Townsend K, Grenha R, Leon L, Lee SY, Lee DM, Brenner MB. Cadherin‐11 regulates fibroblast inflammation. Proc Natl Acad Sci USA 2011;108(20):8402‐7.
Gu, Z., Noss, EH, Hsu, VW, Brenner, MB. Integrins traffic rapidly via circular dorsal ruffles and macropinocytosis during stimulated cell migration. J Cell Biol 2011;193(1):61‐70.
Lee DM, Kiener HP, Agarwal SK, Noss EH, Watts GF, Chisaka O, Takeichi M, Brenner MB. Cadherin‐11 in synovial lining formation and pathology in arthritis. Science 2007;315(5814):1006‐10.
Noss EH, Hausner‐Sypek DL, Weinblatt ME. Rituximab as therapy for refractory polymyositis and dermatomyositis. J Rheumatol. 2006;33(5):1021‐6.
Neufert C, Pai RK, Noss EH, Berger M, Boom WH, Harding CV. Mycobacterium tuberculosis 19‐kDa lipoprotein promotes neutrophil activation. J Immunol 2001;167(3):1542‐9.
Noss EH*, Pai RK*, Sellati TJ, Radolf JD, Belisle J, Golenbock DT, Boom WH, Harding CV. Toll‐like receptor 2‐dependent inhibition of macrophage class II MHC expression and antigen processing by 19‐kDa lipoprotein of Mycobacterium tuberculosis. J Immunol 2001;167(2):910‐8.
Ramachandra L, Noss E, Boom WH, Harding CV. Mycobacterium tuberculosis Ag 85B processing involves intra‐phagosomal formation of peptide:MHC‐II complexes and is modulated by regulation of phagosome maturation. J Exp Med 2001;194:1421‐32.
Dr. Christian Lood studies the role of neutrophils in inflammation and autoimmunity with an emphasis on the contribution of neutrophils to the systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) pathogenesis. Neutrophils are the main immune cells in the circulation, participating in host defense through mechanisms including production of reactive oxygen species (ROS), phagocytosis and formation of neutrophil extracellular traps (NETs), a recently identified neutrophil cell death process in which DNA is extruded together with cytoplasmic and granular content to trap and eliminate extracellular pathogens. Although beneficial from a host-pathogen perspective, exaggerated neutrophil activation and NET formation has been linked to autoimmunity, in particular SLE and RA.
Dr. Lood's research currently pursuing three main research aims, a) assessing how neutrophil-derived mitochondria and mitochondrial DNA are cleared to avoid unwarranted inflammation and autoimmunity, b) investigating the interplay between TLR8 and FcgRIIA in skewing neutrophils towards an inflammatory phenotype and c) identifying novel neutrophil-derived biomarkers related to disease activity and severity, including cardiovascular disease, a leading cause of mortality in young SLE women.
Lood C, Hughes GC. Neutrophil extracellular traps as a potential source of autoantigen in cocaine-associated autoimmunity. Rheumatology 2016 [Epub ahead of print].
Lood C, Tyden H, Gullstrand B, Jonsen A, Kallberg E, Morgelin M, Kahn R, Gunnarsson I, Leanderson T, Ivars F, Svenungsson E, Bengtsson AA. Platelet-derived S100A8/A9 and cardiovascular disease in systemic lupus erythematosus. Arthritis Rheumatol 2016;8:1970-80.
Lood C, Blanco LP, Purmalek MM, Carmona-Rivera C, De Ravin SS, Smith CK, Malech HL, Ledbetter JA, Elkon KB, Kaplan MJ. Neutrophil extracellular traps enriched in oxidized mitochondrial DNA are interferogenic and contribute to lupus-like disease. Nat Med 2016;2:146-53.
Lood C, Tyden H, Gullstrand B, Klint C, Wenglen C, Nielsen CT, Heegaard NH, Jonsen A, Kahn R, Bengtsson AA. Type I interferon-mediated skewing of the serotonin synthesis is associated with severe disease in systemic lupus erythematosus. PLoS One 2015; 4:e0125109.
Colonna L, Lood C, Elkon KB. Beyond apoptosis in lupus. Curr Opin Rheumatol 2014; 5:459-66.
Lood C, Tyden H, Gullstrand B, Sturfelt G, Jonsen A, Truedsson L, Bengtsson AA. Platelet activation and anti-phospholipid antibodies collaborate in the activation of the complement system on platelets in systemic lupus erythematosus. PLoS One 2014;6:e99386.
Lood C, Allhorn M, Lood R, Gullstrand B, Olin AI, Ronnblom L, Truedsson L, Collin M, Bengtsson AA. IgG glycan hydrolysis be endoglycosidase S diminishes the proinflammatory properties of immune compelxes from patients with systemic lupus erythematosus: a possible new treatment? Arthritis Rheum 2012;8:2698-706.
Leffler J, Martin M, Gullstrand B, Tyden H, Lood C, Truedsson L, Bengtsson AA, Blom AM. Neutrophil extracellular traps that are not degraded in systemic lupus erythematosus activate complement exacerbating disease. J Immunol 2012;7:33522-31.
Lood C, Amisten S, Gullstrand B, Jonsen A, Allhorn M, Truedsson L, Sturfelt G, Erlinge D, Bengtsson AA. Platelet transcriptional profile and protein expression in patients with systemic lupus erythematosus: up-regulation of the type I interferon system is strongly associated with vascular disease. Blood 2010;11:1951-7.
Lood C, Gullstrand B, Truedsson L, Olin AI, Alm GV, Ronnblom L, Sturfelt G, Eloranta ML, Bengtsson AA. C1q inhibits immune complex-induced interferon-alpha production in plasmacytoid dendritic cells: a novel link between C1q deficiency and systemic lupus erythematosus pathogenesis. Arthritis Rheum 2009;10:3081-90.
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.
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.
Ng, B. and A. Chu, Factors associated with methotrexate dosing and therapeutic decisions in Veterans with rheumatoid arthritis. Clin Rheumatol. 2013 Aug 11.
Ng B, Chu A, Khan MM. A retrospective cohort study: 10-year trend of disease-modifying antirheumatic drugs and biological agents use in patients with rheumatoid arthritis at Veteran Affairs Medical Centers. BMJ Open. 2013 Apr 5;3(4).
B. Ng, Low-to-Moderate Alcohol Consumption May Be Safe When Taking Methotrexate for Rheumatoid Arthritis or Psoriasis. Open Journal of Rheumatology and Autoimmune Diseases, Vol. 2 No. 3, August 2012, pp. 39-46. doi:10.4236/ojra.2012.23009.
Ng, B; Aslam, F; Petersen, N; Yu, HJ; Suarez-Almazor, M. Identification of Rheumatoid Arthritis Patients Using an Administrative Database: A Veteran Affairs Study. Arthritis Care & Research. Arthritis Care Res (Hoboken), 2012. 64(10): p. 1490-6.
B. Ng, Qurat Ul-Ain Kamili. Current Perspectives on Rheumatic Laboratory Tests. Federal Practitioner 28(4), 2011.
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.
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.
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
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
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, 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.
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.
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.
Porakishvili N, Vispute K, Steele AJ, Rajakaruna N, Kulikova N, Tsertsvadze T, Nathwani A, Damle RN, Clark EA, Rai KR, Chiorazzi N, Lydyard PM.Rewiring of sIgM-mediated intracellular signaling through the CD180 Toll-like receptor. Mol Med. 2015 Jan 14. doi: 10.2119/molmed.2014.00265. [Epub ahead of print] PMID: 25611435
Chappell CP, Giltiay NV, Draves KE, Chen CK, Hayden-Ledbetter MS, Shlomchik MJ, Kaplan DH, Clark EA. Targeting antigens through blood dendritic cell 2 (BCDA2) on plasmacytoid dendritic cells promotes immunologic tolerance, J Immunol 192:5789-5801, 2014.
Giordano D, Li C, Draves KE, Hohl T, Clark EA. Nitric oxide regulates B cell activating factor (BAFF) expression and T cell-independent antibody responses, J Immunol 193:1110-1120, 2014.
Clark EA. Perspective: A short history of the B cell-associated surface molecule CD40. Frontiers Immunol 5:472, doi:10.3389/fimmu.2014.00472, 2014.
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 210:2773-89, 2013.
Chaplin JW, Chappell CP, Clark EA. Targeting antigens to CD180 rapidly induces antigen-specific IgG, affinity maturation and immunologic memory, J Exp Med 210:2135-2146, 2013.
Ma DY, Suthar MS, Kasahara S, Gale M Jr, Clark EA. CD22 is required for protection against West Nile virus infection, J Virol 87: 3361-3375, 2013.
Kasahara S, Clark EA. Dendritic cell-associated lectin 2 (DCAL2) defines a distinct CD8α- dendritic cell subset, J Leukocyte Biol, 91:437-448, 2012.
Watanabe C, Shu GL, Clark EA. Caspase 6 regulates early B cell differentiation, Europ J Immunol, submitted 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.
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.
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.
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.
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.
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.
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.