Research
Basic and Applied Research
Dr. 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 – especially as it relates to lupus (SLE). Loss of tolerance leads to autoantibody production in systemic autoimmune disorders. 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 recently identified novel pathways that involve opsonization of dying cells by serum factors (complement, CRP and natural antibodies) thereby promoting the phagocytosis of apoptotic cells. The 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) 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. This research is applied to human lupus, especially neuropsychiatric disease as well as to murine models. In mouse lupus, attempts are being made to prevent TLR activation of IFN-a by nucleoprotein containing immune complexes.
Cytokine Regulation of Arthritis. Despite the powerful inflammatory effect of cytokines such as tumor necrosis factor (TNF)-a produced by the innate immune system, abundant evidence indicates that T cells are required for initiation and/or chronicity in both human rheumatoid arthritis (RA) and its mouse models. Interleukin (IL)-17 has emerged as a critical T cell cytokine in the pathogenesis of human RA and collagen induced arthritis in mice. IL-17 itself, is positively regulated by TGF-B and IL-6 and negatively regulated by IFN-g, IL-4 and IL-27. Current studies explore the mechanisms responsible for cytokine stimulation, the regulation of Th17 cells as well as therapeutic modalities to alter the cytokine milieu.
Dr. Grant C. Hughes studies the relationship between reproductive hormones 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.
In Dr. Jeff Ledbetter's lab, we study the function of costimulatory receptors in control of effector and regulatory T cells. One receptor we study is CD180, a Toll-like receptor (TLR) homologue expressed by B cells and DCs that regulates cell activation through other TLRs. We are interested in understanding the potential for immunoregulatory therapy in autoimmune disease by CD180 stimulation or inhibition. Other receptors of interest on B cells and APC are CD80, CD86, and CD40. We use recombinant construction and mammalian expression of novel molecules, built from antibody and receptor domains, to test new approaches to biologic therapy of autoimmune disease. New molecules are tested in animal models, and in assays with human cells in vitro to study their properties for potential immunoregulation.
Dr. J. Lee Nelson's research includes:
a. Maternal microchimerism (MMc) in health and autoimmune disease. MMc is being investigated in healthy individuals and in the pathogenesis of selected autoimmune diseases with a current focus on systemic sclerosis (SSc) and rheumatoid arthritis (RA). Studies reported in 2007 examined type 1 diabetes and in prior years systemic and neonatal lupus. HLA alleles and familial HLA-relationships are also being investigated.
b. Fetal microchimerism (FMc) in health and autoimmune disease. FMc is being investigated in healthy individuals and in the pathogenesis of selected autoimmune diseases with a current focus on SSc and RA. HLA alleles and familial HLA-relationships are also being investigated.
c. Maternal microchimerism in HIV and AIDS. MMc is being evaluated in patients with HIV who do and do not progress to AIDS and in maternal-fetal HIV transmission.
d. Fetal microchimerism in breast cancer. FMc is being investigated in protection from breast cancer.
e. Genetics and RA. HLA DRB1, DQA1 and DQB1 alleles are being assessed in risk, protection and clinical phenotype of RA. Other non-HLA genes in the HLA complex are being studied by microsatellite and single nucleotide polymorphism typing.
f. Pregnancy in RA susceptibility and prognosis. Pregnancy and HLA genes 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.
g. 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.
h. 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.
i. Mechanisms governing immune recognition of human nephrin. Intrathymic nephrin expression is being assessed and functional consequences and interactions evaluated in antigen processing and presentation.
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.
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.
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.
Dr. Julia Rhiannon's clinical and research interest in systemic sclerosis developed during her fellowship and faculty year at the University of Colorado. There she had the opportunity to train under David Collier, M.D., in his scleroderma clinic, the only one of its kind in Denver and the surrounding states. Dr. Collier is Colorado's most notable scleroderma subspecialist. Here at the University of Washington, Julia continues to develop expertise in the management of scleroderma and related overlap disorders, and plans to initiate and maintain a weekly scleroderma clinic as soon as possible. She is very interested in facilitating patient access to cutting edge treatment options for scleroderma.
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.