Autoimmune diseases occur when the immune system attacks the body’s own tissues rather than invaders like viruses or bacteria. And in autoimmune disease, gender matters. Women make up more than 80 percent of patients with autoimmune diseases.
In my lab, we are looking at the role that estrogen may play in these differences between men and women and the incidence of autoimmune disease. Cells in the immune system have estrogen receptors, places that estrogen can attach itself and trigger various responses, so we know that estrogen plays a role in the system’s function. Our focus is to determine what that role is and how to apply that knowledge to disease.
A lupus diagnosis is typically made during a woman’s reproductive years, indicating that high levels of estrogen could influence the onset and severity of the disease. On the other side of the equation, rheumatoid arthritis symptoms generally appear in women who are in or nearing menopause. In those cases, decreased estrogen levels seem to worsen the condition. Likewise, as estrogen levels subside, women tend to develop heart disease at the same rate as men.
By learning more about the link between sex-related hormones like estrogen and its impact on the immune response, we hope one day to apply that knowledge to fight lupus, arthritis and heart disease.
Autoimmune diseases preferentially afflict women, and female-male sex influences immune responses, suggesting that estrogens regulate inflammation and immunity. Indeed, immune cells and their progenitors express estrogen receptors (ER). We study the role of ER in the development and function of cells of the innate immune system, termed dendritic cells. These cells are important for initiation of both innate and adaptive immunity. Inflammation and autoimmunity are associated with de novo dendritic cell development from inflammatory monocytes or bone marrow precursors. Our previous studies determined that ER signaling is an important positive regulator of this pro-inflammatory developmental pathway. Our current studies continue to focus on the role of ER signaling in dendritic cell development, as well as function, in healthy mice and in murine models of systemic autoimmunity and atherosclerosis.
ER act as ligand-dependent transcription factors that participate in chromatin-modifying complexes and thus regulate gene expression programs. Recently, we identified the transcription factor interferon regulatory factor 4 (Irf4) as an estradiol-regulated gene during the GM-CSF-induced differentiation of dendritic cells. Our data show that estradiol/ER signaling promotes dendritic cell differentiation by increasing and sustaining expression of IRF4 in myeloid progenitors. Ongoing experiments are defining molecular mechanisms by which ER signaling regulates the Irf4 gene.
To study how ER signaling regulates dendritic cell development in vivo, we are generating mixed ER+/ER-/- bone marrow chimeric mice. These experiments have shown that ER expression differentially regulates dendritic cell and monocyte/macrophage development during inflammation and homeostasis. To study how ER signaling regulates post-developmental immune function, we are developing novel murine models in which ER deficiency is restricted to either DC or B lymphocytes.
Our long-term goals are to define the molecular mechanisms by which ER signaling regulates dendritic cell differentiation from bone marrow progenitors, and to understand how ER signaling modulates dendritic cell development and functional responses in vivo. We are applying the information gained from such studies to murine models of autoimmunity and atherosclerosis.
B.A., University of California, Berkeley, 1984
Ph.D., University of Wisconsin, Madison, 1991
Honors and Awards
1983 Honor Scholarship, University of California, Berkeley
1984-1985 Wisconsin Alumni Research Foundation Fellowship
1985-1988 National Science Foundation Graduate Fellowship
1989 Scholar, designated by the American Society for Histocompatibility and Immunogenetics
1993-1994 Leukemia Society of America Fellowship
1994-1997 National Research Service Award – individual fellowship
1998-1999 Arthritis National Research Foundation fellow
1999-2004 Arthritis Foundation Investigator Award – Duggan Award
2004-2005 Arthritis National Research Foundation fellow
Associate Editor, The Journal of Immunology (2001-2005)
Editorial board member, Current Immunology Reviews
Ad-hoc member, NIH special emphasis and CMI-A, CMI-B grant review panels
Ad-hoc member, Arthritis Research Campaign (United Kingdom) grant review panel
Ad-hoc reviewer for scientific journals
American Association of Immunologists
American Association for the Advancement of Science
Joined OMRF Scientific Staff in 2005.
Ainsua-Enrich E, Hatipoglu I, Kadel S, Turner S, Paul J, Singh S, Bagavant H, Kovats S. IRF4-dependent dendritic cells regulate CD8+ T-cell differentiation and memory responses in influenza infection. Mucosal Immunol, 2019 May, PMID: 31089186, PMCID: PMC6527354
Pan Z, Dumas EK, Lawrence C, Pate L, Longobardi S, Wang X, James JA, Kovats S, Farris AD. Bacillus anthracis Edema Toxin Inhibits Efferocytosis in Human Macrophages and Alters Efferocytic Receptor Signaling. Int J Mol Sci 20, 2019 March, PMID: 30866434, PMCID: PMC6429438
Bajaña S, Roach K, Turner S, Paul J, Kovats S. IRF4 promotes cutaneous dendritic cell migration to lymph nodes during homeostasis and inflammation. J Immunol. 2012 Oct 1;189(7):3368-77. PMID: 22933627 PMCID: PMC3448873
Carreras E, Turner S, Frank MB, Knowlton N, Osban J, Centola M, Park CG, Simmons A, Alberola-Ila J, Kovats S. Estrogen receptor signaling promotes dendritic cell differentiation by increasing expression of the transcription factor IRF4. Blood. 2010 Jan 14;115(2):238-46. PMID: 19880499 PMCID: PMC2808152
Agrawal H, Jacob N, Carreras E, Bajana S, Putterman C, Turner S, Neas B, Mathian A, Koss MN, Stohl W, Kovats S, Jacob CO. Deficiency of type I IFN receptor in lupus-prone New Zealand mixed 2328 mice decreases dendritic cell numbers and activation and protects from disease. J Immunol. 2009 Nov 1;183(9):6021-9. PMID: 19812195 PMCID: PMC2766036
Carreras E, Turner S, Paharkova-Vatchkova V, Mao A, Dascher C, Kovats S. Estradiol acts directly on bone marrow myeloid progenitors to differentially regulate GM-CSF or Flt3 ligand-mediated dendritic cell differentiation. J Immunol. 2008 Jan 15;180(2):727-38. PMID: 18178810
Tsark EC, Wang W, Teng YC, Arkfeld D, Dodge GR, Kovats S. Differential MHC class II-mediated presentation of rheumatoid arthritis autoantigens by human dendritic cells and macrophages. J Immunol. 2002 Dec 1;169(11):6625-33. PMID: 12444176
Arthritis & Clinical Immunology Research Program, MS 24
Oklahoma Medical Research Foundation
825 N.E. 13th Street
Oklahoma City, OK 73104
Phone: (405) 271-8583
Fax: (405) 271-7063
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