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Dr. Margaret Bynoe, an Associate Professor in the Department of Immunology and Infectious Diseases, received her Bachelor of Science degree in Biology from Long Island University in 1991. She received her PhD from Albert Einstein College of Medicine in 1999 where she studied the molecular basis of steroid hormones in the development of the autoimmune disease, systemic lupus erythematosus. She received her postdoctoral training in the laboratory of the late Charles A Janeway, Jr. where she studied the immunological bases of Type1 Diabetes and multiple sclerosis (MS) and later became an Associate Research Scientist at Yale University School of Medicine. Her major source of funding is by the NIH and recently the by the National Multiple Sclerosis Society. Research Interests | Graduate Fields | Lab Members | Related Links | Selected References The focus of the lab is to understand how the immune system works and to elucidate the cellular and molecular basis of immune defects/dysfunctions that manifest in autoimmune diseases {such as MS and inflammatory bowel diseases (IBD)} or failure of the immune system to eradicate cancer. Armed with knowledge gained from these studies, we then aim to develop immune-based therapeutic approaches to mitigate or eliminate these manifestations. We therefore focus on immune regulation at systemic and mucosal sites (including the skin and the gut) and the central nervous system. To accomplish our goals, several areas of study are ongoing in the lab. 1) Understand the function of resident skin immune cells and how they can impact systemic or central nervous system (CNS) immune outcome. These studies are carried out in the context of inducing antigen-specific global immune tolerance using the animal model of MS called experimental autoimmune encephalomyelitis (EAE), an autoimmune disease of the CNS. We use the epicutaneous/transcutaneous method (a skin patch) to deliver antigen via the skin to a) induce tolerance against EAE, or b) in a different immune context to induce antigen-specific immunity against tumor eradication. We are able to induce immune tolerance in several EAE animal models. Identical studies from our findings (Bynoe et al, 2003, Solomon et al, 2011) were performed on MS patients in a clinical trial in Poland with 80% efficacy against MS (See link to published report for more info on trial).
4) CD73-generated adenosine regulates the function and differentiation of epithelial, endothelial and immune cells in the intestinal lumen. Mice deficient in CD73 developed very severe colitis that has very strong correlates with Chron's disease. We are interested in the factors that govern intestinal epithelial permeability that adenosine may act on to mediate gut homeostasis (epithelial function and innate factors). These involve two different approaches. The first project entails using chemical as well as effector cell induced IBD models and the second approach entails modulating adenosine receptor signaling and assess changes in epithelial barrier integrity and the impact on gut microbiota. A final project in this area of study is geared to determine whether inflammation in the gut mucosa can cause brain inflammation and encephalitis.
Dr. Bynoe is a member of the following Graduate Fields:
Bynoe, M., T.J. Evans, C. Viret, and C.A. Janeway Jr. 2003. Epicutaneous immunization with an autoantigen induces T suppressor cells that prevent experimental allergic encephalomyelitis. Immunity. 19:317-328. Recognized by Faculty of 1000 Bynoe, M., C. Viret, R.A. Flavell, and C.A. Janeway Jr. 2005. T cells from epicutaneously immunized mice are prone to T cell receptor revision. Proc. Natl. Acad. Sci. USA. 102:2898-2903. Mills, J.H., L.F. Thompson, C. Mueller, A.T. Waickman*, S. Jalkanen, J. Niemela, L. Airas§, and M.S. Bynoe. 2008. CD73 is required for efficient entry of lymphocytes into the central nervous system during experimental autoimmune encephalomyelitis. Proc. Natl. Acad. Sci. USA. 105:9325-9330. Solomon, B.D., C. Mueller, W.J. Chae, L.M. Alabanza, M.S. Bynoe. 2011. Neuropilin-1 attenuates autoreactivity in experimental autoimmune encephalomyelitis. PNAS USA. 108:2040-2045. Mills J.H., L. Alabanza, B.B. Weksler, P.O. Couraud, I.A. Romero, M.S. Bynoe. 2011. Human brain endothelial cells are responsive to adenosine receptor activation. Purinergic Signal. 7:265-273. Carman A.J., J.H. Mills, A. Krenz, D.G. Kim, M.S. Bynoe. 2011. Adenosine receptor signaling modulates permeability of the blood-brain barrier. J Neurosci. 31:13272-13280. |
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2) One of our major goals is to understand how inflammation is regulated. To accomplish this we study genes or molecules that play a major role in regulation of inflammation. One such molecule is the purine nucleoside extracellular adenosine that is generated by CD73 (Ecto-5'-nucleotidase), a glycosyl phosphatidylinositol (GPI)-linked membrane protein that catalyzes the extracellular dephosphorylation of ATP and AMP to adenosine. Our lab previously demonstrated that CD73-generated adenosine is required for efficient lymphocyte migration into the CNS, and for EAE development (Mills et al, 2008). We are investigating a) the mechanism of adenos ine-mediated immune cell entry into the brain, b) elucidating adenosine’s role in regulating blood-brain endothelial barrier permeability, and determining the impact of altered CNS barrier permeability on treatment for neurological diseases including Alzheimer’s disease (Mills et al, 2011, Carmen et al, 2011 and links to recent press releases) (Figure 1). Another area of study in the lab is related to factors of the coagulation pathway that also regulates inflammation and CNS barrier integrity.
3) Neurothropic pathogens such as herpes simplex virus-1 (HSV1) and Toxoplasma gondii seek refuge in the CNS where they evade the host immune response and can remain for the life of the host. These pathogens can cause encephalitis and are implicated in contributing to or even triggering onset of neurological diseases such as MS, Alzheimer’s and Parkinson’s diseases. We are collaborating with two of our colleagues, Dr. Eric Denkers and Dr. Joel Baines, in studies to understand these pathogens’ contribution to CNS inflammation neurological diseases.