Dr.Melissa Brown

Biographical Sketch

Dr. Brown received her undergraduate degree in biology at the University of Tennessee and earned her PhD degree in at the University of Washington, where she studied the genetic basis of immune responses to retroviruses. As a post-doctoral fellow with Dr. William Paul at the Laboratory of Immunology at NIH, she began her studies on mast cells, with a focus on understanding the mechanisms that regulate Il4 expression. These studies have continued and expanded to include investigation of the functions of mast cells in autoimmune disease and infection. Since her post-doctoral fellowship, she has served on the faculty of the Oregon Health Sciences University and Emory University. She joined the faculty of Northwestern University in 2003.

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Research Abstract

Mast cells, traditionally considered members of the innate immune system, are cells of hematopoietic lineage that exhibit a widespread distribution in the body and express a large of array of mediators that promote local inflammation. Until recently, mast cells have been studied primarily in the context of allergic disease. However, the discovery that mast cells produce cytokines and chemokines involved in regulating T cell differentiation and effector function, has lead to an appreciation of a wider role for these cells in adaptive immune responses.

Of particular interest to our laboratory is the study of the mast cell derived cytokine IL-4. In addition to expression by mast cells, IL-4 is produced only by basophils, eosinophils and a subset of T cells. It plays a pivotal role in shaping the “character” of an adaptive immune response and the tightly regulated expression of IL-4 is necessary for maintaining protective immunity.

Our research is focused in two areas: a) a study of the molecular mechanisms that control expression of Interleukin 4 (IL-4) in mast cells and T cells. These studies include the deciphering of epigenetic factors that regulate the accessibility of the Il4 locus in mast cells and confer the potential for high or low expression; and b) determination of the role of mast cells in protective and pathological immune responses. We are using a mast-cell deficient mouse model to examine the contribution of mast cells and mast cell cytokines to the pathology associated with T cell mediated autoimmune diseases including experimental allergic encephalomyelitis (EAE), the murine model multiple sclerosis and diabetes. The contributions of mast cells to the generation of protective immune responses to bacterial and viral infections are also being explored using this model.

Publications

On IL-4 gene regulation...

Hural, J., M. Kwan, G. Henkel, M.B. Hock and M.A. Brown. An intron transcriptional enhancer regulates IL-4 gene locus accessibility in mast cells, J. Immunol. 165:3230-3249, 2000.

Weiss, D.L. and M.A. Brown. IL-4 gene regulation in mast cells: A paradigm of cell-type specific gene regulation. Immunol. Rev. 179:45-47, 2001.

Sherman, M.A., D. Powell and M.A. Brown. IL-4 induces the proteolytic processing mast cell STAT6. J. Immunol. 169:3811-3818, 2002.

Hock, M.B. and M.A. Brown. NFAT2 transactivation in mast cells: a novel isoform-specific domain confers unique FceRI responsiveness. J. Biol. Chem. 278:26695-26703, 2003.

Kwan, M., D. Powell, T.Y . Nachman and M.A. Brown. An intron GATA-binding site regulates chromatin accessibility and is essential for IL-4 gene expression in mast cells. Eur. J. Immunol. 35:1267-1274, 2005

Gregory, G.D., S.S. Raju, S. Winandy and M.A. Brown. Mast cell Il4 expression is regulated by Ikaros and influences encephalitogenic Th1 cell responses in EAE. J. Clin. Invest. 116:1327-1336, 2006.

On autoimmunity and mast cells...

Secor, V.H, W.E. Secor, C.A. Gutekunst and M.A. Brown. Mast cells contribute to the initiation and severity of disease in a murine model of multiple sclerosis. J.Exp. Med. 191:813-821, 2000.

Brown, M.A., M.Tanzola and M. Robbie. Mechanism underlying mast cell influence on EAE disease course. Mol. Immunol. 38:1373-1378, 2002.

Robbie-Ryan, M., M. Tanzola, V. Secor and M.A. Brown. Cutting Edge: Both activating and inhibitory Fc receptors on mast cells regulate disease severity, J. Immunol. 170:1630-1634, 2003.

Tanzola, M., M. Robbie-Ryan, C. Gutekunst and M.A. Brown. Mast cells exert effects outside the CNS to influence experimental allergic encephalomyelitis disease course, J. Immunol. 171:4385-4391, 2003.

Gregory, G.D., M. Robbie-Ryan, J. Sapbatino and M.A. Brown. Mast cells promote autoreactive T cell responses in a murine model f multiple sclerosis, Eur. J. Immunol. 35:348-3486, 2005.

Gregory, G.D., S.S. Raju, S. Winandy and M.A. Brown. Mast cell Il4 expression is regulated by Ikaros and influences encephalitogenic Th1 cell responses in EAE. J. Clin. Invest. 116:1327-1336, 2006.

Sayed, B.A. and M.A. Brown. Mast cells as modulators of T cell responses. Immunol. Rev. 217:53-64, 2007.

Christy, A.L. and M.A. Brown, The multitasking mast cell: positive and negative roles in the progression of autoimmunity. J. Immunol. 179:2673-2679, 2007.

Sayed, B.A., A.L. Christy, M.R. Quirion and M.A. Brown. Mast cells in Autoimmunity and Tolerance. Ann. Rev. Immunol. in press, 2008.

Contact information

m-brown12@northwestern.edu

312-503-0108 office

312-503-1013 lab

What are mast cells?

Mast cells: from Mastzellen: ‘fattened, well-fed cells’, these cells have multiple cytoplasmic granules (left and middle panel) that contain pre-formed mediators, including histamine, proteases and cytokines. Upon activation (right panel), the mast cell “degranulates” and is an immediate source of multiple inflammatory mediators.

Best known for their role in allergy, they have many other functions.

-Not only in mucosal tissues of the respiratory tract and gut but exhibit widespread distribution in the skin, CNS, conjunctiva of the eye

-Unlike many white blood cells, which circulate, they remain fixed in tissues until activated.

Mast cells have the potential to influence many stages of both adaptive and innate immune /inflammatory responses

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