Richard Bucala M.D., Ph.D. Professor of Medicine and Pathology S-411, The Anlyan Center Phone: 203-785-2454 Fax: 203-785-7053 e-mail: richard.bucala@yale.edu

Research Activities

We seek to understand the mechanisms by which host immunity converts from a protective response to one producing disease and tissue pathology. Several years ago, we cloned an immunoregulatory protein from the pituitary gland that was determined to be the mouse homologue of human macrophage migration inhibitory factor (MIF). We since have discovered that MIF has hormone-like properties, circulates normally in blood, and acts to counter-regulate glucocorticoid action during the innate and acquired immune response. MIF expression is tightly linked to the expression of many autoimmune and inflammatory diseases, and anti-MIF strategies are effective in reducing immunopathology in many experi-mental animal models of disease.

Our laboratory investigations encompass the biochemical, biological, and genetic-- characterization of MIF, and we remain focused on understanding MIF’s role in physiology and pathology. We have uncovered a unique action for MIF in sustaining ERK-1/2 (p44/p42) activation, a pathway that impacts on the proliferation and long-term activation of many cell types including the fibroblasts within the rheumatoid synovium. Our studies support an important role for MIF in inhibiting p53-dependent growth arrest, an action that sustains the pro-inflammatory phenotype of monocytes/macrophages in conditions such as endo-toxemia. We have discovered functionally important polymorphisms in the promoter for human Mif that are associated with rheumatoid arthritis severity. An important goal for us is to comprehend the emergence of steroid resistance, a clinical problem that seriously restricts the effective treatment of auto-immune diseases such as rheumatoid arthritis.

We have initiated studies of MIF’s role in the development of severe malarial anemia. While anemia is frequently a feature of chronic inflammation and infection, it has been identified to be the proximate cause of death in almost half of the 3-4 million malarial deaths that occur annually. Bone marrow progenitor cells become resistant to the action of erythropoietin during malaria infection, and we have uncovered a molecular pathway by which MIF interferes with erythro-poietin signal transduction. We collabo-rate closely with the Macha Mission Hospital in the Zambia to study the clinical fre-quency of Mif polymorphisms in an effort to understand why fatal anemia develops in certain children but not in others.

In a separate line of investigation, we study the inflammatory biology of fibrocytes, a blood-borne cell with fibrogenic and antigen-presentation properties. We first characterized these cells in studies of wound repair and granuloma formation, and we are exploring the role of these cells in scleroderma, a rapidly progressive, fibrosing condition with an autoimmune etiology.

Selected Recent Publications

1. Bucala, R. 2000. A most interesting factor. Nature 408:146-147.
2. Abe, R., S.C. Donnelly, T. Peng, R. Bucala, and C.N. Metz. 2001. Peripheral blood fibrocytes: Differentiation pathway and migration to wound sites. J. Immunol. 166:7556-7562.
3. Mitchell, R., H. Laio, J. Chesney, G. Fingerle-Rowson, J. Baugh, J. David, and R. Bucala R. 2002. MIF sustains macrophage function and survival by inhibiting p53: Regulatory role in the innate immune response. Proc. Natl. Acad. Sci. USA 99:345-350.
4. Baugh JA, Chitnis S, Donnelly S, Lin X, Wolfe F, Gregerson P, and Bucala R. 2002. A functional promoter polymorphism in teh macrophage migration inhibition factor MIF gene associated with disease severity in rheumatoid arthritis. Genes & Immunity 3, 170-176.
5. Leng L., Metz C, Fang Y, Xu J, Donnelly S, Baugh J, Delonery T, Chen Y, Mitchell RA, and Bucala R. 2003. MIF Signal Transduction Initiated by Binding to CD74. J Exp Med 197, 1467-1476.
6. Fingerle-Rowson G, Petrenko O, Metz CN, Forsthuber TG, Mitchell R, Huss RR, Moll U, Muller W, and Bucala R. 2003. The p53-dependent effects of macrophage migration inhibitory factor revealed by gene targeting. Pro Natl Acad Sci USA 100, 9354-9359.