Africa; Epidemiology; Macrophage Migration-Inhibitory Factors; Malaria; Pathology; Public Health; Rheumatology; Stem Cells; Global Health; Communicable Diseases, Emerging; Infectious Disease Medicine
Public Health Interests
Emerging Diseases; Genetic epidemiology; Genetics; Human Subjects Research; Immune functions; Infectious Disease; Parasitology; Tropical Diseases
Skin Diseases Research Center, Yale
The goal of our studies is to understand the mechanisms by which host immunity converts from a protective response to one producing disease. We focus significant attention on the role of host cytokine, MIF, which we cloned in 1993, in the development of the inflammatory complications of different infections and autoimmune diseases. MIF is an endogenous counter-regulator of the immunosuppressive action of glucocorticoids and its role in human disease has been underscored by the discovery of functional promoter polymorphisms in the human gene, which are associated with different inflammatory and infectious disorders. Our studies of MIF encompass structure-function, immunological, and pharmacologic targeting studies. We also are pursuing the genetic epidemiology of MIF; for example, we direct studies of malaria and tuberculosis susceptibility in sub-Saharan Africa, and we are investigating the role of MIF alleles in different autoimmune and infectious diseases. A separate line of inquiry is directed at the fibrocyte, which is a novel circulating leukocyte that contributes to the immunopathogenesis of fibrosing disorders.
Specialized Terms: Mechanisms by which host immunity converts from a protective response to one producing disease and tissue pathology; Emergence of steroid resistance; Biochemical, biological, and genetic characterization of the MIF cytokine family; MIF's role in malaria and global infectious diseases; Pharmacologic immuniomodulation of the MIF pathway; Role of fibrocytes in different systemic fibroses
Extensive Research Description
We seek to understand the mechanisms by which host immunity converts from a protective response to one producing disease and tissue pathology. A main focus of our efforts is on the cytokine, MIF, which we cloned from the pituitary gland and discovered to counter-regulate the immunosuppressive actions of glucocorticoids. MIF production is tightly linked to the expression of many autoimmune and inflammatory diseases, and anti-MIF strategies are effective in reducing immunopathology in many experimental models of disease.An important goal for us is to elucidate the emergence of steroid resistance, aclinical problem that restricts the effective treatment of autoimmune diseases such as rheumatoid arthritis.
Our laboratory investigations encompass the biochemical, biological, andgenetic 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 inflammatory signal transduction, a pathway that impacts on the proliferation and long-term activation of many cell types. Our studies support an important role for MIF in inhibiting p53-dependent growth arrest, which isan action that sustains the pro-inflammatory phenotype of monocytes/macrophages. We have discovered functionally important polymorphisms in the promoter for human MIFthat are associated with the severity immunologic diseases such as rheumatoid arthritis, asthma, and SLE.Additionally, they play a role in the inflammatory pathogenesis of malignancies such as prostate cancer and in the neurodevelopmental disorder, autism.
We initiated studies of MIF's role in the development of severe malarial anemia, which is the proximate cause of death in the nearly 1.5 million deaths that occur annually from malaria. We conduct clinical studies in Zambia to examine the clinical frequency of different MIF genetic polymorphisms in an effort to understand why severe malaria develops in certain children. Additional studiesare underway in to examine the role of MIF in Leishmaniasis and in tuberculosis. Population stratification of high and low expression forms of the MIF gene appear to account for differential susceptibility to malaria or autoimmunity.
In a separate line of investigation, we study the biology of fibrocytes,a blood-borne cell with inflammatory and fibrogenic properties. We first characterized these cells in studies of wound repair and granuloma formation, and we are exploring their role in different systemic fibroses.
Dual effect of the macrophage migration inhibitory factor gene on the development and severity of human systemic lupus erythematosus
Sreih A, Ezzeddine R, Leng L, Lachance A, Yu G, Mizue Y, Subrahmanyan L, Pons-Estel BA, Abelson AK, Gunnarsson I, Svenungsson E, Cavett J, Glenn S, Zhang L, Montgomery R, Perl A, Salmon J, Alarcón-Riquelme ME, Harley JB, Bucala R. 2011. Dual effect of the macrophage migration inhibitory factor gene on the development and severity of human systemic lupus erythematosus .Arthritis Rheum. 2011 Dec;63(12):3942-51
A small-molecule MIF antagonist protects against glomerulonephritis in lupus-prone NZB/NZW F1 and MRL/lpr mice
Leng L, Chen L, Fan J, Greven D, Arjona A, Du X, Austin D, Kashgarian M, Yin Z, Huang XR, Lan HY, Lolis E, Nikolic-Paterson D, Bucala R. 2011. A small-molecule MIF antagonist protects against glomerulonephritis in lupus-prone NZB/NZW F1 and MRL/lpr mice. J Immunol. 186:527-538. PMCID: PMC3124407
Receptor agonists of macrophage migration inhibitory factor
Jorgensen WL, Gandavadi S, Du X, Hare AA, Trofimov A, Leng L, Bucala R. 2010. Receptor agonists of macrophage migration inhibitory factor. Bioorg Med Chem Lett. 20:7033-7036. PMCID: PMC2989669
MIF Promoter Polymorphisms and Susceptibility to Severe Malarial Anemia
Awandare GA, Martinson JJ, Were T, Ouma C, Davenport GC, Ong'echa JM, Wang W, Leng L, Ferrell RE, Bucala R, Perkins DJ. 2009. MIF Promoter Polymorphisms and Susceptibility to Severe Malarial Anemia. J Infect Dis. 15: 629-637. PMCID: PMC3607439
Macrophage Migration Inhibitory Factor: A Probable Link between Inflammation and Cancer
Bucala R, Donnelly SC. 2007. Macrophage Migration Inhibitory Factor: A Probable Link between Inflammation and Cancer. Immunity 26:281-285.
Abrogation of macrophage migration inhibitory factor decreases West Nile virus lethality by limiting viral neuroinvasion
Arjona A, Foellmer HG, Town T, Leng L, McDonald C, Wang T, Wong SJ, Montgomery RR, Fikrig E, Bucala R. 2007. Abrogation of macrophage migration inhibitory factor decreases West Nile virus lethality by limiting viral neuroinvasion. J Clin Invest 117:3059-3066. PMCID: PMC1994625
The macrophage migration inhibitory factor-glucocorticoid dyad: regulation of inflammation and immunity
Flaster H, Bernhagen J, Calandra T, Bucala R. 2007. The macrophage migration inhibitory factor-glucocorticoid dyad: regulation of inflammation and immunity. Mol Endocrinol. 21:1267-1280.