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American Liver Foundation Postdoctoral Research Fellowship Award
Yale University School of Medicine, New Haven, Connecticut
“The role of Macrophage Migration Inhibitory Factor (MIF) in Autoimmune Hepatitis”
Autoimmune hepatitis (AIH) is a disease with a variable presentation and clinical course. It is a condition of dysregulated immunity, however much of the pathophysiology and inciting events are incompletely understood. Most patients sustain chronic disease activity, thus long-term therapy with steroids/immunomodulators is often required. There are few markers to distinguish patients with a more aggressive clinical course from those with quiescent disease. Macrophage migration inhibitory factor (MIF) is a pro-inflammatory cytokine, increasingly recognized as a key participant in sustained immune response to sepsis, rheumatoid arthritis (RA) and Systemic Lupus Erythematosus (SLE). MIF and its transmembrane receptor molecule, CD74, have not yet been studied in the context of AIH or in other autoimmune liver diseases. Both MIF and the pathologic process of AIH operate along the Th(1) immune/cytokine pathway, and thus there is reason to suspect that sustained inflammation in AIH could be related in part to MIF activity. MIF is encoded in a polymorphic locus and high expression alleles have been linked to disease severity in RA and SLE. Results of recent preliminary analysis of blood samples from patients with AIH at Yale University revealed markedly elevated levels of serum MIF as compared to healthy controls. Furthermore, preliminary data showed that the MIF polymorphism which results in high-cytokine expression was over-represented in AIH patients, suggesting a role in the pathogenesis of AIH. The goal of Dr. Assis’s project is to further study these initial findings, to determine if MIF is a suitable biomarker for disease activity in AIH, and whether the genetics of MIF expression are involved in the pathogenesis of disease. Hypothesis-generating work will also examine MIF and CD74 expression in liver tissue from patients with AIH. This translational project will take place at Yale University, with subjects enrolled through the Yale Liver Center Patient Registry. Patient records, blood and tissue samples will be analyzed. Laboratory work will include serum MIF and CD74 measurement via ELISA, genotype polymorphism analysis via PCR and pyrosequencing techniques, and liver tissue study via immunohistochemistry. It is anticipated that these results will demonstrate a role for MIF in the susceptibility to, and clinical course of, AIH thereby generating a basis for further investigation of MIF as a tool in the management of this disease.