Rheumatoid arthritis causes significant disability and increased mortality. Research into its pathogenesis currently focuses on the mechanisms by which host immunity becomes dysregulated to produce pathologic changes. Macrophage migration inhibitory factor (MIF) is an upstream regulator of the immune response that is produced both by innate (monocyte/macrophage) and adaptive (T cell) immune cells. We have discovered that the human MIF gene (Mif) is encoded by functionally distinct alleles, and that high-expression Mif alleles are over-represented in patients with rheumatoid arthritis. We also have identified the cell surface protein, CD74, to be a cellular receptor for MIF. We suggest that MIF overproduction by the innate or the adaptive immune response and its binding to CD74 play an intrinsic role in the pathogenesis of rheumatoid arthritis. The objective of this application is to define the cellular basis of MIF production and action in inflammatory arthritis. The central hypothesis is that inflammatory arthritis results from an overproduction of MIF by monocytes/macrophages or by T cells, coupled with MIF activation of target cells by binding to CD74. The rationale for this proposed research is that once the molecular basis for MIF production and action in inflammatory arthritis is known, then a more precise understanding of immune dysregulation in this disease will have been achieved. We will test our hypothesis and accomplish the objective of this application by pursuing three specific aims: 1) Define MIF's Role in Inflammatory Arthritis by Studying Monocyte-specific and T cell-specific Mif-Knockout Mice. We will examine arthritis development in Mif-floxed mice made genetically-deficient either for monocyte-derived MIF, or for T cell-derived MIF. 2) Establish the Pathologic Role of the MIF/CD74 Interaction In Vivo. We will establish the pathologic importance of the MIF/CD74 interaction by administering a neutralizing anti- CD74 mAb, or a soluble CD74 protein (sCD74), to wild-type mice with experimental arthritis. 3) Define the Role of High- versus Low-expression Mif alleles in MIF Production, Cellular Activation, and Downstream Cytokine Expression by Human Monocytes and T Cells. We will obtain monocytes and T cells from patients with rheumatoid arthritis, analyze the Mif genotype, and study MIF production, cellular activation, and downstream cytokine expression. These results will be significant because they will provide a more precise understanding of MIF's role in the pathways that link innate and adaptive immunity, and which become dysregulated to produce inflammatory arthritis. Moreover, they will provide a scientific rationale for identifying individuals who may be a high risk for severe rheumatoid arthritis - based on their Mif alleles, so that steps can be taken to better treat their erosive disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
1R01AR050498-01
Application #
6704788
Study Section
Special Emphasis Panel (ZRG1-OBM-2 (03))
Program Officer
Gretz, Elizabeth
Project Start
2004-01-23
Project End
2008-11-30
Budget Start
2004-01-23
Budget End
2004-11-30
Support Year
1
Fiscal Year
2004
Total Cost
$371,963
Indirect Cost
Name
Yale University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
You, Sungyong; Koh, Jung Hee; Leng, Lin et al. (2018) The Tumor-Like Phenotype of Rheumatoid Synovium: Molecular Profiling and Prospects for Precision Medicine. Arthritis Rheumatol 70:637-652
Benedek, Gil; Meza-Romero, Roberto; Jordan, Kelley et al. (2017) MIF and D-DT are potential disease severity modifiers in male MS subjects. Proc Natl Acad Sci U S A 114:E8421-E8429
Yao, Jie; Leng, Lin; Sauler, Maor et al. (2016) Transcription factor ICBP90 regulates the MIF promoter and immune susceptibility locus. J Clin Invest 126:732-44
Yoo, Seung-Ah; Leng, Lin; Kim, Bum-Joon et al. (2016) MIF allele-dependent regulation of the MIF coreceptor CD44 and role in rheumatoid arthritis. Proc Natl Acad Sci U S A 113:E7917-E7926
de Souza, H S; Tortori, C A; Lintomen, L et al. (2015) Macrophage migration inhibitory factor promotes eosinophil accumulation and tissue remodeling in eosinophilic esophagitis. Mucosal Immunol 8:1154-65
Gu, Ran; Santos, Leilani L; Ngo, Devi et al. (2015) Macrophage migration inhibitory factor is essential for osteoclastogenic mechanisms in vitro and in vivo mouse model of arthritis. Cytokine 72:135-45
De la Cruz-Mosso, U; Bucala, R; Palafox-Sánchez, C A et al. (2014) Macrophage migration inhibitory factor: association of -794 CATT5-8 and -173 G>C polymorphisms with TNF-? in systemic lupus erythematosus. Hum Immunol 75:433-9
Binsky-Ehrenreich, I; Marom, A; Sobotta, M C et al. (2014) CD84 is a survival receptor for CLL cells. Oncogene 33:1006-16
Fan, Huapeng; Kao, Wenping; Yang, Yuan H et al. (2014) Macrophage migration inhibitory factor inhibits the antiinflammatory effects of glucocorticoids via glucocorticoid-induced leucine zipper. Arthritis Rheumatol 66:2059-70
Meza-Romero, Roberto; Benedek, Gil; Yu, Xiaolin et al. (2014) HLA-DR?1 constructs block CD74 expression and MIF effects in experimental autoimmune encephalomyelitis. J Immunol 192:4164-73

Showing the most recent 10 out of 65 publications