Rheumatoid Arthritis Gene-Regulating Mechanisms Uncovered

Rheumatoid Arthritis Gene-Regulating Mechanisms Uncovered

Yale School of Medicine researchers have uncovered the molecular key players that regulate a gene known to be linked to susceptibility to infectious and autoimmune diseases such as rheumatoid arthritis. The research paper, “Transcription factor ICBP90 regulates the MIF promoter and immune susceptibility locus,” was published in The Journal of Clinical Investigation.

Macrophage migration inhibitory factor (MIF) is a regulatory cytokine known to contribute to the pathogenesis of autoimmune and infectious diseases and cancer. It results in the inhibition of apoptosis and the survival of different cell types, the inhibition of the immunosuppressive action of glucocorticoids, and the high expression of cytokines and other molecules involved in the immune system response.

Despite the clear association between the overexpression of this specific gene and the pathogenesis of a large range of conditions, the molecular mechanisms controlling this response have remained elusive.

The team, led by Prof. of Medicine Dr. Richard Bucala, looked at the variants of MIF that cause overexpression of the gene, reproducing them in the lab and studying their function in monocytes, which are white blood cells of the innate immune system. Through a series of different techniques such as liquid chromatography — mass spectrometry for analysis of nuclear proteins — scientists identified a transcription factor that regulates MIF activity: the ICBP90 protein.

Importantly, in the context of the synovial membrane of rheumatoid arthritis patients, the expression levels of ICBP90 and MIF strongly correlated, suggesting this molecular pathway is indeed crucial for the inflammatory response and warrants further investigation.

“Now that we know the exact transcription factor, we can begin to design drugs that will interfere specifically with the disease pathway,” Bucala said in a press release. “It opens the way for the most precise form of drug development that is possible. Knowing what the transcription factor is presents the possibility of a real personalized medicine approach.”

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