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New understanding of autoimmune diseases

January 26, 2016

Thanks to a recent Yale study, physicians may soon adopt a new method to combat rheumatoid arthritis and other autoimmune diseases.

Researchers at the Yale School of Medicine have discovered a transcription factor, ICBP90, that has been shown to regulate the expression levels of MIF — a gene that has been implicated in a number of diseases, primarily autoimmune diseases and cancer. The transcription factor, a protein responsible for facilitating the production of RNA from DNA, binds to MIF’s promoter region, which helps to regulate and initiate transcription. According to the study authors, by identifying the connection between ICBP90 and MIF, researchers can develop new methods of drug treatment for diseases including rheumatoid arthritis and cancer by targeting the gene in a more precise and personalized way.

“The study discovered ICBP90 and validated the fact that if you influence the expression of the transcription factor, you influence the expression of the MIF target gene,” medical school professor and senior author Richard Bucala said. Prior to the study, Bucala discovered a common genetic variation in the promoter region of MIF. The increased expression of MIF depends on how many microsatellite repeats are present in the promoter. A microsatellite is a short stretch of nucleotides, the smallest unit of DNA, Bucala said.

In the case of MIF, the microsatellite CATT is repeated five to eight times, varying in people and in different populations. An increased number of CATT repeats indicates high expression of MIF. Bucala’s team created synthetic promoter regions that had five to eight repeats or none at all. They then devised a way to identify proteins that bind to the high-repeat forms, and they were able to single out the factor ICBP90 from other possible nuclear proteins, Bucala added.

Low expression of MIF has been shown to have benefits against certain diseases. Bucala noted that low expression of MIF confers resistance to death from malaria. Low expression also decreases susceptibility to autoimmune diseases and lessens their severity.

Consequently, MIF is a good target for drugs, Bucala explained. Currently, drug treatments attempting to block the protein coded by MIF are in phase II clinical trials. The drugs have a selective effect based on genotype and work best on patients with high levels of MIF expression, he added.

The findings of this research are a further step toward personalized medicine for treating autoimmune diseases, such as rheumatoid arthritis and lupus, Bucala said. Now that the regulatory protein has been identified, it is possible that, instead of using biological antibodies to block the RNA or expressed protein of the MIF gene, scientists could devise small molecules that target the regulatory binding in the nucleus by the transcription factor before the gene is even transcribed, he added.

There are two potential therapeutic implications of the study, according to Maor Sauler, study co-author and medical school professor. The first will allow researchers to better understand how MIF is involved in disease, particularly in differentiating what is caused by environmental stimuli, and what is caused by the gene. The second implication is that scientists will be able to identify the MIF polymorphism in individual patients. This will help to indicate patients’ susceptibility to autoimmune diseases as well as signal which patients will respond best to anti-MIF or anti-ICBP90 therapy, Sauler added.

Medical school professor Martin Kriegel, who was not involved with the study, believes the findings of the study are significant, but said the impact in the clinical setting is still far from clear.

“I think it is a step forward, but there is still a lot of work to be done,” Kriegel said.

He emphasized that MIF is a very potent gene that has many effects, and specifically targeting ICBP90 may not have as broad an effect on the body as scientists hope.

Sauler noted that understanding the connection between MIF and ICBP90 can help establish new research on diseases related to the gene’s expression. Both the transcription factor and the gene can be analyzed “side by side,” providing a fuller picture. He also emphasized the benefits of personalized medicine, which the successful clinical implementation of this study can help to improve.

Personalized medicine is important in creating individually based therapies, rather than just optimizing on the general benefit of an entire population.

“I think this is how disease needs to be treated,” Sauler said. “If we think everyone is the same, then we’re going to be stuck with the same therapies and the same treatment. Only by understanding the parts of us that make us unique and individuals are we going to tailor the right therapies for the right person for the right disease.”

According to the American College of Rheumatology, rheumatoid arthritis affects more than 1.3 million United States adults.

Submitted by Lisa Brophy on January 29, 2016