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The human body is involved in a constant fight to defend itself and maintain its integrity. Aggressions —from infections, for example—are warded off by molecules that, like soldiers, flood a particular area, repel the invaders and repair damage. The body’s first line of defense is called innate immunity. But how does the body prevent the war zone from spreading disproportionately?
A research team at the Institut de recherches cliniques de Montréal (IRCM) / Montreal Clinical Research Institute led by Christian F. Deschepper may have come up with some answers. In collaboration with the University of Montreal Hospital Research Centre, the team has identified a gene that may be essential to all living beings for controlling certain innate immune responses.
Controlling the fire
“Innate immune responses are essential to fend off intruders that could contaminate our bodies,” explains Dr. Deschepper, Director of the IRCM Experimental Cardiovascular Biology research unit, Full Research Professor in the Department of Medicine at Université de Montréal and Adjunct Professor in the Department of Medicine at McGill University. “Problems arise, however, when the response is not well controlled.”
If uncontrolled, immune responses may attack areas that are not directly threatened by invaders. When the defense reactions spread too much, inflammatory disorders called autoimmune diseases, which include lupus or rheumatoid arthritis, may occur.
What, under normal circumstances, helps the body to stop this from happening?
A domino effect
To answer this question, the IRCM team examined the genomes of 90 mice derived from 22 different strains.
“Through our observations and bioinformatics analyses, we identified a region called a hotspot, which can regulate the innate immune response,” says Saloua Jeidane, PhD student in Dr. Deschepper’s laboratory and first author of this article.
Saloua’s research shows that a specific gene, called Ypel5, acts like a policeman: it controls the activation of a group of nearly 190 other genes. “When Ypel5 is inactive, cells respond to attacks by producing up to three times more interferons (molecules normally secreted when intruders are present). Cells without Ypel5 produce interferons even in the absence of intruders,” says Saloua, who has studied Ypel5 both mouse and human cell lines.
“It’s like a domino effect,” says Dr. Deschepper. “If we remove Ypel5, the other genes in the hotspot become hyperactive, one after the other, and the immune response spirals out of control.”
A highly-conserved gene
Could the extinction of Ypel5 be therefore the cause of certain autoimmune diseases? It may be a little more complicated than that.
All organisms in the animal kingdom (even those made up of a single cell) are born with a copy of the Ypel5 gene or a very similar gene. “The fact that this gene has remained so conserved in all living beings for such a long time during evolution is probably an indication that it has an essential role,” says Dr. Deschepper. “We observed that when Ypel5 was inactive in a mouse embryo, gestation was quickly interrupted.”
However, it remains possible that Ypel5 could mutate at some later stage as in the case of some cancers.
“Our study is one of the first to describe this gene’s role, but we can already say that that it plays an important role in the development, in the control of immune response and perhaps also in certain cancers,” the IRCM researcher concludes. “We need to clarify its role to see whether it can help us outsmart these diseases.”
About the study
The research project was carried out at the IRCM Experimental Cardiovascular Biology Research Unit by Saloua Jeidane, Marie-Pier Scott-Boyer, Sophie Cardin, Sylvie Picard and Christian F. Deschepper. Nicolas Tremblay, Martin Baril and Daniel Lamarre, from the CHUM Research Centre, were also involved in the study. The research was funded by the Canadian Institutes of Health Research. Saloua Jeidane also received an IRCM Challenge Scholarship from the IRCM Foundation.
About the IRCM
Founded in 1967, the Institut de recherches cliniques de Montréal (IRCM) / Montreal Clinical Research Institute is a non-profit organization that conducts fundamental and clinical biomedical research in addition to training high-level young scientists. With its cutting-edge technology facilities, the institute brings together 33 research teams, which work in cancer, immunology, neuroscience, cardiovascular and metabolic diseases, systems biology and medicinal chemistry. The IRCM also operates a research clinic specialized in hypertension, cholesterol, diabetes and cystic fibrosis, as well as a research centre on rare and genetic diseases in adults. The IRCM is affiliated with the Université de Montréal and associated with McGill University. Its clinic is affiliated with the Centre hospitalier de l’Université de Montréal (CHUM). The IRCM is supported by the Ministère de l’Économie, de la Science et de l’Innovation (Quebec ministry of Economy, Science and Innovation).
Source:
Anne-Marie Beauregard, Communications Officer
Institut de recherches cliniques de Montréal (IRCM) / Montreal Clinical Research
514 987-5555 | anne-marie.beauregard@ircm.qc.ca
