Montréal, March 27, 2014 – IRCM researchers led by Javier M. Di Noia, PhD, uncovered a new function of AID, a crucial enzyme for the immune response. The discovery, recently published by the scientific journal Proceedings of the National Academy of Sciences (PNAS), helps explain a rare genetic disorder that causes an immunodeficiency syndrome.
The Montréal research team studies the enzyme AID, or activation-induced deaminase, that can be found in B lymphocytes (the group of white blood cells whose main function is to produce antibodies to fight against infections). AID creates deliberate mutations in DNA to modify the antibody genes, which is necessary to produce an appropriate immune response. However, inappropriate functioning of AID can also have harmful effects and lead to certain oncogenic (cancer-causing) mutations.
"One of AID's roles is to trigger antibody class switching, a critical mechanism for immune responses," explains Dr. Di Noia, Director of the Mechanisms of Genetic Diversity research unit at the IRCM. "Class switching is the process that allows a B cell to produce different classes of antibodies, so the immune system can respond to and eliminate a wide variety of antigens."
AID initiates a mechanism whereby a break occurs in the DNA, within the antibody genes, and a segment is removed. The free ends on either side of the removed fragment must be rejoined to repair the DNA strand and, thus, produce a new class of antibody.
"Not only is AID responsible for triggering class switching, but we also discovered that it facilitates DNA repair during this process," says Astrid Zahn, PhD, research associate in Dr. Di Noia's laboratory and first author of the study. "In addition, we identified which domain of the enzyme controls this novel activity. These findings show that AID provides a link between the DNA damage and repair steps during class switching."
"Our study also helps explain a rare disease known as hyper-IgM syndrome type 2 (HIGM2) that is caused by mutations affecting AID," adds Dr. Zahn. "The disease is part of a family of genetic disorders in which patients only produce Immunoglobin M (the default class of antibody produced by B lymphocytes), but none of the other classes of antibodies elicited during infections. This dramatically compromises the immune system's ability to fight infectious diseases."
In the human genome, two copies (or alleles) of a gene exist for every protein, one coming from each parent. HIGM2 is usually caused by a total AID deficiency because both alleles of the gene are inactivated. However, in about 10 per cent of HIGM2 patients, only one allele of AID is mutated. This mutated enzyme is therefore dominant, as it causes the disease despite the simultaneous presence of normal AID in the B cell. The researchers found that all mutated AID variants were specifically lacking the domain identified in their study as being important for DNA repair.
"In HIGM2 patients, the absence of this region makes AID exceptionally efficient at producing DNA damage but without the ability to initiate the necessary repair mechanisms," concludes Dr. Di Noia. "As a result, the mutated AID interferes with the normal mechanism of class switching and becomes toxic for B cells, thus causing the immunodeficiency syndrome."
About the study
Dr. Di Noia's research was funded by the Canadian Institutes of Health Research and the Canada Research Chairs program. The project was conducted at the IRCM by Astrid Zahn, Anil K. Eranki, Anne-Marie Patenaude, Stephen P. Methot, Paul Foster and Javier M. Di Noia, in collaboration with Ramiro E. Verdun, PhD, from the Miller School of Medicine at the University of Miami, and Dr. Anne Durandy at the Neckers-Enfants Malades hospital in Paris. For more information, please refer to the article summary published online by PNAS: http://www.pnas.org/content/111/11/E988.abstract.
About Javier M. Di Noia
Javier Marcelo Di Noia obtained a PhD in biochemistry from the University of Buenos Aires in Argentina. He is Associate IRCM Research Professor and Director of the Mechanisms of Genetic Diversity research unit. Dr. Di Noia is also associate research professor in the Department of Medicine (accreditation in biochemistry, and microbiology and immunology) at the Université de Montréal, and adjunct professor in the Department of Medicine (Division of Experimental Medicine) at McGill University. He is a Canada Research Chairholder in Genetic Diversity. For more information, visit http://www.ircm.qc.ca/dinoia.
About the IRCM
Founded in 1967, the Institut de recherches cliniques de Montréal is currently comprised of 35 research units in various fields, namely immunity and viral infections, cardiovascular and metabolic diseases, cancer, neurobiology and development, systems biology and medicinal chemistry. It also houses four specialized research clinics (cholesterol, cystic fibrosis, diabetes and obesity, hypertension), eight core facilities and three research platforms with state-of-the-art equipment. The IRCM employs 425 people and is an independent institution affiliated with the Université de Montréal. The IRCM Clinic is associated to the Centre hospitalier de l'Université de Montréal (CHUM). The IRCM also maintains a long-standing association with McGill University. The IRCM is funded by the Quebec ministry of Higher Education, Research, Science and Technology.
Journal
Proceedings of the National Academy of Sciences