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Understanding the Genetic Basis of Immunity
CHORI Investigators Undertake First-Time Overview of Killer-Cell Immunoglobulin-like Receptor (KIR) Population Genetics

July 2012 – Natural killer cells are key players in the innate immune system. Only in the last decade or so have scientists begun to appreciate the incredible genetic diversity of a class of receptors on the surface of these cells, the killer cell immunoglobulin-like receptors (KIR) , and how that diversity may play a role in health and disease. CHORI scientists Jill Hollenbach, PhD, MPH and Elizabeth A. Trachtenberg, MS, PhD, and their colleagues have undertaken the largest to date population genetics study investigating variations in KIR genes, utilizing samples from the Human Genome Diversity Project-Centre d’Etude du Polymorphisme Humain (HGDP-CEPH) panel.

“This kind of overview of the genetics of KIR in a broad population sample has never been done before,” says Dr. Hollenbach. “The HGDP-CEPH collection is extremely well-characterized, and covers an incredible number of different world populations. That makes the KIR variation we’ve described that much more important in terms of our overall understanding of human genetic diversity.”

“This kind of overview of the genetics of KIR in a broad population sample has never been done before.”



The innate immune system is the body's first line of defense against viruses and tumors. Because natural killer cells are key players in the innate immune system, examining the KIR gene system through population genetics studies like this one is the first step in understanding the evolutionary history of the gene system, which in turn helps in the understanding of their function in innate immunity and human health and disease. KIR variation also appears to play a role in transplant outcome.

"Looking at which KIR genes are present in different populations, such as Amerindians, for example, or isolated African tribes, and comparing those KIR genes to KIR genes in other populations provides us with critical information about how genetic variation between different populations may or may not impact how the innate immune system functions," says Dr. Hollenbach. "This information can eventually be used in the treatment or prevention of human disease."

The primary role of NK cells is to travel around the body and look for cells that don't look right. The KIR on the outside of the NK cells either activate the NK cells to kill suspicious cells, or inhibit NK cells to prevent killing of healthy tissue.
“Viruses infect human cells and make them do things they wouldn't normally do. Hopefully the viruses or tumors make the cells look different enough that the NK cells can identify and kill them.”
"Viruses normally infect human cells and make them do things they wouldn't normally do," says Dr. Hollenbach. "Hopefully the viruses or tumors make the cells look different enough that the NK cells can identify and kill them."

While sounding simple enough, it turns out that the genes that encode KIR are both incredibly complex and incredibly diverse. Only by fully understanding the variation in the KIR genes across different populations will researchers be able to know how to use genetic information about KIR in the treatment of human diseases.

The major findings of the Hollenbach study were characterizing for the first time the global variation in the KIR gene system, and discovering that two regions of the KIR gene complex are evolving differently.
"Our study represents a milestone in terms of understanding what the variation of these genes looks like, so that we can eventually understand what that variation means in terms of transplant outcome, as well as treatment or prevention in human health," says Dr. Hollenbach.

Not only that, but also serves as model for how to look at any kind of genetic variation on a global basis, which geneticists from any subspecialty can now utilize.

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Friday, December 28, 2012 1:30 PM

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