Thanks to the human genome project, scientists know that a big chunk of human chromosome 6 consists of an array of dozens of genes that make each person unique — or at least makes their tissues unique.
The activity of those genes, known collectively as major histocompatibility complex genes, or MHC genes for short, determines whose donor tissues will match if a patient needs an organ transplant.
Individuals whose cells feature similar MHC proteins, such as a sibling or twin, can donate tissue without the recipient’s immune system recognizing it as foreign. But MHC genes wield influence far beyond organ transplantation: they help protect against infectious diseases and may influence the course of cancer cell growth.
Marcia Miller, Ph.D., professor in the Division of Molecular Biology, has studied this bewilderingly complicated gene family at City of Hope for 26 years — not in humans, but in chickens, which express a similar array of genes.
“Chickens have been a very important experimental model for years,” explained Miller. “We know about B-cells and T-cells because of studies of chickens, and also a lot about oncogenesis.”
What makes one hen in the chicken coop “unique” may seem like an exotic question, but Miller believes that understanding how MHC genes vary from chicken to chicken could reveal how the human immune system recognizes some cancer cells as foreign and then kills them.
In a study in the June 1 issue of Journal of Immunology, Miller identified candidate chicken MHC genes that may protect birds from cancer. That cancer is a fatal form of T-cell lymphoma called Marek’s Disease, which is caused by the Marek’s Disease virus, or MDV, a member of the herpes virus family.
In humans, herpes viruses cause diseases ranging from benign warts to cancer. Immunocompromised AIDS patients can develop at least two herpes virus-related cancers: Kaposi’s sarcoma and AIDS-related lymphoma.
Interestingly, though, some chickens infected with MDV never develop cancer and remain indistinguishable from uninfected birds, apparently because genes within their MHC complex suppress tumor growth. No one has identified these genes, but Miller is on the case.
For the Journal of Immunology study, Miller and colleagues sequenced the DNA of regions next to the previously characterized “core” chicken MHC genes and found genes that might account for cancer resistance.
Among these were genes encoding a protein called Blec2, which is expressed on the surface of natural killer cells, lymphocyte-like cells that kill virally infected or tumor cells.
They also found tripartite motif (TRIM) genes, which encode proteins associated with virus-fighting activities. One particularly intriguing observation: certain regions of TRIM proteins are responsible for the HIV resistance seen in Old World monkeys.
Given that so many of the genes identified are related to immune response, Miller predicts that at least one is responsible in part for MHC-conferred resistance to Marek’s Disease. "There is a hypothesis in the literature that it is one of the genes down in the core region that makes chickens resistant,” she said, but she believes the story is more complex.
“The door is still open that it is genes in this other region,” she said. “And we think we know which one.” Ongoing studies in her lab should determine whether she is right.
Other contributors included senior research associate Ronald Goto at City of Hope, W. Elwood Briles, Ph.D., a longtime colleague at Northern Illinois University in DeKalb, and a team of collaborators from Tokai University School of Medicine in Kanagawa, Japan, including lead author Takashi Shiina, Ph.D.
Grants from the National Science Foundation, the National Cancer Institute and the United States Department of Agriculture funded the research.