In search of the answers, the National Institutes of Health (NIH) is heading an initiative to catalog the HLA gene complex and explore its differences among populations worldwide. Nearly $20 million over five years will go to the International Histocompatibility Working Group (IHWG), a network of almost 200 laboratories in more than 70 countries, to set up a centralized HLA gene database and develop new and improved tools to decipher this genetic Rosetta Stone of immunology.

"The HLA gene complex comprises the most diverse and variable region in the human genome," explains Anthony S. Fauci, M.D., director of the National Institute of Allergy and Infectious Diseases (NIAID), which is the project's lead sponsor. "Knowledge about its diversity and how these genes direct immune responses could improve our ability to predict, diagnose and treat immune-mediated disorders and infectious diseases."

John A. Hansen, M.D., at the Fred Hutchinson Cancer Research Center (FHCRC) in Seattle, will head the project. According to Dr. Hansen, head of FHCRC's Human Immunogenetics Program and a professor of medicine at the University of Washington, the project could have immediate clinical benefits, for example, for finding better matches for bone marrow transplant recipients.

"But the potential impact of these new studies goes way beyond immunogenetics," says Dr. Hansen. "This project will apply recent advances in genome technology to important questions about specific diseases and help explain how the rich genetic differences in HLA among individuals can either strengthen the immune response or open the door to autoimmune disease and infection."

The HLA gene complex, known more generally as the major histocompatibility complex (MHC), is responsible for encoding proteins that stud the surface of the body's cells, marking them as our own. Anything not marked as "self" can come under attack from the immune system. This includes foreign matter such as viruses and bacteria as well as cancerous cells and transplanted tissue. Even organs from a close blood relative can display very different HLA markers due to the underlying distinctions within each individual's HLA gene complex; a perfect HLA-type match exists only between identical twins.

The effectiveness of a person's immune defenses for detecting and destroying trespasser antigens depends largely on his or her HLA gene complex. Similarly, these genes are suspected of playing a role when the immune system mistakenly targets the body's own cells as foreign, which is the case with autoimmune disorders such as multiple sclerosis, rheumatoid arthritis and type 1 diabetes. The IHWG will accelerate investigations seeking to discover the fundamental mechanics of how HLA genes direct beneficial and harmful immune responses.

"The IHWG represents more than 30 years of collaborative research among the world's leading scientists in population-based genetics," says Daniel Rotrosen, M.D., director of NIAID's Division of Allergy, Immunology and Transplantation. "Its extensive international network of laboratories will contribute significantly to NIAID's efforts to address the global health problems caused by infectious and immune-mediated diseases."

A primary goal of the IHWG is to create a searchable HLA database linking multiple interacting genes with function, ethnicity and disease. A more centralized database will make it easier for scientists to find and contribute new data. It also will help clinical investigators use the information as a platform for future research on immune-mediated diseases.

Other IHWG objectives include the following:

• finding more accurate DNA-based techniques to replace current methods for identifying organ donor matches for transplantation;

• stimulating vaccine development by defining candidate vaccine targets in diverse populations;

• clarifying the role of HLA genes in susceptibility and resistance to autoimmune diseases;

• developing standardized molecular tools to explore the genetic diversity of the HLA gene complex.

Knowledge about the patterns of HLA gene combinations prevalent in different ethnic groups also could illuminate the historical relationships among the world's subpopulations. Theoretically, someday scientists could custom-build vaccines based on HLA genes. Such vaccines could provide better protection against diseases endemic to a group or geographic area, such as malaria and the varying subtypes of the human immunodeficiency virus (HIV) appearing in different parts of the world.

Participating with NIAID in funding the cooperative agreement with the IHWG are several other NIH sponsors, including the National Cancer Institute, the National Institute of Diabetes and Digestive and Kidney Diseases, the National Human Genome Research Institute, and the National Center for Biotechnology Information at the National Library of Medicine. Another sponsor is the nonprofit Juvenile Diabetes Foundation International.

For details about IHWG research plans and workshop meetings, visit http://www.ihwg.org.

NIAID is a component of the NIH. NIAID conducts and supports research to understand basic immunology and to prevent, diagnose and treat infectious diseases and immune-mediated disorders, including HIV disease and other sexually transmitted diseases, tuberculosis, malaria, autoimmune disorders, asthma and allergies. NIH is an agency of the U.S. Department of Health and Human Services.

Press releases, fact sheets and other NIAID-related materials are available on the NIAID Web site at http://www.niaid.nih.gov.