Immune-related genes investigated

A cluster of nearly 220 genes known as the human leukocyte

antigen (HLA) gene complex holds clues to many unsolved

medical questions: why do transplants sometimes fail despite

close donor-recipient matches? What makes certain people

more susceptible to specific diseases? Why do vaccines

protect some individuals better than others?

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


–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.

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