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Immune-related genes investigated

  [ 22 votes ]   [ Discuss This Article ] • September 6, 2000

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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