Newly Discovered 'ng' Process Helps Immune System Cells Pick Their Fights

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Source: Washington University School of Medicine

Date: 2005-05-18

Newly Discovered 'ng' Process Helps Immune System Cells Pick

Their Fights

May 17, 2005 — Scientists have uncovered a new method the immune system

uses to label foreign invaders as targets to be attacked. Researchers

showed that the immune system can brand foreign proteins by chemically

modifying their structure, and that these modifications increased the

chances that cells known as lymphocytes would recognize the trespassers

and attack them.

" Now that we know that some T cells need to see these types of

modifications to identify an invader, we can see if incorporating such

changes into the proteins is helpful for vaccination, " says senior

author Emil R. Unanue, M.D., the Mallinckrodt Professor and head

of Pathology and Immunology.

The finding may also be relevant to autoimmune conditions where the

immune system erroneously attacks healthy tissues. Such disorders

include rheumatoid arthritis, multiple sclerosis and type 1 diabetes.

" We show in this study that during some infections, these same types of

modifications can be made to our own proteins, potentially leading to T

cell attacks on the self, " says Unanue.

Unanue and colleagues, who publish their results on May 31 in the

Proceedings of the National Academy of the Sciences, conducted their

studies in mice and in cultures of mouse cells. Herzog, a

research associate in Unanue's lab, did many of the experiments and was

the lead author of the study.

T cells belong to a class of immune cells known as thymic-lymphocytes,

which in turn are a component of the branch of the immune system known

as adaptive immunity. This branch responds to pathogens after they

interact with the other major branch, the innate immune system. T cells

kill pathogens or produce molecules like cytokines that stop their

growth.

Scientists have known for some time that a second class of innate

immune system cells known as antigen-presenting cells helps T cells

determine what to attack. They do this by displaying fragments of

proteins they have picked up on their surfaces for inspection by T

cells. Fragments of proteins are called peptides.

Researchers also knew that when antigen-presenting cells are activated

by inflammatory factors or microbial products, they start putting out

chemically unstable compounds such as nitric oxide and superoxide.

Together, these compounds generate peroynitrate, a highly potent

chemical that modifies many proteins.

Unanue's group showed that this chemical modifies the peptides

presented by antigen-presenting cells in several distinct ways. For

example, they attach a nitrate group to the amino acid tyrosine in the

peptides, changing it to nitrotyrosine.

Unanue's lab then showed that these changes increased the chances that

various types of T cells would react to the modified peptides shown to

them by antigen-presenting cells.

Unanue's group is working to substantiate their findings and explore

their potential relevance to different areas of biomedical research. He

notes that insulin-producing beta cells, the pancreatic cells attacked

by T cells in type 1 diabetes, also generate reactive compounds similar

to those made by antigen-presenting cells.

" The beta cells could therefore be modifying their own proteins in the

same way that antigen-presenting cells are modifying foreign proteins, "

he says. " We're now investigating whether such modifications can cause

T cells to attack the beta cells. "

Damaging oxidative reactions are also believed to play a role in

atherosclerosis. Scientists suspect oxidative damage in the blood

vessel walls may lead to immune reactivity that contributes to

narrowing and stiffening of blood vessels.

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Herzog J, Maekawa Y, Cirrito TP, Illian BS, Unanue ER. Activated

antigen-presenting cells select and present chemically modified

peptides recognized by unique CD4 T cells. Proceedings of the National

Academy of the Sciences, 102 (22), 7928-7933.

Funding from the National Institutes of Health and the Kilo Diabetes

and Vascular Research Foundation supported this research.