Immune System Balance Avoids Autoimmune Diseases

[Guest guest]

Immune System Balance Avoids Autoimmune Diseases

Scientists know that the potential to generate dangerous antibodies that

attack our own cells and tissues -- one of the defining characteristics of

autoimmune disorders like lupus -- exists in everyone.

That potential is unrealized in healthy individuals, but spins out of

control in those who develop disease.

So, what are the factors that push the potential for producing these

antibodies into action and cause autoimmunity in some individuals?

A new study from researchers at the Wistar Institute suggests that health

depends on maintaining a balance of normal, but countervailing processes in

the immune system. New approaches to developing treatments for autoimmunity

might focus on influencing this balance.

In lupus and other autoimmune diseases, antibodies against our own cells and

tissues are produced by B cells. The body contains billions of B cells that

can make antibodies that target infecting viruses and bacteria, but these

antibodies can also include ones that can react with " self " -- an

immunologist¹s term for our own bodies.

One process that normally prevents these B cells from causing harm is that

their activity depends on receiving " help " from T helper cells that also

become stimulated when an infection occurs.

However, another kind of T cell, called a regulatory T cell, may be

important in preventing T helper cells from activating B cells with the

potential to generate self-reactive antibodies.

Under normal circumstances, according to the Wistar study, a critical

balance may exist between T helper cells and regulatory T cells. The

researchers saw that providing T helper cells to healthy mice could cause

autoreactive B cells to become active, and that removing T helper cells

could alleviate disease in lupus-prone mice.

They also found that regulatory T cells could stop T helper cells from

activating the B cells, suggesting that the presence of self-reactive T

helper cells with too few regulatory T cells may be crucial for the

activation of B cells producing self-reactive antibodies in lupus.

A report on the research appears in the April issue of Immunity.

" We first established in the laboratory that auto-reactive B cells do

respond to stimulation from T helper cells by producing antibodies against

self, " explains Wistar associate professor Jan son, Ph.D., senior author

on the study. " This was not in itself unexpected because studies by others

had suggested this might be the case. We were, however, somewhat surprised

at how easy it was to trigger this potentially damaging production of

auto-reactive antibodies in the lab. "

" When we looked to see how the process might unfold in mice predisposed to

develop lupus, we saw that, while the same thing happened, it was delayed.

What was exciting to us was that a class of immune cells called T regulatory

cells appeared to actively suppress the development of autoimmunity in these

lupus-prone mice, at least for a time. "

son notes that lupus is a disease that primarily affects women in their

reproductive years, suggesting that a similar delaying process may be at

work in people who will later in life develop the disease.

In terms of possible new therapies for autoimmune disorders, the new

findings also shift attention from the antibody-generating B cells to the T

cells that interact with them.

" One approach to lupus that has been considered is to delete from the

circulation the subset of B cells that are self-reactive, " son says.

" Our work suggests that knowing more about the specificity of the T cells

that stimulate and suppress B cells might be an important path to explore

too. "

The Wistar study focused on some of the precursor events that lead to

autoimmunity. To make eventual use of findings of this kind in a clinical

setting, it would be critical to know if findings made in these animal

models predict whether a particular person might be at risk for developing

lupus or a similar disorder.

" The work we¹re doing looks at the beginnings of disease, before there are

clinical symptoms, " son says. " Other researchers are working to iron out

the genetics of predisposition to autoimmune diseases such as lupus. That

work and ours may come together at some point in the future. "

The lead author on the Immunity study is Su-jean Seo at the Wistar

Institute. The other Wistar-based coauthors are Michele L. Fields, Jodi L.

Buckler, Amy J. , Mandik-Nayak, and Simone A. Nish. Wistar

associate professor J. Caton, Ph.D., collaborated on the study, as

did Randolph J. Noelle at Dartmouth Medical School, ce A. Turka at the

University of Pennsylvania Medical Center and Fred D. Finkelman at the

University of Cincinnati College of Medicine.

Funding for the research was provided by the National Institutes of Health,

the Arthritis Foundation, and, with support for Michele L. Fields, the

Medical Institute.

The Wistar Institute is an independent nonprofit biomedical research

institution dedicated to discovering the causes and cures for major

diseases, including cancer, cardiovascular disease, autoimmune disorders,

and infectious diseases.

Founded in 1892 as the first institution of its kind in the nation, the

Wistar Institute today is a National Cancer Institute-designated Cancer

Center -- one of only eight focused on basic research. Discoveries at Wistar

have led to the development of vaccines for such diseases as rabies and

rubella, the identification of genes associated with breast, lung, and

prostate cancer, and the development of monoclonal antibodies and other

significant research technologies and tools. - By lin Hoke

[Contact: lin Hoke, n Wyce]

17-Apr-2002