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False alarm can spark autoimmune disease

CORNELL (US) — An unchecked signaling mechanism could be the reason the immune system sometimes goes off track to attack the body’s own cells.

The problem lies in what are called innate immune cells, the first responders to infection, says Cynthia Leifer, assistant professor of microbiology and immunology at Cornell University. The findings may open the door for new therapies for diseases like lupus and arthritis.

“Innate immune cells have internal watchdogs called TLR-9 receptors that set off alarms whenever they encounter invaders. They look for general classifying patterns (in DNA) to determine whether something is a virus, bacterium, protozoan, or part of self.”

But as reported in the European Journal of Immunology, some of these patterns exist both in invading organisms and the body’s own cells, so mistakes can arise.

“We are mapping the critical regulatory mechanisms that keep these receptors from responding to self-DNA so that we can know if and how they predispose people to autoimmune disorders when they fail,” Leifer says.

Innate immune cells engulf things that look dangerous, tear them open, and release their components, including DNA. When TLR-9 receptors see DNA that identifies microbes, they send a signal to fire up more immune-system activity, including inflammation and the creation of antibodies. But before a receptor can work, enzymes in the cell must prepare it by chopping off part of the receptor molecule and leaving a part that can bind to microbe DNA.

From there, Leifer believes it’s a numbers game. If too many receptors are prepared, they may respond to the small amount of self-DNA that makes its way into immune cells, triggering an autoimmune response. So the immune cell has a regulatory mechanism, an enzyme pathway that cuts prepared receptors in a second place.

Working with cells in culture, Leifer identified this second chopping event, which cuts TLR-9 at a different site. This produces a molecule that binds to DNA, blocking it from reaching the prepared receptors, and does not send a signal.

“People without autoimmune diseases have the right balance of these two chopping events,” Leifer says. “Our studies suggest that people with a propensity for these diseases might have a defect in this pathway that allows more prepared receptors to signal for immune responses. This may be a potential target for therapies designed to help quiet those alarms.”

A second but interrelated problem Leifer has tackled involves how TLR-9 moves through an immune cell from the place where it is created to its working site. In earlier work she described the protein sequences in TLR-9 that act as address labels guiding where the receptor travels.

“We think they’re interrelated because if you don’t travel properly you don’t get chopped properly,” she says. “If TLR-9 ends up in the wrong place at the wrong time, it can sound a false alarm.”

Leifer’s research is supported by the National Institutes of Health.

More news from Cornell University: http://www.news.cornell.edu/

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3 Comments

  1. carlos a. roca

    very interesting ,, again a differanciation problem,, the real question still is can the system be realined,,, is there some kind of reset or default,, ? yes quiet the alams reduces the attack level,, ? but to make it so that the alarm is not sent at all,,? It is very good to see the level of interest in the AI disorders,, the only question is it properly funded ? i think that it is the right track and we can save a lot of lives,,,,

  2. Diane H

    I suffered with many autoimmune disorders all my life. I am hopeful that with continued research we may one day find a cure.

  3. Lau Skriver

    I’m aged 58 and have suffered from SLE for 9 years now. Luckily my ‘case’ is not more serious than I can still take care of my daily work and live an almost normal life. However, as there are not that many people suffering from these immune disorders, – in Denmark around 1800 of a population of about 6 million, – I feel that research in this field is giving low priority, which might be natural and understandble, compared to the number of people suffering from other and more serious deseases.
    But it is nice to experience that some research is being carried out, after all.

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