Quantity Can Turn Immune System from Friend To Enemy

by Ralph M. Steinman, M.D.

March 1, 2007

“There are two sides to the coin” is an adage we use a lot in immunology: the immune system has many molecules and mechanisms that desirably protect us against infection, but each one also has a downside that can result in unwanted symptoms or disease.

In the “desirable” category, immunologists are starting to use the innate, or built-in, immune system to identify adjuvants, substances that enhance the efficacy of vaccines. The article from New Scientist (“Vaccines Set to Target Immune Panic Button”) covers research in this area.

British researchers are designing vaccines that contain an adjuvant to trigger an innate immune pathway called RIG-I. This pathway allows the body to produce interferon to protect itself against viral infection. When interferon is made by the right cells and in the right amounts, it can also serve as an effective adjuvant, according to current research.

On the other hand, the innate immune system can go into overdrive and produce dangerously high, sometimes lethal amounts of cytokines, immune system substances that would be protective in small amounts. An excess is called a “cytokine storm.”

An article from the scientific literature reports on a team of scientists from Canada and Japan that studied what happens when the 1918 pandemic influenza virus infects monkeys, a close model to infection in humans (“Influenza: Fatal Immunity and the 1918 Virus”). They found that the pandemic strains have a one-two punch.

First, the virus is poor at inducing protective interferons. The pandemic flu virus carries a form of a protein that seems to block the RIG-I pathway mentioned above. It thereby evades the innate mechanism to protect virus-infected cells.

Punch No. 2 is that the virus triggers additional innate pathways excessively, bringing about a storm of cytokines and other immune substances called chemokines. Each of these produces severe inflammation in the lungs, which is lethal during pandemic flu.

A molecule called interleukin-23, or IL-23, which we highlighted in the December 2006 issue, also has a dual identity. Scientists are just starting to figure out the value of IL-23, which appears designed to protect against certain kinds of infection at parts of the body including the lung, skin, and genital tract.

The other side of the coin is that IL-23 is produced inappropriately in several diseases. We highlighted inflammatory bowel disease in December, but the first instance where scientists found IL-23 to be going awry was in a skin disease, psoriasis.

Now the Deseret Morning News in Salt Lake City reports on a New England Journal of Medicine study in which IL-23 has been blocked in psoriasis patients using a particular type of antibody (“New Psoriasis Treatment Highly Effective, May Help Irritable Bowel”).

In these studies, the blockade of IL-23 was repeatedly beneficial for the patients. Scientists are still trying to figure out how the bad side of the IL-23 coin comes about. Why is it produced in the first place during psoriasis? It should be helpful to study patients before and after anti-IL-23 therapy to get some answers.