Have you heard the one about the boy who ran through the kitchen into the backyard and dropped dead? No, this is not a bad joke. It is a real case report published in the 80’s. Imagine, if you will, a young boy with a known allergy to fish running through the kitchen while his mother is boiling some fish stock. He inhales a few molecules of the fish protein that dissolved in the cooking vapor, and dies within minutes! To put things in perspective, we are not talking here about toxins that can kill at microgram concentrations (millionth of a gram), and not even nanogram concentrations (billionth of a gram), but picograms (trillionth of a gram). This is probably as potent a killer as they come.

 

Anaphylactic shock

The cause of this deadly attack is known only in general terms. People who are allergic have a certain immunoglobulin, called IgE, at above normal concentrations. These antibodies, like all other types of antibodies, are specific to certain antigens, or allergens. One of the most common is house-dust, another common group of allergens comes from pollens of a variety of grasses and flowers. But there are literally hundreds and thousands of other allergens, some of them extremely rare. Whatever the specific allergen, the IgE destined to bind with it will do just that—and will in turn bind to a receptor, the IgE receptor, on a cell called mast cell. These cells line up blood vessels, primarily small veins and capillaries. Once the complex of IgE/allergen binds to the IgE receptor—all hell breaks loose. The mast cell releases its stores of histamine, which in turn causes the runny nose, the hives, or the asthma attack. But some people, mostly people who have allergies, but also some who haven’t had any known allergies, will react in a much more violent type of reaction—the anaphylactic type. In this reaction, the histamine release by the mast cells is vastly more massive than in the run of the mill allergic reaction. This causes increased permeability of the blood vessels and a flood of blood plasma rushing out into the surrounding tissues. The end result is difficulty breathing, profound hypotension (low blood pressure), slowdown in heart rate, or even cardiac arrest, reduced supply of blood to the brain, the kidneys, and all other organs—leading to a generalized failure of all body systems. Pretty scary stuff.

 

What makes these people vulnerable?

This is a question that occupied the best minds in allergy research for decades—but with little or no results. Until now, that is.

In a publication in Nature Immunology Online, Kirk M. Druey and his colleagues of the National Institute of Allergy and Infectious Diseases (NIAID) report that a protein in mice known as RGS13 suppresses allergic reactions, including the severe, life-threatening reaction of anaphylaxis. RGS13 is one of a large group of regulator of G protein signaling (RGS) proteins that act as traffic lights for signaling networks within cells. Though the biochemical actions of most RGS proteins in laboratory tests are known, their physiological functions in the body are still a mystery. Therefore, the current findings may have broader implications for many different biological processes, such as metabolism, cancer progression, cardiac function, and others.

RGS13 is known to inhibit cellular responses induced by G-protein-coupled receptors (GPCR), which are the most abundant cell surface receptors in the body. It is also known that these receptors are the targets of approximately 60% of therapeutic drugs for various diseases. Since RGS13 is expressed in mast cells, Dr. Druey and his NIAID colleagues decided to explore the role of RGS13 in mouse models of anaphylaxis. Through genetic engineering, they made a group of mice deficient in the RGS13 gene. Normal mice served as the control group. To test for systemic anaphylaxis, they injected the allergen, IgE antibody, and a blue dye directly into the veins of the mice. The organs of RGS13-deficient mice showed an anaphylactic response that was twice as large as that of the normal mice. The results indicate that RGS13 suppresses the anaphylactic response in mice, whereas RGS13 deficiency and abnormal RGS13 expression and function contribute to increased mast cell activity, which occurs during an allergic response, including anaphylaxis.

 

Surprise, surprise

The study is also important because, for the first time, researchers have shown that RGS13 inhibits the activity of PI3 kinase (PI3K), an enzyme involved in many biological processes, including those involved in cancer and diabetes. Therefore, the research has implications for numerous other diseases and medical conditions in addition to allergies.

Which brings me to the larger point I never tire of making: The beauty and excitement of scientific research is in its total and utter unpredictability.

Once the researchers confirm their mouse findings in humans (highly likely), they could use this knowledge to synthesize drugs that would mimic the action of RGS13, thereby treating people prone to extreme allergic reactions. But they could also design drugs that would inhibit RGS13, for the treatment of diabetes and several cancers.

Could anybody ask for a more bountiful harvest of scientific results? And for the policy mavens among us, can you find a return on investment that would come even close?

Dov Michaeli, MD, PhD
Dov Michaeli, MD, PhD loves to write about the brain and human behavior as well as translate complicated basic science concepts into entertainment for the rest of us. He was a professor at the University of California San Francisco before leaving to enter the world of biotech. He served as the Chief Medical Officer of biotech companies, including Aphton Corporation. He also founded and served as the CEO of Madah Medica, an early stage biotech company developing products to improve post-surgical pain control. He is now retired and enjoys working out, following the stock market, travelling the world, and, of course, writing for TDWI.