By David N. Leff

Some people are allergic to peanuts (Arachis hypogaea); some are not. Those who are tend to break out in hives, hay fever, asthma or other manifestations of an immune system in overkill mode — i.e., an allergic response.

When a peanut-sensitive individual ingests one, here's what happens: A component of the immune system, namely immunoglobulin E (IgE) latches on to the goober's antigens, then attaches its catch to its perch on mast cells lurking around blood vessels and mucous membranes. These unleash a swarm of molecules dedicated to triggering an acute hypersensitivity reaction. This in turn sets up inflammation of skin, airways and/or lungs, in a typical allergic response.

IgE antibodies honcho that hit, but they owe their own existence and proliferation to a key cytokine, interleukin-4 (IL-4), and its all-important receptor. Among that cell's jobs is inducing the immune system's B lymphocytes to open the IgE spigot wide.

"You have to make IgE to make an allergic response," observed immunologist Talal Chatila, of Washington University, in St. Louis. "This is a big bottleneck in that response. Some people make more IgE than others do."

In the U.S., 40 to 50 million Americans make more IgE than is good for them, and so are susceptible to allergic reactions that leave the rest of the population unharmed. In other words, their immune systems are atopic — hair-triggered.

"We were interested in people who make lots of IgE," Chatila recounted, "to find out if there isn't anything unique about their IL-4 receptor." In pursuit of this question, he and the team in his immunology lab at Washington University have discovered a mutation on the IL-4 receptor gene.

They report it in today's New England Journal of Medicine, dated Dec. 11, 1997. Their article is titled: "The association of atopy with a gain-of-function mutation in the * subunit of the interleukin-4 receptor."

"What we have identified," Chatila told BioWorld Today, "is a mutated gene that makes some people more susceptible to develop allergies. We demonstrated that their altered IL-4 receptor gene product is hyperresponsive compared to a normal gene. This mutation makes the receptor function better, so it signals the cells to make IgE antibodies more effectively than it would have done otherwise. Therefore, people with this altered receptor gene are more likely to develop allergies.

"This mutation," he pointed out, "imparts a relative risk for the presence of allergy by around 10-fold."

Mutations And IgE Turn Up In Allergic People

Chatila and his co-authors scanned the genomes of seven volunteers with severe atopic dermatitis over 20 percent or more of their skin. They found the same missense mutation of the IL-4 receptor gene in four of them, on chromosome 16. A substitution of guanine for adenine in the DNA sequence encoded an amino-acid switch from glutamine to arginine in the gene product.

Three other subjects, with high levels of IgE in their sera, all proved positive for the mutation on their chromosome 16.

The team's third test cohort consisted of 50 randomly chosen adults. They exposed blood sera from this sample to three egregious perpetrators of inhaled allergic reactions, to wit: cat dander, the house-dust mite (Dermatophagoides pteronyssinus) and the common mold (Alternaria alternata). Twenty of those 50 reacted strongly to the allergens, indicating that 40 percent of that test population was atopic — susceptible to allergic responses.

Among those 20, 13 had the gene mutation, vs. only five of the 30 non-atopic subjects.

"We know that the process by which some people develop allergies is not random, but genetically determined," Chatila pointed out.

Atopic individuals inherit their allergic susceptibility the same way Gregor Mendel's garden peas acquired their traits, by the lottery inherent in their paternal and maternal chromosomes. Thus, one of the seven dermatitis subjects had the mutated gene on both chromosomes — i.e., had homozygous inheritance. Three others were heterozygous, with only one of their two parental genes affected by the altered IL-4 receptor gene.

Mutation Helped Prehistoric Ancestors

Chatila suspects that this mutation goes way back in the history of Homo sapiens. "In those olden times," he observed, "it probably was beneficial to have something like this, because this component of the immune system is involved in fighting parasites. So in essence, our prehistoric ancestors had survival advantages by having this protection."

Nowadays, he asked rhetorically, "Why should 30 percent or 40 percent of the population in Western societies have these allergic diseases?"

He impugned "the change in diet, in living conditions, in the houses in which we spend our time. What was beneficial at one point has become detrimental."

Chatila sees two potential benefits in pinpointing allergy susceptibility genes. "One, once you can identify people at high risk, you can start targeting intervention strategies, and assessing them in those individuals before they develop a disease. Two, you can target therapies to the gene product itself, or to pathways regulated by the product to get more specific therapy."

Chatila and his co-authors are now extending their study of the gene's prevalence to various ethnic population groups, "doing molecular archaeology. We're looking at specific disease groups that have this mutation, to see if it disposes to any one disease vs. another. It's highly likely that we'll find such variations.

"And we're looking too," he concluded, "for other gene mutations in the IL-4 receptor signaling pathway. I think there will be not one gene, but a number, and I don't think that number will be so big, probably less than 10; more likely, less than five." *