A mafia of immune-system molecules gangs up to inflict hay fever andasthma on large percentages of the population. Its godfather isImmunoglobulin-E (IgE). Other co-conspirators include Interleukin-4(IL-4) and certain white blood cells called basophils.Of course, each of these alleged perpetrators of allergy wears a whitehat as well as a black one, performing essential service in the body'simmune defenses.The wheezing in the chest of asthma, and the nasal dripping and eye-itching of hay fever are both allergic afflictions that run in families.David G. Marsh and a covey of co-workers at the Johns HopkinsAsthma and Allergy Center in Baltimore set out to reveal the geneticbasis of this rhino-bronchial inheritance.Their paper, in the May 20 issue of Science, reports "Linkage Analysisof IL4 and Other Chromosome 5q31.1 Markers and Total SerumImmunoglobulin E Concentrations." That is, their study of 170individuals from 11 extended Amish families found evidence linkingfive markers in or near the tip of chromosome 5's long arm with a genecontrolling IgE.Asthma sufferers in the U.S. number in the millions, Marsh observed,"6 or 7 percent of the population." Hay fever claims three or four timesas many.Asthma risk coincides with total IgE blood levels, Marsh toldBioWorld Today. His team studied genetically isolated Amish families,he explained, because these have very large pedigrees, uniform farm-based lifestyles, rarely smoke, and are exposed to common air-borneallergens causing these diseases.Why some asthmatics have elevated IgE levels in the apparent absenceof reaction to specific antigens is unclear, Marsh said. This non-cognate form provided a handle for genomic linkage analysis of theIgE pattern in the Amish families, and its presumed connection toasthma.Their key finding, confirming their hunch, was to link IgE with thegene for IL-4, a cytokine that can switch other immunoglobulins, suchas IgG, IgA and so on, to become IgE, and so increase its concentrationin the blood."We found linkage between non-cognate IgE production and geneticmarkers, very close to and in the IL-4 gene." Receptors on basophilsbind IgE with high affinity, leading to the release of IL-4.The 10,000-nucleotide IL-4 gene perches on a region of chromosome 5densely populated with known genes for other cytokines. For instance,IL-13 also switches other Ig classes to IgE, Marsh noted, "so they arenot out of the running at all in up-regulating IgE biosynthesis as fellowallergy perpetrators. Switching," he added, "appears to be the criticalissue."Does this genetic discovery hold out any hope for therapies to preventor relieve asthma and hay fever?"Very definitely," said Marsh. "In the future, once we have identifiedthe so-called functional polymorphism, that is, the variation in IL-4 ora neighboring gene, this should enable a rational design of newtherapeutic agents." He added, "We're working actively right now tofind such nucleotide differences between high and low IL-4 producers."If the functional polymorphism turns out to be located in an exon, thatpart of a gene encoding protein, the variation might lead to a changedamino acid. If this trait is in a heterozygote, one might down-regulatethe aberrant IL-4 form, perhaps by an antisense approach."

-- David N. Leff Science Editor

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