Science Editor

Allergies can be a big nuisance, but most often they are at least not more than that.

But what makes them a bigger headache for the sufferers - or, especially in the case of young children suffering from food allergies, their worried parents - is the off chance that an allergic response will spin out of control into anaphylactic shock.

Anaphylaxis is rare, and anaphylactic deaths are rarer still. "Most allergic individuals never go into anaphylaxis," Juan Rivera told BioWorld Today.

But when anaphylaxis does occur, it can be fatal. And because there is no way to predict who might have an anaphylactic response, there is by and large no option but a better-safe-than-sorry approach that assumes the worst could happen with any allergen exposure, some times leading to severe restrictions on allergy sufferers themselves as well as their environment.

In the April 19, 2010, edition of the Journal of Clinical Investigation, senior author Rivera, who is chief of the Laboratory of Molecular Immunogenetics at the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health, and his colleagues reported that the signaling lipid sphingosine-1-phosphate plays a role in anaphylaxis.

The work, though currently preclinical, could pay dividends in identifying individuals who are at higher-than-average risk for anaphylactic shock. It also points to some subtypes of the sphingosine-1-phosphate receptor as worth investigating as potential antianaphylaxis targets.

Rivera and his team looked at the role of two kinases that make sphingosine-1-phosphate, sphingosine kinase 1 and sphingosine kinase 2, in recovering from an anaphylactic response. Earlier work by the team had implicated the kinases in the onset of anaphylactic responses; the new work showed that they also play a role in recovery, especially sphingosine kinase 1.

They found that knocking out SK1 led to poor recovery from anaphylactic shock in the animals, while knocking out SK2, somewhat surprisingly, had a beneficial effect - somewhat surprisingly, since both molecules make sphingosine phosphate. Rivera said that why the knockouts have opposing effects is unclear at this point, though it is possible that knocking out SK2 paradoxically increases the levels of sphingosine-1-phosphate via indirect compensatory mechanisms.

When Rivera and his colleagues knocked out different subtypes of the sphingosine-1-phosphate receptor, mice lacking subtype 2 also recovered more slowly from anaphylactic shock. Injecting partial knockouts of that receptor - "and even wild-type animals," first author Ana Olivera pointed out - improved recovery, providing what Rivera termed "indirect but strong evidence" that sphingosine -1- phosphate acts through the receptor subtype to regulate recovery.

The kinases, Rivera said, appear to be "critical with regards to regulating blood pressure," and helping to excrete histamine - which floods the body during an anaphylactic response, leading to symptoms that can include flushing, low blood pressure and trouble breathing - through the kidneys.

Rivera and his team are investigating the effects of sphingosine kinases in allergic responses more generally. On a practical level, the results suggested that receptor subtype 2 agonists, "potentially in combination with receptor subtype 1 agonists (as described in a study by others)" might be a therapeutic option worth exploring further.

Such an approach, Rivera stressed, would not replace the current treatment - epinephrine shots - completely; but "there is a fairly large population of individuals" - for example, those with cardiac problems - that are susceptible to quite serious side effects" from epinephrine.

Even in people where epinephrine is unproblematic, sphingosine-1-phosphate levels, if they correlate with susceptibility to anaphylaxis, might be a useful diagnostic tool. Paradoxically, high blood levels of sphingosine-1-phosphate may be the classical piece of good-news, bad-news. Such individuals "may be more susceptible to anaphylaxis," Rivera said. "But they may also be more able to get out of anaphylaxis . . . that kind of a study needs to be done."