December 3, 2007

Gene's role in immunological response is
new lead for allergy treatment
Research points the way to new relief strategies targeting a range of human allergies
Medical researchers have known for decades what in general underlies a range of
immune reactions in humans, from slight localized swelling in the case of insect bites, tohives and worse for people with hypersensitivity to certain foods and chemicals.
Researchers at RIKEN are reporting they have isolated what they believe is the specificfactor in such allergic responses: a calcium-linked protein activated by a gene in
mammalian mast cells.
The discovery may lead to new gene-based approaches on how to treat certain
allergies and even prevent anaphylactic shock, which can be fatal in the worst cases offood and chemical allergies.
Mast cells are resident cells of several types of human tissues, including the skin, andcontain granules rich in histamine and heparin that play a key part in the body's
immunological protection. When activated, the mast cell rapidly releases its granules
and various hormonal mediators. Mast cells can be stimulated to 'degranulate' by direct
injury, cross-linking of immune receptors, or - in the case of a mosquito bite - as aresponse to previous exposure to proteins resident in mosquito saliva.
What induces the cells to do this has been the focus of several earlier immunologicalstudies that explored a chain reaction in which calcium (Ca2+) is released as part of a
two-stage process in the body's immune response. In the first stage, stores of Ca2+
within the tissue cells are released at or near the site of the invasion or injury. In thesecond stage, a sustained influx of extracellular Ca2+ occurs across the plasma
membrane of the cells. Initiation of this second step had been thought to result directlyfrom the emptying of the Ca2+ stores, thus activating Ca2+ channels within the plasma
membrane. But the earlier research has not been conclusive on this point.
Until now, just how this calcium influx is specifically triggered has not been understood.
To gain greater insight, the RIKEN researchers used a genome screen of mouse RNA

and subsequently identified a gene, Stim1, which acts as a sensor to alert when there isa depletion of the calcium stores. Working backwards, they removed the STIM1 proteinfrom the tissues of lab mice. Through a series of tests they showed that the absence of
the STIM1 protein either substantially or completely abolished Ca2+ influx in the mouse
tissues when they were subjected to test allergens.
The researchers also noted that the failure of some people to exhibit normal immunity
may be another consequence of deficiencies in STIM1-dependent immune response
caused by defective intracellular signaling activity in mast cells. If so, among otherpossible applications, a 'genetic fix' might be useful in boosting the body's sagging
natural defenses by raising the expression level of Stim1.
The RIKEN study showed as well that STIM1 figures in the body's anaphylactic
response to tissue damage or biological or chemical invasions, including minisculeamounts that can kill hypersensitive individuals. These include bee stings, peanutingestion and exposure to trace chemicals in the workplace. The researchers noted thatthe role STIM1 plays in such dangerous hypersensitivity warrants further investigation.
The findings were reported by a research team headed by Tomohiro Kurosaki at RIKEN
Research Center for Allergy and Immunology in Yokohama.
Original work:
Baba, Y., Nishida, K., Fujii, Y., Hirano, T., Hikida, M. and Kurosaki, T.
Essential role for STIM1 in mast cell activation and anaphylactic responses
Nature Immunology, published online on Dec. 3, 2007

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