Editors' ChoiceInflammatory Disease

Allergic to the Cold

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Science Translational Medicine  01 Feb 2012:
Vol. 4, Issue 119, pp. 119ec18
DOI: 10.1126/scitranslmed.3003774

As I write this article on a frigid January day in Chicago, it is not hard for me to appreciate how cold temperatures can alter physiological processes. Yet despite the accepted wisdom that not zipping up your coat will result in catching a cold, the impact of temperature on the immune system is not well understood. In a group of conditions called cold urticaria, individuals have severe allergic-type reactions to cold temperatures involving the degranulation of mast cells. A recent study by Ombrello et al. provides a fascinating molecular insight into a monogenic form of cold urticaria. This study identifies mutations in the PLCG2 gene encoding phospholipase Cγ2 as the culprit and demonstrates that aberrant activation of this enzyme results in altered signaling in immune cells at cold temperatures.

Cold urticaria is an uncommon condition in which mast cells degranulate at low temperatures, resulting in symptoms that range from hives to anaphylactic shock. Different forms of this condition exist, some of which show a Mendelian dominant inheritance pattern that suggests a mutation in a single gene may be the underlying cause. The authors studied three families with a dominant form of cold urticaria and used linkage studies to implicate a region of chromosome 16 in the disease. The leading candidate gene in this region was phospholipase Cγ2 (PLCG2), and targeted sequencing of the families demonstrated in-frame deletions in the regulatory domain of this enzyme that segregated perfectly with disease status. PLCG2 encodes an enzyme present in mast cells, B cells, and natural killer (NK) cells that is involved in several signaling cascades. The authors studied immune cells from the affected subjects and demonstrated that mast cells carrying the disease-associated deletion underwent degranulation at low temperatures but not at 37°C. Additionally, B cells and NK cells carrying the deletion showed reduced activation at physiological temperatures and increased activation at cold temperatures.

This study reminds us of the importance of the effects of environmental factors on the clinical expression of genetic risk factors, even those for classic monogenic dominant conditions. Although the exact molecular mechanisms by which temperature exerts an influence on the mutant PLCG2 enzyme are unknown, the identification of a molecular target for this type of cold urticaria will enable temperature-dependent follow-up experiments that hopefully will pave the way for developing new therapeutics targeted to mutant PLCG2 and the signaling pathways it modulates.

M. J. Ombrello et al., Cold urticaria, immunodeficiency, and autoimmunity related to PLCG2 deletions. N. Engl. J. Med. 366, 330–338 (2012). [Abstract]

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