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Too much of an allergy-related gene makes anaphylaxis worse

Published: July 23, 2020
Approximately 1 in 10 Americans will experience a systemic, potentially life-threatening allergic reaction – known as anaphylaxis – at least once in their lifetime. With the continually increasing number of people suffering allergic diseases such as food allergy world-wide, anaphylaxis incidence is likely to increase. Anaphylaxis occurs when an individual is exposed to a substance, such as a food, insect sting, or medicine, against which their immune system has been primed to make the allergic antibody IgE. Immediate symptoms of IgE-mediated reactions are caused by release of pre-made substances such as histamine and tryptase from allergic effector cells called mast cells that reside next to blood vessels throughout the body, including in the skin, gut lining and lungs. Despite the frequency and potentially life-threatening nature of anaphylaxis, few risk factors have been identified to predict which ‘primed’ individuals will react. Elevated baseline serum tryptase levels are an exception and have consistently been reported as a risk factor for anaphylaxis for unproven reasons. Likewise, few preventative strategies exist, with strict avoidance of allergens remaining the principle method to prevent anaphylaxis. Given this limitation, identifying genetic factors that contribute to severe IgE-mediated reactions will lead to new ways to treat, and potentially prevent, anaphylaxis.

In 2016 in the journal Nature Genetics, Lyons et al. first characterized the genetic trait hereditary alpha-tryptasemia (HaT). This common genetic condition leads to increased serum tryptase levels, affects approximately 1 in 20 Caucasians, and is caused by extra inherited copies of the Tryptase a/b 1 (TPSAB1) gene that, in these individuals, makes extra a-tryptase. In that study, the team noticed that individuals with HaT were 10 times more likely to report anaphylaxis resulting from stinging insects, such as yellowjackets and bees, than were healthy volunteers without HaT. To test this association, Dr. Lyons has since led a team of international collaborators from Italy, Slovenia, and the U.S., characterizing the prevalence and impact of HaT on anaphylaxis more generally.

First, two large European groups of individuals (Italian and Slovenian) with stinging insect allergy were screened for HaT. In the Italian group, all study participants had experienced the most severe classification of anaphylaxis (grade IV out of IV on the Mueller scale) and had also been carefully scrutinized for an acquired disorder called mastocytosis – which also can lead to severe sting reactions. In the Slovenian group, individuals experiencing all four grades of anaphylaxis were tested for HaT and screened for possible mastocytosis using a blood test. Next, to determine whether other forms of anaphylaxis might also be impacted by HaT, patients from the NIH Clinical Center in the United States with mastocytosis and individuals with recurrent anaphylaxis of unknown cause (idiopathic) who did not have evidence of mastocytosis were also screened. Finally, the authors performed a series of laboratory experiments using human umbilical vein endothelial cells (HUVECs) to model the effects of tryptases on blood vessel permeability. Their findings are reported in The Journal of Allergy and Clinical Immunology (JACI).

In both European cohorts, the researchers found that HaT was nearly twice as common among individuals with grade IV anaphylaxis to stinging insects when compared to the general population or individuals with less severe (Mueller grades I-III) anaphylaxis. A surprisingly large number of individuals who had both HaT and mastocytosis were also identified, and all of them had grade IV anaphylaxis. When examining patients from the NIH, the Lyons team not only found that mastocytosis patients with HaT were twice as likely to have anaphylaxis, but that HaT was also much more common among patients with mastocytosis (2.5 times more common) idiopathic anaphylaxis (3 times more common). Lyons and colleagues went on to demonstrate a possible mechanism where specific tryptases that are increased in mast cells from patients with HaT were able to cause cultured blood vessel cells to leak readily, while other tryptases were not.

This is the first study to demonstrate a common inheritable genetic risk factor for anaphylaxis and further clarifies the long-held associations between elevated serum tryptase levels and anaphylaxis. In aggregate, the data in this study demonstrate that in predisposed individuals, HaT at least doubles the risk for severe anaphylaxis. It also concludes that that the total number of people with HaT and allergic reactions to stinging insects did not appear to be increased compared to the general population, indicating that having HaT does not necessarily make an individual more likely to react, rather, having HaT is associated with a greater likelihood of having a severe reaction in an individual who is going to react. An unexpected and significant finding was the association with the acquired mast cell disorder mastocytosis. Whether HaT may increase the likelihood that individuals acquire mastocytosis or only modify symptoms of individuals who have already developed mastocytosis remains unproven. Finally, the authors find that blood vessel derived cells (HUVECs) leak in response to tryptases, but only to a specific version that contains a-tryptase, which is made in excess by individuals with HaT Additional studies need to be performed to better characterize the effect of tryptases on other mast cell associated disorders. However, as the authors point out, there has been renewed interest in targeting tryptases for clinical benefit, and this study suggests a group of individuals who might significantly benefit from tryptase inhibition.

The Journal of Allergy and Clinical Immunology (JACI) is an official scientific journal of the AAAAI, and is the most-cited journal in the field of allergy and clinical immunology.

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