Researchers discover critical new allergy pathway

Mouse study discovery points to potential new drug targets for treating asthma, hay fever, and other inflammatory disorders

JOHNS HOPKINS UNIVERSITY BLOOMBERG SCHOOL OF PUBLIC HEALTH

 

Researchers at Johns Hopkins Bloomberg School of Public Health have identified the sequence of molecular events by which tiny, tick-like creatures called house dust mites trigger asthma and allergic rhinitis.

The researchers, whose study was published online June 22 in Nature Immunology, found that allergy-triggering molecules from dust mites can interact with an immune protein called SAA1, which is better known as a sentinel against bacteria and other infectious agents. The researchers showed step-by-step how this interaction between mite-molecules and SAA1 triggers an allergic-type immune response in mice.

The findings reveal what may be a significant new pathway by which allergic and inflammatory disorders arise. They also suggest that blocking the pathway could potentially work as a preventive or treatment strategy against asthma and other allergic reactions.

"We think that the signaling interactions that occur immediately downstream of the mite-proteins' activation of SAA1 may be good targets for future drugs," says study senior author Marsha Wills-Karp, PhD, the Anna M. Baetjer Professor of Environmental Health and Chair of the Department of Environmental Health and Engineering at the Bloomberg School.

Asthma affects between 8 to 15 percent of people in the U.S., and is typically triggered by dust mites, tree and grass pollens, and other allergens. Researchers suspect that this inappropriate immune triggering happens when the immune system mistakes allergens--which are otherwise harmless--for pieces of bacteria or other infectious agents. However, the molecular mechanisms underlying this misidentification haven't been well understood.

In their study, Wills-Karp and her colleagues zeroed in on SAA1, an immune protein that is found, among other places, in the fluid that lines the airways and other mucosal surfaces. A member of the evolutionarily ancient "innate immune system" of mammals, SAA1 is thought to have evolved as a sentinel or early-responder molecule that, for example, recognizes and helps clear away certain types of bacteria and other infectious agents.

The researchers found that exposure to dust-mite proteins causes an asthma-like sensitization of the airways of the control group mice. In contrast, exposure to dust-mite proteins hardly had any effect in mice in which SAA1 was neutralized by antibodies, or in mice whose genes for SAA1 were knocked out. Further experiments confirmed that SAA1, when it is present, directly binds certain dust-mite allergens called fatty-acid binding proteins, which have structural similarities with proteins found in some bacteria and parasites. This allergen-SAA1 interaction releases SAA1 into its active form, wherein it activates a receptor called FPR2 on airway-lining cells. The airway cells then produce and secrete large quantities of interleukin-33, a protein known for its ability to stimulate allergic-type immune responses.

Confirming the likely relevance to humans, the researchers found evidence of increased production of SAA1 and FPR2 in nasal airway-lining cells from patients with chronic sinusitis--which is often linked to dust-mite allergens--compared to healthy controls.

"We think that different allergens take different routes to the activation of interleukin-33 and related allergic responses, and this SAA1-FPR2 route seems to be one that is taken by some dust-mite allergens," Wills-Karp says.

She and her colleagues now plan to investigate why some people develop allergic disorders in which this pathway is hyperactive, while most don't. They also plan to explore the possibility of blocking this pathway, perhaps at the SAA1-FPR2 interaction, as a way of treating asthma and other allergic disorders.

The researchers suspect that the newly described SAA1-FPR2 allergic pathway may be relevant not only in asthma and hay fever-type disorders but also in atopic dermatitis (eczema) and food allergies--possibly even in chronic inflammatory disorders such as rheumatoid arthritis and atherosclerosis.

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First author Ursula Smole, PhD, worked on the study while at the Bloomberg School.

"Serum amyloid A is a soluble pattern recognition receptor that drives type 2 immunity" was written by Ursula Smole, Naina Gour, Jordan Phelan, Gerhard Hofer, Cordula Köhler, Bernhard Kratzer, Peter Tauber, Xiao Xiao, Nu Yao, Jan Dvorak, Luis Caraballo, Leonardo Puerta, Sandra Rosskopf, Jamila Chakir, Ernst Malle, Andrew Lane, Winfried Pickl, Stephane Lajoie, and Marsha Wills-Karp.

Funding was provided by the National Institute of Allergy and Infectious Diseases (U19AI070235, R01 AI083315), the National Institutes of Health (R56AI118791, R01AI127644, R01AI132590), and the Austrian Science Fund (DK W1248, SFB F4609).