Scientists have identified a genetic² basis for determining the severity of allergic³（过敏的） asthma⁴（哮喘） in experimental models of the disease. The study may help in the search for future therapeutic⁵ strategies to fight a growing medical problem that currently lacks effective treatments, researchers from Cincinnati Children's Hospital Medical Center report in the Aug. 29 Nature Immunology.

The prevalence（流行，普遍） of asthma has been increasing in recent years, according to Marsha Wills-Karp, Ph.D., director of the division of Immunobiology at Cincinnati Children's and the study's senior investigator⁶. The disease can be triggered in susceptible⁷（易受影响的） people by a variety of environmental contaminants（污染物） – such as cigarette smoke, allergens（过敏原） and airborne（空运的） pollution.

Dr. Wills-Karp's research team has found a molecular⁸ tipping point that upsets a delicate balance between underlying⁹ mild disease and more severe asthma. They identify the pro-inflammatory protein, interleukin-17 (IL-17A), as the chief culprit（犯人，罪犯） behind severe asthma-like symptoms in mice.

"This study suggests that at some point it may be possible to treat or prevent severe forms of asthma by inhibiting¹⁰ pathways that drive the production of IL-17A," Dr. Wills-Karp said.

The disease process appears to begin when airway¹¹ exposure to environmental allergens causes dysfunctional regulation of a gene¹ called complement¹² factor 3 (C3), which works through a part of the immune system called the complement activation¹³ cascade¹⁴（层叠，小瀑布） . This leads to overzealous（过分热心的） production of IL-17A by airway cells and sets off what the scientists describe as an "amplification¹⁵ loop," when IL-17A in turn induces more C3 production at the airway surface.

The amplification loop perpetuates¹⁶ increasing inflammatory responses involving irregular T helper cells, other interleukin（白介素） proteins (IL-13 and IL-23), as well as airway hyper-responsiveness and airflow obstruction¹⁷.

Previous studies have shown the presence of IL-17A proteins in human asthma but no apparent role. Earlier research involving mouse models of the disease has suggested possible roles for IL-17A in asthma, and this study expands on those findings.

The current study involved mice bred genetically¹⁸ to closely resemble people susceptible to severe asthma. Mouse airways¹⁹ were exposed to house dust mite²⁰（小虫） allergen extract to gauge²¹（测量，估计） the severity of disease and analyze²² biochemical responses in airway tissues.

One group of mice was deficient²³ in the immune system gene C5, which normally prevents harmful airway immune responses to inhaled²⁴ environmental allergens. These mice generated high numbers of T helper cells (known specifically in this instance as TH17 cells) that produced significant IL-17A and caused airway hyper-responsiveness. When researchers blocked IL-17A production in this group, the mice had less airway hyper-responsiveness.

A second group of mice was deficient in the C3aR gene (a receptor for C3), which regulates the dysfunctional response to airway allergens that lead to asthma. These mice had fewer IL-17A producing TH17 cells and less airway hyper-responsiveness. When researchers increased the amount of IL-17A in the airways of this group, the mice experienced greater airway hyper-responsiveness.

As Dr. Wills-Karp and her colleagues continue their research, they will study the relationship between C3 and IL-17A in severe asthmatics（气喘患者） , and explore the effectiveness of targeting either the C3 or IL-17A pathways for the treatment of severe asthma. A drug that blocks the function of C3 is currently under development and testing outside of Cincinnati Children's for treatment of the eye disease macular degeneration（黄斑变性） .