With an antibody whose duty's double, a step towards ending asthma trouble?

Asthma is a debilitating chronic inflammatory disease of the airways that results in shortness of breath, wheezing and coughing, often triggered by inhalation of common allergens. The prevalence and severity of asthma has increased dramatically over the last several decades to the point where several hundred million people worldwide are affected and each year tens of thousands of individuals die prematurely from asthma symptoms. The rise in disease prevalence is particularly evident in the developed world, where childhood exposure to bacteria and viruses has decreased dramatically, while the use of antibiotics, especially early in life, and births by Caesarean section have increased significantly; correlations that support the hygiene hypothesis. Central to the pathogenesis of asthma are the roles of T_H2-type cytokines, including IL (interleukin)-4, IL-5, IL-9 and IL-13, in stimulating and perpetuating an inflammatory cascade that drives detrimental changes in airway structure and function. IL-4 and IL-13, in particular, have been targets of therapeutic development because, together, they specifically promote nearly all of the clinical features of asthma. Their inflammatory functions are highly complementary, but not identical, in large part because they share cell-surface receptors and transcription factors through which they stimulate cell signalling. In this issue of the Biochemical Journal, Redpath et al. have taken advantage of the shared receptor nature of the IL-4- and IL-13-mediated inflammatory responses to generate a novel antibody to the third ectodomain (D3) of IL-13Rα1 (IL-13 receptor α1), which forms a requisite binding site for both interleukins. This antibody potently neutralizes both IL-4 and IL-13 activities in vitro. Using X-ray crystallography complemented by molecular interaction and functional analyses, they clearly define its mechanism of dual cytokine neutralization as one of molecular mimicry of the interleukin-receptor interaction. Considering the complexity of the cytokine-mediated inflammatory cascade that defines asthma pathogenesis, such therapeutics that can effectively and simultaneously neutralize the actions of multiple cytokines and may play a significantly expanded role in the treatment and prevention of asthma in the future.