期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2014
卷号：111
期号：46
页码：E4963-E4971
DOI：10.1073/pnas.1418959111
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceHelminths and allergens stimulate type 2 immune responses by largely unknown mechanisms. Proteolytic activity is a common feature of many helminths and allergens and can promote activation of the immune system. Signaling pathways activated by these proteases remain poorly characterized and are the focus of this study. Using basophils as model type 2 immune cells, we identified roles for the immunoreceptor tyrosine-based activation motif (ITAM)-containing adaptor Fc receptor {gamma}-chain and calcium signaling in protease-stimulated basophil activation. We suggest models to explain how protease sensing, ITAM signaling, and nuclear factor of activated T cells pathways contribute to produce allergic type 2 responses. Elucidation of these signaling pathways and ultimately the identity of protease allergen sensors will be important for the development of pharmacologic strategies to target the initiation of allergic responses. Allergic diseases represent a significant burden in industrialized countries, but why and how the immune system responds to allergens remain largely unknown. Because many clinically significant allergens have proteolytic activity, and many helminths express proteases that are necessary for their life cycles, host mechanisms likely have evolved to detect the proteolytic activity of helminth proteases, which may be incidentally activated by protease allergens. A cysteine protease, papain, is a prototypic protease allergen that can directly activate basophils and mast cells, leading to the production of cytokines, including IL-4, characteristic of the type 2 immune response. The mechanism of papain's immunogenic activity remains unknown. Here we have characterized the cellular response activated by papain in basophils. We find that papain-induced IL-4 production requires calcium flux and activation of PI3K and nuclear factor of activated T cells. Interestingly, papain-induced IL-4 production was dependent on the immunoreceptor tyrosine-based activation motif (ITAM) adaptor protein Fc receptor {gamma}-chain, even though the canonical ITAM signaling was not activated by papain. Collectively, these data characterize the downstream signaling pathway activated by a protease allergen in basophils.
