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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 γ-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.

Original publication




Journal article


Proceedings of the National Academy of Sciences of the United States of America

Publication Date





E4963 - E4971


Howard Hughes Medical Institute and Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520.


Basophils, Cells, Cultured, Animals, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Knockout, Mice, Papain, Leucine, Calcium Channels, Receptors, IgE, Receptors, IgG, Adaptor Protein Complex Subunits, Calcium Channel Blockers, Interleukins, Interleukin-4, Interleukin-13, Allergens, Cysteine Proteinase Inhibitors, Immunization, Specific Pathogen-Free Organisms, Signal Transduction, MAP Kinase Signaling System, Calcium Signaling, Gene Expression Regulation, NFATC Transcription Factors, Proto-Oncogene Proteins c-akt, Phosphatidylinositol 3-Kinases, Interleukin-33