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Sci Immunol. 2018 Feb 23;3(20). pii: eaam9841. doi: 10.1126/sciimmunol.aam9841.

Dysregulated invertebrate tropomyosin-dectin-1 interaction confers susceptibility to allergic diseases.

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Department of Environmental Health and Engineering, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA.
Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University, Baltimore, MD 21205, USA.
Department of Environmental Health and Engineering, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA.
Department of Medicine and Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, CA 94158, USA.
Centre de Recherche, Institut Universitaire de Cardiologie et de Pneumologie de Québec, Université Laval, Québec, Québec, Canada.
Division of Immunopathology, Department of Pathophysiology and Allergy Research, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria.
Division of Rhinology and Sinus Surgery, Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins School of Medicine, Baltimore, MD 21287, USA.


The key factors underlying the development of allergic diseases-the propensity for a minority of individuals to develop dysfunctional responses to harmless environmental molecules-remain undefined. We report a pathway of immune counter-regulation that suppresses the development of aeroallergy and shrimp-induced anaphylaxis. In mice, signaling through epithelially expressed dectin-1 suppresses the development of type 2 immune responses through inhibition of interleukin-33 (IL-33) secretion and the subsequent recruitment of IL-13-producing innate lymphoid cells. Although this homeostatic pathway is functional in respiratory epithelial cells from healthy humans, it is dramatically impaired in epithelial cells from asthmatic and chronic rhinosinusitis patients, resulting in elevated IL-33 production. Moreover, we identify an association between a single-nucleotide polymorphism (SNP) in the dectin-1 gene loci and reduced pulmonary function in two cohorts of asthmatics. This intronic SNP is a predicted eQTL (expression quantitative trait locus) that is associated with reduced dectin-1 expression in human tissue. We identify invertebrate tropomyosin, a ubiquitous arthropod-derived molecule, as an immunobiologically relevant dectin-1 ligand that normally serves to restrain IL-33 release and dampen type 2 immunity in healthy individuals. However, invertebrate tropomyosin presented in the context of impaired dectin-1 function, as observed in allergic individuals, leads to unrestrained IL-33 secretion and skewing of immune responses toward type 2 immunity. Collectively, we uncover a previously unrecognized mechanism of protection against allergy to a conserved recognition element omnipresent in our environment.

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