Type 2 immunity defends against macro-parasites and can cause allergic diseases. Our understanding of the mechanisms governing the initiation of type 2 immunity is limited, whereas we know more about type 1 immune responses. Type 2 immunity can be triggered by a wide array of inducers that do not share common features and via diverse pathways and mechanisms. To address the complexity of the type 2 initiation pathways, we suggest a framework that conceptualizes different modes of induction of type 2 immunity. We discuss categories of type 2 inducers and their immunogenicity, types of tissue perturbations that are caused by these inducers, sensing strategies for the initiation of Th2 immune responses, and categorization of the signals that are produced in response to type 2 challenges. We describe tissue-specific examples of functional disruption that could lead to type 2 inflammation and propose that different sensing strategies that operate at the tissue level converge on the initiation of type 2 immune responses.
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