Review synthesizes Type 2 immunity's role in chronic atopic inflammation, proposing a self-amplifying cytokine cycle

Atopic diseases, including atopic dermatitis, arise from an immunological imbalance where regulatory mechanisms fail to maintain homeostasis, leading to chronic inflammation in epithelial organs. Current understanding points to deficient or insufficient regulatory T cells (Tregs) and aberrant regulatory mechanisms. Type 2 (T2) immunity, originally evolved to combat helminths and toxins, involves innate and adaptive immune pathways, with cytokines and alarmins driving mucous production, hyperplasia, and tissue remodeling. The gap addressed is how this T2 response becomes unchecked, leading to chronic T2 inflammation in genetically susceptible individuals.

This paper reviews existing evidence linking host Type 2 immunity with Type 2 inflammatory mechanisms in various atopic diseases. It systematically explores the hypothesis that these conditions are perpetuated by a central imbalance between Th2 vs. Th1, Th3, and Tregs responses. The review integrates insights into tissue-dependent, local environmental-insult-driven innate cell responses, emphasizing how these are interconnected by a cycle of self-amplifying cytokine signaling.

The review highlights that Type 2 immunity is a conserved response, involving numerous cytokines and alarmins that recruit and activate immune cells, leading to mucous production, hyperplasia, and tissue remodeling. These responses, while protective against parasites, become maladaptive in atopic disorders. The paper synthesizes evidence suggesting that reduced parasitic exposure may contribute to T2 responses being triggered by low environmental stimuli in susceptible individuals. This leads to unchecked T2 inflammation across multiple barrier surfaces. The core finding is the proposed model where atopic diseases are perpetuated by a central imbalance between Th2 and other T helper cell subsets (Th1, Th3, Tregs), driven by local environmental insults and a self-amplifying cytokine signaling loop. This cycle involves key immune cells and mediators, reinforcing chronic inflammation.

The review proposes that atopic diseases are perpetuated by a central imbalance between Th2 vs. Th1, Th3, and Tregs, influenced by tissue-dependent innate cell responses and a self-amplifying cytokine signaling cycle.