Figure 1.

Disrupted barrier function and the atopic march. (A) Disrupted skin barrier through primary disorders of the skin or external factors enable allergen entry; uptake by dendritic cells in the presence of alarmin signals such as TSLP and IL-33 promotes dendritic cell maturation and migration to the draining LN. Genes noted in red indicate monogenic IEI affecting this pathway. (B) Dendritic cells present allergen-derived peptide:MHCII to naive CD4⁺ T cells to induce Th2 effector cells and Tfh cells that drive IgE responses to allergen. (C) A portion of Th2 cells traffic back to skin and permanently reside as tissue-resident memory cells to drive local inflammation through release of type 2 cytokines such as IL-4, -5, and -13 upon re-encountering allergen. (D) Systemic IL-33 from keratinocytes and IL-25 from intestinal tuft cells synergize to activate ILC2s, which in turn produce IL-4 and activate mast cell degranulation (anaphylaxis) in response to oral allergen exposure.