Increased frequencies of basophils, type 2 innate lymphoid cells and Th2 cells in skin of patients with atopic dermatitis but not psoriasis

Abstract

Background: Pathogenesis of atopic dermatitis (AD) involves interaction between type 2 cells that include basophils, mast cells, innate lymphoid type 2 cells (ILC2), and Th2 cells. Levels of IL-4 and IL-13 are elevated in AD patients. Objective: Here, we investigated the distribution of type 2 cells and the source of IL-4 and IL-13 in skin and blood of AD relative to psoriasis. Methods: Lesional skin biopsies and blood were collected from patients. Skin cell suspensions were prepared by mild enzymatic digestion and mechanical dissociation. IL-4 and IL-13 expression was analyzed at single-cell level before or after stimulation using flow cytometry. Results: Frequencies of basophils, ILC2 and Th2 but not mast cells were significantly elevated in skin, and not blood, of AD relative to psoriasis. IL-4 production by circulating basophils and Th2 cells, and IL-13 by ILCs and Th2 cells was similar in both diseases. In contrast, skin T cells expressed IL-4 and IL-13 prior to stimulation in AD when compared to psoriasis. Moreover, skin basophils, which were detected in AD only, expressed IL-4 following stimulation. Interestingly, basophils and ILC2 were positively correlated in skin, whereas skin basophils were inversely correlated with blood ILC2. Conclusions: Lesional AD skin harbors a distinctive innate and adaptive type 2 profile, which is characterized by basophils producing IL-4, Th2 cells expressing IL-4 or IL-13, and ILC2. This underlies the therapeutic efficacy of targeting IL-4 and IL-13 signaling pathways in AD.

Type 2 Cytokine Responses: Regulating Immunity to Helminth Parasites and Allergic Inflammation

“…For example, basophils have been shown to play a role in the induction of inflammation in murine models of AD-like disease and have also been shown to promote optimal type 2 cytokine responses in a model of airway inflammation (64, 68). Consistent with these studies, basophils are increased in the lesional skin of patients suffering from AD and are elevated in the airways of patients suffering from asthma (68, 142). Moreover, murine studies have also demonstrated a non-redundant role for basophils in prompting the pathology associated with eosinophilic esophagitis (EoE)-like inflammation.…”

The IL‐13–OVOL1–FLG axis in atopic dermatitis

“…Interleukin‐4 and IL‐13 share IL‐4R α in their signaling cascades and induce similar biological responses. However, IL‐13 likely preferentially participates in peripheral tissues, including the skin, because tissue‐residing ILC2s produce IL‐13 but not IL‐4 . An IL‐13‐dominant microenvironment is evident in the lesional skin of AD, and the IL‐13‐rich local milieu causes barrier dysfunction by the down‐regulation of the OVOL1–FLG axis .…”

“…In addition to its production in Th2 cells, IL‐13 is produced in ILC2s . Mouse and human ILC2s are phenotypically comparable, lineage‐negative, non‐T and non‐B lymphocytes that produce high levels of IL‐13 and IL‐5 . Unlike IL‐13, no or only negligible IL‐4 is produced by ILC2s .…”

“…Unlike IL‐13, no or only negligible IL‐4 is produced by ILC2s . The ILC2s reside in the skin and are increased in number in AD lesions …”

Role of mast cells and basophils in pruritus

“…However, substance P can initiate the release of IL‐3 and IL‐8, and various chemokines (eg, monocyte chemoattractant protein‐1 [MCP‐1], CCL‐5) . The significance of SP in inflammatory processes is further reflected by its increased expression in lesional skin of patients with AD, which concomitantly present elevated numbers of SP/NK 1 R + mast cells and basophils . Additionally, the chronic itching routinely observed in AD patients has been associated with SP, but not with mast cell function.…”