PD07 Transcriptomic study of lesion evolution in photoaggravated atopic dermatitis indicates early involvement of innate immunity, T helper (Th)1 and Th22 responses, and a predominant Th2 signature
Authors: Rutter Kirsty , Peake Michael , Hawkshaw Nathan , Jamieson Lynne , Scholey Rachel , Friedmann Peter , Farrar Mark , Rhodes Lesley E 
Published: June 2024

Abstract
Photoaggravated atopic dermatitis (PAD) is a subtype of atopic dermatitis (AD) that is exacerbated or provoked by exposure to ultraviolet radiation. However, its early pathomechanisms are poorly understood. Our aims were (i) to investigate cutaneous clinical, barrier, cellular and molecular changes in the evolution of PAD following low-dose solar simulated ultraviolet radiation (SSR) exposure, and (ii) to compare the findings in healthy controls exposed to the same SSR challenge. Three consecutive daily low-dose (10 J cm−2) SSR exposures were delivered to upper buttock skin of six patients with PAD and six healthy controls. Biopsies were taken from unexposed skin and from SSR-exposed skin at 30 min, 3 h and 24 h after the first exposure, and at 24 h after the third exposure (4 days from baseline). Biopsies were analysed by RNA sequencing using immunohistochemistry and Ingenuity Pathway Analysis. Baseline (unexposed) comparison of PAD vs. healthy control skin revealed 838 differentially expressed genes including significant upregulation of molecules associated with AD, such as inflammatory cytokines and chemokines (CCL1, CCL13, CCL18; all P &lt; 0.01) and epidermal differentiation and proliferation markers (LCE3A, SPRR2B, S100A7; all P &lt; 0.01), along with functional enrichment of immune cell trafficking, T helper (Th)2 pathway response, and cell signalling. Following SSR, clinically and histologically eczematous responses were provoked in patients with PAD, with histological abnormalities becoming progressively more abnormal from baseline to 4 days. Erythema scores were higher in PAD skin than in healthy controls at 24 h and 4 days (24-h erythema score 11.3 vs. 6.8, P &lt; 0.01). In PAD 3 h post-SSR, transcriptomic analysis indicated activation or recruitment of lymphocytes, neutrophils and antigen-presenting cells (all P &lt; 0.001 vs. unexposed skin). Upregulated cytokine genes included IL22, IL20 and IL6 (all P &lt; 0.01 vs. unexposed skin). Interleukin (IL)-1α, tumour necrosis factor and several Toll-like receptors were identified as activated upstream regulators. These findings were not seen in healthy controls, and indicated that innate, Th1 and Th22 activation was provoked by SSR at an early stage. By 24 h post-SSR, additional upregulation of IL13 and CCL17 was consistent with augmented Th2 responses alongside more histologically eczematous features, including lymphocytic infiltration, acanthosis and spongiosis. The evolving dermal inflammatory infiltrate included dual positive CD4+ GATA3+, as well as CD69+ and CD11c+ cells, suggesting involvement of resident memory cells, myeloid dendritic cells and Th2 lymphocytes. In conclusion, PAD was characterized by a predominant Th2 signature, with the additional early involvement of pattern recognition responses, and innate and adaptive immune cells. These findings may inform treatment strategies for flares of both PAD and AD.