PubMed · 6925531
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V N Grebeniuk. 1982. [Allergic dermatitis].. https://pubmed.ncbi.nlm.nih.gov/6925531/
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BACKGROUND: Atopic dermatitis (AD), a common chronic inflammatory skin disease, has been extensively studied using single-cell genomics. However, keratinocytes, as key effector cells in AD, have underlying mechanisms remain incompletely understood and require further investigation. METHODS: We integrated single-cell transcriptomic data from skin tissues of healthy controls, chronic active AD patients, spontaneously healed AD (SHAD) patients, and an ovalbumin-induced AD mouse model. The study particularly emphasized the gene expression and cellular dynamics of keratinocytes across the different groups, as well as their interactions with immune cells. RESULTS: Compared to healthy controls, we observed significant changes in the keratinocyte transcriptome, cellular state, and keratinocyte-immune cell ligand-receptor interactions in AD skin, particularly the marked activation of genes involved in antigen processing and presentation. Interestingly, such gene activation was not observed in keratinocytes from the ovalbumin-induced AD mouse model, despite its phenotype closely resembling human AD. Furthermore, in SHAD, we identified a recovery of both the ligand-receptor interaction patterns and antigen processing and presentation genes, accompanied by a notable shift in the transcriptome. This involved a significant downregulation of genes related to cytoplasmic transcription and oxidative phosphorylation. Notably, this pattern was not observed in the self-healing mouse model following the removal of ovalbumin stimulation. CONCLUSION: Our results suggest that the persistent activation of antigen processing and presentation pathways in keratinocytes may be a key driver of chronic inflammation in AD. Therefore, redirecting anti-allergic therapeutic strategies from solely targeting immune cells to targeting of keratinocyte-mediated antigen presentation may offer a more effective approach. Furthermore, we raise concerns about the use of ovalbumin-induced mouse models to recapitulate human chronic AD, as the underlying mechanisms may differ significantly.
During the past few years, the Atopy Patch Test (APT) has become a valuable additional tool in the diagnostic work-up of food allergy in infants and children with atopic dermatitis. A positive APT may help to prevent restrictive and unnecessary diets which may be the consequence of misjudging late reactions by clinical assessment alone. Furthermore, the combination of positive atopy patch tests together with defined levels of specific IgE (cow milk = 0.35 kU/l and egg = 17.5 kU/l) makes DBPCFC superfluous for suspected milk and egg allergy. However, several open questions indicate the need for further studies.
Atopic dermatitis is regarded as mediated by Th2-type immunity. In fact, it frequently coincides with the elevation of immunoglobulin (Ig)-E in patients' sera. Due to the pivotal role of interleukin (IL)-4 in regulation of IgE, we hypothesized if atopic dermatitis represents a hyper-reactive condition in response to IL-4 when it coincides the higher serum level of IgE. To address this possibility, peripheral blood mononuclear cells (PBMC) isolated from patients with atopic dermatitis with the high serum IgE level, from those with psoriasis or from healthy volunteers were stimulated with recombinant IL-4 and analyzed for activation of transcription factors including activator protein (AP)-1 or signal transducers and activators of transcription (STAT)-6 by employing electrophoretic mobility shift assays. Although no significant difference between atopy patients and other groups was observed in the STAT-6 binding activity in IL-4-stimulated PBMC, it over-activated the binding of AP-1 in PBMC of the patients with atopic dermatitis. The AP-1 binding was interfered by the use of an antibody directed against JunB. This is the indication that IL-4-overactivated AP-1 is composed of JunB. Furthermore, semi-quantitative RT-PCR analyses revealed marked down-modulation of a Th1 cytokine, interferon (IFN)-gamma, in IL-4-stimulated PBMC derived from atopy patients, but not that from healthy individuals. Together, our present study indicates that AP-1 is over-activated by IL-4 in PBMC of the atopic patients with the higher IgE level, thereby implying that IL-4-induced over-activation of AP-1 might be one of pathogenic factors in atopic dermatitis.