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Objective: The current study collected skin biopsies from healthy volunteers before and after UVB radiation and linked UVB-induced effects in the skin to immunosuppression in the same individuals. Methods: A total of 62 healthy volunteers were recruited and randomly assigned to three groups: negative, positive, and UVB-exposed. Diphenylcyclopropenone was applied topically to induce contact hypersensitivity (CHS) responses. Skin punch biopsies were collected before and after UVB for analysis. Results: UVB exposure significantly suppressed CHS compared to the positive control. However, among 26 individuals, 7 (27%) were resistant (UVB-R), while the rest were susceptible (UVB-S) to UVB-induced immunosuppression. RNA-seq analysis of skin biopsies showed that UVB induced a higher level of immunosuppressive inflammation in UVB-S than in UVB-R individuals. Further analysis showed that UVB significantly activated the damage-associated molecular patterns only in UVB-S, but not in UVB-R individuals. Conclusion: Given the role of DAMP pathways in the development of inflammation, the results reveal a previously unrecognized mechanism: UVB-induced activation of DAMP pathways is linked to UVB-induced immunosuppressive inflammation in skin and susceptibility to immunosuppression in humans.<\/jats:p>","DOI":"10.3390\/cells15191732","type":"journal-article","created":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T10:17:26Z","timestamp":1790158646000},"page":"1732","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Human Susceptibility to UVB-Induced Immunosuppression Is Associated with UVB-Induced Activation of the DAMP Pathway in the Skin"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5871-0262","authenticated-orcid":false,"given":"Carlos Alberto","family":"Mier-Aguilar","sequence":"first","affiliation":[{"name":"Department of Dermatology, Heersink School of Medicine, 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