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In this study, we report that a contact allergen, 1-chloro-2,4-dinitrobenzene (DNCB), elicits contact hypersensitivity through binding the protein we identify. Starting from an unbiased sampling of proteomics, we found nine candidate proteins with unique DNCB-modified peptide fragments. More than half of these fragments belonged to heat shock protein 90 (HSP90), a common stress-response protein and a damage-associated molecular pattern, and showed the highest probability of incidence. Inhibition and short hairpin RNA knockdown of HSP90 in human monocyte cell line THP-1 suppressed the potency of DNCB by &amp;gt;80%. Next, we successfully reduced DNCB-induced contact hypersensitivity in HSP90-knockout mice, which confirmed our findings. Finally, we hypothesized that DNCB-modified HSP90 activates the immune cells through HSP90\u2019s receptor, CD91. Pretreatment of CD91 in THP-1 cell lines and BALB\/c mice attenuated the potency of DNCB, consistent with the result of HSP90-knockout mice. Altogether, our data show that DNCB-HSP90 binding plays a role in mediating DNCB-induced contact hypersensitivity, and the activation of CD91 by DNCB-modified HSP90 proteins could mediate this process.<\/jats:p>","DOI":"10.4049\/jimmunol.2101023","type":"journal-article","created":{"date-parts":[[2022,7,14]],"date-time":"2022-07-14T16:23:59Z","timestamp":1657815839000},"page":"2622-2631","source":"Crossref","is-referenced-by-count":5,"title":["Heat Shock Protein 90\u2019s Mechanistic Role in Contact Hypersensitivity"],"prefix":"10.1093","volume":"208","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5264-8843","authenticated-orcid":false,"given":"Seong-Min","family":"Kim","sequence":"first","affiliation":[{"name":"Pritzker School of Molecular Engineering, The University of Chicago , Chicago, IL"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bradley","family":"Studnitzer","sequence":"additional","affiliation":[{"name":"Pritzker School of Molecular Engineering, The University of Chicago , Chicago, IL"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1273-0951","authenticated-orcid":false,"given":"Aaron","family":"Esser-Kahn","sequence":"additional","affiliation":[{"name":"Pritzker School of Molecular Engineering, The University of Chicago , Chicago, IL"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2022,6,15]]},"reference":[{"key":"2025021009092247100_r1","doi-asserted-by":"crossref","first-page":"1152","DOI":"10.1111\/j.1398-9995.2011.02652.x","article-title":"Mechanisms of chemical-induced innate immunity in allergic contact dermatitis","volume":"66","author":"Martin","year":"2011","journal-title":"Allergy"},{"key":"2025021009092247100_r2","doi-asserted-by":"crossref","first-page":"S1","DOI":"10.1186\/1710-1492-7-S1-S1","article-title":"An introduction to immunology and immunopathology","volume":"7","author":"Warrington","year":"2011","journal-title":"Allergy Asthma Clin. 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