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Immunol."],"abstract":"<jats:p>The immunomodulatory effects of regulatory T cells (Tregs) and co-signaling receptors have gained much attention, as they help balance immunogenic and immunotolerant responses that may be disrupted in autoimmune and infectious diseases. Drug hypersensitivity has a myriad of manifestations, which ranges from the mild maculopapular exanthema to the severe Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms\/drug-induced hypersensitivity syndrome (DRESS\/DIHS). While studies have identified high-risk human leukocyte antigen (HLA) allotypes, the presence of the HLA allotype at risk is not sufficient to elicit drug hypersensitivity. Recent studies have suggested that insufficient regulation by Tregs may play a role in severe hypersensitivity reactions. Furthermore, immune checkpoint inhibitors, such as anti-CTLA-4 or anti-PD-1, in cancer treatment also induce hypersensitivity reactions including SJS\/TEN and DRESS\/DIHS. Taken together, mechanisms involving both Tregs as well as coinhibitory and costimulatory receptors may be crucial in the pathogenesis of drug hypersensitivity. In this review, we summarize the currently implicated roles of co-signaling receptors and Tregs in delayed-type drug hypersensitivity in the hope of identifying potential pharmacologic targets.<\/jats:p>","DOI":"10.3389\/fimmu.2021.597761","type":"journal-article","created":{"date-parts":[[2021,2,26]],"date-time":"2021-02-26T13:58:08Z","timestamp":1614347888000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":28,"title":["The Roles of Immunoregulatory Networks in Severe Drug Hypersensitivity"],"prefix":"10.3389","volume":"12","author":[{"given":"Yun-Shiuan Olivia","family":"Hsu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kun-Lin","family":"Lu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yun","family":"Fu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chuang-Wei","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chun-Wei","family":"Lu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu-Fen","family":"Lin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wen-Cheng","family":"Chang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kun-Yun","family":"Yeh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuen-Iu","family":"Hung","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wen-Hung","family":"Chung","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chun-Bing","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,2,26]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.2500\/aap.2012.33.3561","article-title":"Chapter 28: Classification of hypersensitivity reactions","author":"Uzzaman","year":"2012","journal-title":"Allergy Asthma Proc"},{"key":"B2","volume-title":"Delayed Hypersensitivity Reactions","author":"Justiz Vaillant","year":"2020"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1684\/ejd.2009.0686","article-title":"Allergic and irritant contact dermatitis","volume":"19","author":"Nosbaum","year":"2009","journal-title":"Eur J Dermatol"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2222.2007.02742.x","article-title":"Delayed drug hypersensitivity reactions - new concepts","volume":"37","author":"Posadas","year":"2007","journal-title":"Clin Exp Allergy"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2010.11.046","article-title":"Drug hypersensitivity: pharmacogenetics and clinical syndromes","volume":"127","author":"Phillips","year":"2011","journal-title":"J Allergy Clin Immunol"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.2165\/00128071-200001060-00003","article-title":"Drug-induced Stevens-Johnson syndrome\/toxic epidermal necrolysis","volume":"1","author":"Fritsch","year":"2000","journal-title":"Am J Clin Dermatol"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199411103311906","article-title":"Severe adverse cutaneous reactions to drugs","volume":"331","author":"Roujeau","year":"1994","journal-title":"N Engl J Med"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1001\/archderm.129.1.92","article-title":"Clinical classification of cases of toxic epidermal necrolysis, Stevens-Johnson syndrome, and erythema multiforme","volume":"129","author":"Bastuji-Garin","year":"1993","journal-title":"Arch Dermatol"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1016\/j.amjmed.2011.01.017","article-title":"The DRESS syndrome: a literature review","volume":"124","author":"Cacoub","year":"2011","journal-title":"Am J Med"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1111\/bjd.12501","article-title":"Drug reaction with eosinophilia and systemic symptoms (DRESS): an original multisystem adverse drug reaction. 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