PMID- 33717075 OWN - NLM STAT- MEDLINE DCOM- 20210702 LR - 20240331 IS - 1664-3224 (Electronic) IS - 1664-3224 (Linking) VI - 12 DP - 2021 TI - The Roles of Immunoregulatory Networks in Severe Drug Hypersensitivity. PG - 597761 LID - 10.3389/fimmu.2021.597761 [doi] LID - 597761 AB - 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. CI - Copyright (c) 2021 Hsu, Lu, Fu, Wang, Lu, Lin, Chang, Yeh, Hung, Chung and Chen. FAU - Hsu, Yun-Shiuan Olivia AU - Hsu YO AD - Department of Medical Education, Chang Gung Memorial Hospital, Linkou, Taiwan. AD - College of Medicine, Chang Gung University, Taoyuan, Taiwan. FAU - Lu, Kun-Lin AU - Lu KL AD - College of Medicine, Chang Gung University, Taoyuan, Taiwan. AD - Department of Dermatology, Drug Hypersensitivity Clinical and Research Center, Chang Gung Memorial Hospital, Linkou, Taiwan. AD - Department of Dermatology, Drug Hypersensitivity Clinical and Research Center, Chang Gung Memorial Hospital, Taipei, Taiwan. AD - Department of Dermatology, Drug Hypersensitivity Clinical and Research Center, Chang Gung Memorial Hospital, Keelung, Taiwan. FAU - Fu, Yun AU - Fu Y AD - College of Medicine, Chang Gung University, Taoyuan, Taiwan. AD - Department of Dermatology, Drug Hypersensitivity Clinical and Research Center, Chang Gung Memorial Hospital, Linkou, Taiwan. AD - Department of Dermatology, Drug Hypersensitivity Clinical and Research Center, Chang Gung Memorial Hospital, Taipei, Taiwan. AD - Department of Dermatology, Drug Hypersensitivity Clinical and Research Center, Chang Gung Memorial Hospital, Keelung, Taiwan. FAU - Wang, Chuang-Wei AU - Wang CW AD - College of Medicine, Chang Gung University, Taoyuan, Taiwan. AD - Cancer Vaccine and Immune Cell Therapy Core Laboratory, Chang Gung Memorial Hospital, Chang Gung Immunology Consortium, Linkou, Taiwan. FAU - Lu, Chun-Wei AU - Lu CW AD - College of Medicine, Chang Gung University, Taoyuan, Taiwan. AD - Department of Dermatology, Drug Hypersensitivity Clinical and Research Center, Chang Gung Memorial Hospital, Linkou, Taiwan. AD - Department of Dermatology, Drug Hypersensitivity Clinical and Research Center, Chang Gung Memorial Hospital, Taipei, Taiwan. AD - Immune-Oncology Center of Excellence, Chang Gung Memorial Hospital, Linkou, Taiwan. FAU - Lin, Yu-Fen AU - Lin YF AD - Immune-Oncology Center of Excellence, Chang Gung Memorial Hospital, Linkou, Taiwan. AD - Department of Nursing, Chang Gung Memorial Hospital, Linkou, Taiwan. FAU - Chang, Wen-Cheng AU - Chang WC AD - College of Medicine, Chang Gung University, Taoyuan, Taiwan. AD - Immune-Oncology Center of Excellence, Chang Gung Memorial Hospital, Linkou, Taiwan. AD - Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital at Linkou, Chang Gung University College of Medicine, Taoyuan, Taiwan. FAU - Yeh, Kun-Yun AU - Yeh KY AD - College of Medicine, Chang Gung University, Taoyuan, Taiwan. AD - Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital, Keelung, Taiwan. FAU - Hung, Shuen-Iu AU - Hung SI AD - College of Medicine, Chang Gung University, Taoyuan, Taiwan. AD - Cancer Vaccine and Immune Cell Therapy Core Laboratory, Chang Gung Memorial Hospital, Chang Gung Immunology Consortium, Linkou, Taiwan. FAU - Chung, Wen-Hung AU - Chung WH AD - College of Medicine, Chang Gung University, Taoyuan, Taiwan. AD - Department of Dermatology, Drug Hypersensitivity Clinical and Research Center, Chang Gung Memorial Hospital, Linkou, Taiwan. AD - Department of Dermatology, Drug Hypersensitivity Clinical and Research Center, Chang Gung Memorial Hospital, Taipei, Taiwan. AD - Department of Dermatology, Drug Hypersensitivity Clinical and Research Center, Chang Gung Memorial Hospital, Keelung, Taiwan. AD - Cancer Vaccine and Immune Cell Therapy Core Laboratory, Chang Gung Memorial Hospital, Chang Gung Immunology Consortium, Linkou, Taiwan. AD - Immune-Oncology Center of Excellence, Chang Gung Memorial Hospital, Linkou, Taiwan. AD - Department of Dermatology, Chang Gung Hospital, Xiamen, China. AD - Department of Dermatology, Beijing Tsinghua Chang Gung Hospital, School of Clinical Medicine, Tsinghua University, Beijing, China. AD - Department of Dermatology, Ruijin Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China. AD - Genomic Medicine Core Laboratory, Chang Gung Memorial Hospital, Linkou, Taiwan. FAU - Chen, Chun-Bing AU - Chen CB AD - College of Medicine, Chang Gung University, Taoyuan, Taiwan. AD - Department of Dermatology, Drug Hypersensitivity Clinical and Research Center, Chang Gung Memorial Hospital, Linkou, Taiwan. AD - Department of Dermatology, Drug Hypersensitivity Clinical and Research Center, Chang Gung Memorial Hospital, Taipei, Taiwan. AD - Department of Dermatology, Drug Hypersensitivity Clinical and Research Center, Chang Gung Memorial Hospital, Keelung, Taiwan. AD - Cancer Vaccine and Immune Cell Therapy Core Laboratory, Chang Gung Memorial Hospital, Chang Gung Immunology Consortium, Linkou, Taiwan. AD - Immune-Oncology Center of Excellence, Chang Gung Memorial Hospital, Linkou, Taiwan. AD - Department of Dermatology, Chang Gung Hospital, Xiamen, China. AD - Genomic Medicine Core Laboratory, Chang Gung Memorial Hospital, Linkou, Taiwan. AD - College of Medicine, Graduate Institute of Clinical Medical Sciences, Chang Gung University, Taoyuan, Taiwan. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't PT - Review DEP - 20210226 PL - Switzerland TA - Front Immunol JT - Frontiers in immunology JID - 101560960 RN - 0 (Biomarkers) RN - 0 (Costimulatory and Inhibitory T-Cell Receptors) RN - 0 (Cytokines) SB - IM MH - Animals MH - Biomarkers MH - Costimulatory and Inhibitory T-Cell Receptors/metabolism MH - Cytokines/metabolism MH - Diagnosis, Differential MH - Disease Susceptibility/*immunology MH - Drug Hypersensitivity/diagnosis/*etiology MH - Gene Expression Regulation MH - Humans MH - *Immunomodulation MH - Severity of Illness Index MH - Signal Transduction MH - T-Lymphocyte Subsets/immunology/metabolism PMC - PMC7953830 OTO - NOTNLM OT - Stevens-Johnson Syndrome OT - contact dermatitis OT - cosignaling pathways OT - delayed type hypersensitivity OT - drug reaction with eosinophilia and systemic symptoms OT - immune checkpoints OT - regulatory T cells OT - toxic epidermal necrolysis COIS- The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. EDAT- 2021/03/16 06:00 MHDA- 2021/07/03 06:00 PMCR- 2021/01/01 CRDT- 2021/03/15 06:57 PHST- 2020/08/21 00:00 [received] PHST- 2021/01/18 00:00 [accepted] PHST- 2021/03/15 06:57 [entrez] PHST- 2021/03/16 06:00 [pubmed] PHST- 2021/07/03 06:00 [medline] PHST- 2021/01/01 00:00 [pmc-release] AID - 10.3389/fimmu.2021.597761 [doi] PST - epublish SO - Front Immunol. 2021 Feb 26;12:597761. doi: 10.3389/fimmu.2021.597761. eCollection 2021.