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The Emerging Role of the Innate Immune Response in Idiosyncratic Drug Reactionss Supplemental Material can be found at: /content/suppl/2021/05/30/73.3.861.DC1.html 1521-0081/73/3/861–896$35.00 /content/suppl/2021/07/14/73.3.861.DC2.html https://doi.org/10.1124/pharmrev.120.000090 PHARMACOLOGICAL REVIEWS Pharmacol Rev 73:861–896, July 2021 Copyright © 2021 by The Author(s) This is an open access article distributed under the CC BY Attribution 4.0 International license. ASSOCIATE EDITOR: ERIC BARKER The Emerging Role of the Innate Immune Response in Idiosyncratic Drug Reactionss Samantha Christine Sernoskie,1 Alison Jee,1 and Jack Paul Uetrecht Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy (S.C.S., J.P.U.), and Department of Pharmacology and Toxicology, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada (A.J., J.P.U.) Abstract. ....................................................................................863 Significance Statement ......................................................................863 I. Introduction. ..............................................................................863 II. Review of Types of Idiosyncratic Drug Reactions . ..........................................864 A. Idiosyncratic Drug-Induced Liver Injury. ................................................864 1. Hepatocellular Liver Injury...........................................................864 2. Autoimmune Liver Injury ............................................................864 3. Cholestatic Liver Injury . ............................................................864 B. Severe Cutaneous Adverse Reactions.....................................................865 Downloaded from 1. Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis. .........................865 2. Drug Reaction with Eosinophilia and Systemic Symptoms.............................865 3. Acute Generalized Exanthematous Pustulosis .........................................866 C. Idiosyncratic Drug-Induced Blood Dyscrasias. ..........................................866 1. Idiosyncratic Drug-Induced Agranulocytosis. ..........................................866 2. Idiosyncratic Drug-Induced Hemolytic Anemia . .....................................866 by guest on October 2, 2021 3. Idiosyncratic Drug-Induced Thrombocytopenia . .....................................867 D. Other Idiosyncratic Drug Reactions ......................................................867 1. Idiosyncratic Drug-Induced Autoimmune Reactions ...................................867 2. Idiosyncratic Drug-Induced Nephropathy . ..........................................867 E. Rationale for Current Review ............................................................868 III. Innate Mechanisms Contributing to Adaptive Immune Activation . .........................869 A. Cells of the Innate Immune System ......................................................869 1. Granulocytes . ........................................................................869 a. Neutrophils .......................................................................869 b. Eosinophils .......................................................................870 c. Basophils . ........................................................................870 d. Mast cells. ........................................................................870 2. Professional Antigen-Presenting Cells. ................................................871 a. Dendritic cells . ..................................................................871 b. Monocytes ........................................................................871 c. Macrophages......................................................................872 3. Innate Lymphoid Cells . ............................................................872 4. Other Innate Immune Cells ..........................................................873 5. Nonimmune Cells . ..................................................................873 Address correspondence to: Jack Paul Uetrecht, Leslie Dan Faculty of Pharmacy, 144 College St., 10th Floor, Rm. 1007, University of Toronto, Toronto, ON M5S 3M2, Canada. E-mail: [email protected] This work was supported by the Canadian Institutes of Health Research [Grant 142329]. S.C.S. was supported by an Ontario Graduate Scholarship, a Mitacs Research Training Award, and a University of Toronto Fellowship. A.J. was supported by a Natural Sciences and Engineering Research Council of Canada doctoral scholarship. No author has an actual or perceived conflict of interest with the contents of this article. 1S.C.S. and A.J. contributed equally to this work. s This article has supplemental material available at pharmrev.aspetjournals.org. https://doi.org/10.1124/pharmrev.120.000090. 861 862 Sernoskie et al. a. Hepatocytes.......................................................................873 b. Mesenchymal stem cells...........................................................873 c. Fibroblasts........................................................................873 B. Antigen Formation and Cell Damage.....................................................874 1. Hapten Hypothesis . ..................................................................874 2. p-i Concept. ........................................................................874 3. Altered Peptide Repertoire Model.....................................................874 4. Danger Hypothesis . ..................................................................874 5. Endoplasmic Reticulum Stress and the Unfolded Protein Response . ...................875 6. Mitochondrial Toxicity................................................................875 C. Mediators of Inflammation. ............................................................876 1. Damage-Associated Molecular Patterns ...............................................876 2. Cytokines, Chemokines, and Acute Phase Proteins ....................................876 a. Interleukin-1 cytokines and their activation . .....................................876 3. Bioactive Lipids ......................................................................877 4. Pattern Recognition Receptors . ......................................................877 5. Transcriptional Regulation of Inflammation. ..........................................878 6. Other Contributing Factors ...........................................................878 a. Interaction with the microbiome. ................................................878 b. Communication with the nervous system...........................................878 D. Antigen Reception/Uptake by Antigen-Presenting Cells ...................................878 1. Presentation by Major Histocompatibility Complex I: Endogenous Protein, Crosspresentation . ..................................................................879 2. Presentation by Major Histocompatibility Complex II: Phagocytosis, Endocytosis, Macropinocytosis, Autophagy . ......................................................879 3. Crossdressing: Trogocytosis, Extracellular Vesicles, Nanotubes ........................879 E. Naïve Lymphocyte Activation by Antigen-Presenting Cells. ...............................879 1. Helper T Cells .......................................................................880 2. Cytotoxic T Cells . ..................................................................880 3. B Cells . ..............................................................................880 F. Fate of the Adaptive Immune Response . ................................................880 IV. Support for Immune Activation Using Model Drugs ..........................................881 A. Amodiaquine ............................................................................882 1. Data from Rodent and Human Studies................................................882 B. Amoxicillin ..............................................................................883 1. Data from Rodent and Human Studies................................................883 C. Nevirapine ..............................................................................884 1. Data from Rodent and Human Studies................................................885 D. Clozapine . ..............................................................................885 1. Data from Rodent and Human Studies................................................886 E. Summary. ..............................................................................887 V. Conclusions and Perspectives ................................................................888 Acknowledgments . ........................................................................889 References ..................................................................................889 ABBREVIATIONS: AGEP, acute generalized exanthematous pustulosis; AIN, acute interstitial nephritis; ALP, alkaline phosphatase; ALT, alanine aminotransferase; AMPK, AMP-activated protein kinase; APC, antigen-presenting cell; BSEP, bile salt export pump; BSO, buthionine sulphoximine; CCL, chemokine (C-C motif) ligand; cDC, conventional DC; CXCL, C-X-C motif chemokine ligand; DAMP, damage-associated molecular pattern; DC, dendritic cell; DIAIN, drug-induced acute interstitial nephritis; DRESS, drug reaction with eosinophilia and systemic symptoms; ER, endoplasmic reticulum; HIV, human immunodeficiency virus; HLA, human leukocyte antigen; HMGB1, high mobility group box 1; IDIAG, idiosyncratic drug-induced agranulocytosis; IDILI,
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