UpToDate
Official reprint from UpToDate®
www.uptodate.com ©2017 UpToDate, Inc. and/or its affiliates. All Rights Reserved.

Drug allergy: Pathogenesis

Author
Werner J Pichler, MD
Section Editor
N Franklin Adkinson, Jr, MD
Deputy Editor
Anna M Feldweg, MD

INTRODUCTION

A drug allergy is an adverse drug reaction that results from stimulation of the immune system by a medication. The pathogenesis of different types of drug-allergic reactions will be reviewed here. The classification and clinical features of drug-allergic reactions are discussed elsewhere. (See "Drug allergy: Classification and clinical features".)

INTERACTION OF DRUGS WITH THE IMMUNE SYSTEM

Drugs can elicit drug-specific immune responses in two ways (table 1):

The drug may act as an antigen and elicit one of several classic immune responses.

The drug may directly interact with immune receptors and under certain circumstances, lead to activation of specific immune cells [1].

Some drugs can bind directly to effector cells of the immune system (eg, mast cells) and cause mast cell degranulation with the clinical symptoms of urticaria or anaphylaxis [2]. Such symptoms are very similar to some drug-allergic reactions (immunoglobulin E [IgE]) and are called pseudoallergic or nonallergic hypersensitivity reactions. They do not involve drug-specific antibodies or T cells and are thus not truly immune-mediated reactions. Common examples include most reactions to nonsteroidal anti-inflammatory drugs (NSAIDs) and radiocontrast agents, which are discussed elsewhere (See "NSAIDs (including aspirin): Allergic and pseudoallergic reactions" and "Immediate hypersensitivity reactions to radiocontrast media: Clinical manifestations, diagnosis, and treatment".)

                   
To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information on subscription options, click below on the option that best describes you:

Subscribers log in here

Literature review current through: Sep 2017. | This topic last updated: Sep 18, 2017.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2017 UpToDate, Inc.
References
Top
  1. Pichler WJ, Adam J, Watkins S, et al. Drug Hypersensitivity: How Drugs Stimulate T Cells via Pharmacological Interaction with Immune Receptors. Int Arch Allergy Immunol 2015; 168:13.
  2. McNeil BD, Pundir P, Meeker S, et al. Identification of a mast-cell-specific receptor crucial for pseudo-allergic drug reactions. Nature 2015; 519:237.
  3. Cousin S, Italiano A. Molecular Pathways: Immune Checkpoint Antibodies and their Toxicities. Clin Cancer Res 2016; 22:4550.
  4. Lafaye P, Lapresle C. Fixation of penicilloyl groups to albumin and appearance of anti-penicilloyl antibodies in penicillin-treated patients. J Clin Invest 1988; 82:7.
  5. Padovan E. T-cell response in penicillin allergy. Clin Exp Allergy 1998; 28 Suppl 4:33.
  6. Martin SF. Allergic contact dermatitis: xenoinflammation of the skin. Curr Opin Immunol 2012; 24:720.
  7. Levine BB. Immunochemical mechanisms of drug allergy. Annu Rev Med 1966; 17:23.
  8. Brander C, Mauri-Hellweg D, Bettens F, et al. Heterogeneous T cell responses to beta-lactam-modified self-structures are observed in penicillin-allergic individuals. J Immunol 1995; 155:2670.
  9. Lavergne SN, Wang H, Callan HE, et al. "Danger" conditions increase sulfamethoxazole-protein adduct formation in human antigen-presenting cells. J Pharmacol Exp Ther 2009; 331:372.
  10. Naisbitt DJ, Gordon SF, Pirmohamed M, et al. Antigenicity and immunogenicity of sulphamethoxazole: demonstration of metabolism-dependent haptenation and T-cell proliferation in vivo. Br J Pharmacol 2001; 133:295.
  11. Kearns GL, Wheeler JG, Childress SH, Letzig LG. Serum sickness-like reactions to cefaclor: role of hepatic metabolism and individual susceptibility. J Pediatr 1994; 125:805.
  12. Park BK, Pirmohamed M, Kitteringham NR. The role of cytochrome P450 enzymes in hepatic and extrahepatic human drug toxicity. Pharmacol Ther 1995; 68:385.
  13. Meekins CV, Sullivan TJ, Gruchalla RS. Immunochemical analysis of sulfonamide drug allergy: identification of sulfamethoxazole-substituted human serum proteins. J Allergy Clin Immunol 1994; 94:1017.
  14. Farrell J, Naisbitt DJ, Drummond NS, et al. Characterization of sulfamethoxazole and sulfamethoxazole metabolite-specific T-cell responses in animals and humans. J Pharmacol Exp Ther 2003; 306:229.
  15. Sanderson JP, Naisbitt DJ, Farrell J, et al. Sulfamethoxazole and its metabolite nitroso sulfamethoxazole stimulate dendritic cell costimulatory signaling. J Immunol 2007; 178:5533.
  16. Naisbitt DJ, Farrell J, Gordon SF, et al. Covalent binding of the nitroso metabolite of sulfamethoxazole leads to toxicity and major histocompatibility complex-restricted antigen presentation. Mol Pharmacol 2002; 62:628.
  17. Naisbitt DJ, Farrell J, Wong G, et al. Characterization of drug-specific T cells in lamotrigine hypersensitivity. J Allergy Clin Immunol 2003; 111:1393.
  18. Wu Y, Farrell J, Pirmohamed M, et al. Generation and characterization of antigen-specific CD4+, CD8+, and CD4+CD8+ T-cell clones from patients with carbamazepine hypersensitivity. J Allergy Clin Immunol 2007; 119:973.
  19. Baldo BA, Fisher MM, Pham NH. On the origin and specificity of antibodies to neuromuscular blocking (muscle relaxant) drugs: an immunochemical perspective. Clin Exp Allergy 2009; 39:325.
  20. Vervloet D, Arnaud A, Senft M, et al. Anaphylactic reactions to suxamethonium prevention of mediator release by choline. J Allergy Clin Immunol 1985; 76:222.
  21. Zanni MP, von Greyerz S, Schnyder B, et al. HLA-restricted, processing- and metabolism-independent pathway of drug recognition by human alpha beta T lymphocytes. J Clin Invest 1998; 102:1591.
  22. Pichler WJ. Pharmacological interaction of drugs with antigen-specific immune receptors: the p-i concept. Curr Opin Allergy Clin Immunol 2002; 2:301.
  23. Allele frequencies in the general population can be found at http://www.allelefrequencies.net/hla6006a.asp (Accessed on September 18, 2017).
  24. Pavlos R, Mallal S, Ostrov D, et al. T cell-mediated hypersensitivity reactions to drugs. Annu Rev Med 2015; 66:439.
  25. Chung WH, Chang WC, Lee YS, et al. Genetic variants associated with phenytoin-related severe cutaneous adverse reactions. JAMA 2014; 312:525.
  26. Chung WH, Chang WC, Stocker SL, et al. Insights into the poor prognosis of allopurinol-induced severe cutaneous adverse reactions: the impact of renal insufficiency, high plasma levels of oxypurinol and granulysin. Ann Rheum Dis 2015; 74:2157.
  27. Yun J, Cai F, Lee FJ, Pichler WJ. T-cell-mediated drug hypersensitivity: immune mechanisms and their clinical relevance. Asia Pac Allergy 2016; 6:77.
  28. Pichler WJ. Direct T-cell stimulations by drugs--bypassing the innate immune system. Toxicology 2005; 209:95.
  29. Depta JP, Altznauer F, Gamerdinger K, et al. Drug interaction with T-cell receptors: T-cell receptor density determines degree of cross-reactivity. J Allergy Clin Immunol 2004; 113:519.
  30. Nassif A, Bensussan A, Dorothée G, et al. Drug specific cytotoxic T-cells in the skin lesions of a patient with toxic epidermal necrolysis. J Invest Dermatol 2002; 118:728.
  31. Schnyder B, Burkhart C, Schnyder-Frutig K, et al. Recognition of sulfamethoxazole and its reactive metabolites by drug-specific CD4+ T cells from allergic individuals. J Immunol 2000; 164:6647.
  32. Pichler WJ. Delayed drug hypersensitivity reactions. Ann Intern Med 2003; 139:683.
  33. Watkins S, Picher WJ. Activating interactions of sulfanilamides with T cell receptors. Open J Immunol 2013; 3:139.
  34. Watkins S, Pichler WJ. Sulfamethoxazole induces a switch mechanism in T cell receptors containing TCRVβ20-1, altering pHLA recognition. PLoS One 2013; 8:e76211.
  35. Chung WH, Hung SI, Hong HS, et al. Medical genetics: a marker for Stevens-Johnson syndrome. Nature 2004; 428:486.
  36. Hung SI, Chung WH, Liou LB, et al. HLA-B*5801 allele as a genetic marker for severe cutaneous adverse reactions caused by allopurinol. Proc Natl Acad Sci U S A 2005; 102:4134.
  37. Mallal S, Phillips E, Carosi G, et al. HLA-B*5701 screening for hypersensitivity to abacavir. N Engl J Med 2008; 358:568.
  38. Pavlos R, Mallal S, Phillips E. HLA and pharmacogenetics of drug hypersensitivity. Pharmacogenomics 2012; 13:1285.
  39. Yun J, Adam J, Yerly D, Pichler WJ. Human leukocyte antigens (HLA) associated drug hypersensitivity: consequences of drug binding to HLA. Allergy 2012; 67:1338.
  40. Illing PT, Vivian JP, Dudek NL, et al. Immune self-reactivity triggered by drug-modified HLA-peptide repertoire. Nature 2012; 486:554.
  41. Adam J, Eriksson KK, Schnyder B, et al. Avidity determines T-cell reactivity in abacavir hypersensitivity. Eur J Immunol 2012; 42:1706.
  42. Adam J, Wuillemin N, Watkins S, et al. Abacavir induced T cell reactivity from drug naïve individuals shares features of allo-immune responses. PLoS One 2014; 9:e95339.
  43. Ostrov DA, Grant BJ, Pompeu YA, et al. Drug hypersensitivity caused by alteration of the MHC-presented self-peptide repertoire. Proc Natl Acad Sci U S A 2012; 109:9959.
  44. Norcross MA, Luo S, Lu L, et al. Abacavir induces loading of novel self-peptides into HLA-B*57: 01: an autoimmune model for HLA-associated drug hypersensitivity. AIDS 2012; 26:F21.
  45. Wei CY, Chung WH, Huang HW, et al. Direct interaction between HLA-B and carbamazepine activates T cells in patients with Stevens-Johnson syndrome. J Allergy Clin Immunol 2012; 129:1562.
  46. Ko TM, Chung WH, Wei CY, et al. Shared and restricted T-cell receptor use is crucial for carbamazepine-induced Stevens-Johnson syndrome. J Allergy Clin Immunol 2011; 128:1266.
  47. Yun J, Marcaida MJ, Eriksson KK, et al. Oxypurinol directly and immediately activates the drug-specific T cells via the preferential use of HLA-B*58:01. J Immunol 2014; 192:2984.
  48. Wuillemin N, Adam J, Fontana S, et al. HLA haplotype determines hapten or p-i T cell reactivity to flucloxacillin. J Immunol 2013; 190:4956.
  49. Wuillemin N, Terracciano L, Beltraminelli H, et al. T cells infiltrate the liver and kill hepatocytes in HLA-B(∗)57:01-associated floxacillin-induced liver injury. Am J Pathol 2014; 184:1677.
  50. Clark RA, Chong B, Mirchandani N, et al. The vast majority of CLA+ T cells are resident in normal skin. J Immunol 2006; 176:4431.
  51. Schaerli P, Ebert L, Willimann K, et al. A skin-selective homing mechanism for human immune surveillance T cells. J Exp Med 2004; 199:1265.
  52. Cheng CY, Su SC, Chen CH, et al. HLA associations and clinical implications in T-cell mediated drug hypersensitivity reactions: an updated review. J Immunol Res 2014; 2014:565320.
  53. Zhang FR, Liu H, Irwanto A, et al. HLA-B*13:01 and the dapsone hypersensitivity syndrome. N Engl J Med 2013; 369:1620.
  54. Morel E, Escamochero S, Cabañas R, et al. CD94/NKG2C is a killer effector molecule in patients with Stevens-Johnson syndrome and toxic epidermal necrolysis. J Allergy Clin Immunol 2010; 125:703.
  55. Genin E, Chen DP, Hung SI, et al. HLA-A*31:01 and different types of carbamazepine-induced severe cutaneous adverse reactions: an international study and meta-analysis. Pharmacogenomics J 2014; 14:281.
  56. Schnyder B, Adam J, Rauch A, et al. HLA-B*57:01(+) abacavir-naive individuals have specific T cells but no patch test reactivity. J Allergy Clin Immunol 2013; 132:756.
  57. Yawalkar N, Shrikhande M, Hari Y, et al. Evidence for a role for IL-5 and eotaxin in activating and recruiting eosinophils in drug-induced cutaneous eruptions. J Allergy Clin Immunol 2000; 106:1171.
  58. Ben m'rad M, Leclerc-Mercier S, Blanche P, et al. Drug-induced hypersensitivity syndrome: clinical and biologic disease patterns in 24 patients. Medicine (Baltimore) 2009; 88:131.
  59. Peyrière H, Dereure O, Breton H, et al. Variability in the clinical pattern of cutaneous side-effects of drugs with systemic symptoms: does a DRESS syndrome really exist? Br J Dermatol 2006; 155:422.
  60. Mauri-Hellweg D, Bettens F, Mauri D, et al. Activation of drug-specific CD4+ and CD8+ T cells in individuals allergic to sulfonamides, phenytoin, and carbamazepine. J Immunol 1995; 155:462.
  61. Hertl M, Geisel J, Boecker C, Merk HF. Selective generation of CD8+ T-cell clones from the peripheral blood of patients with cutaneous reactions to beta-lactam antibiotics. Br J Dermatol 1993; 128:619.
  62. Schnyder B, Frutig K, Mauri-Hellweg D, et al. T-cell-mediated cytotoxicity against keratinocytes in sulfamethoxazol-induced skin reaction. Clin Exp Allergy 1998; 28:1412.
  63. Schmid S, Kuechler PC, Britschgi M, et al. Acute generalized exanthematous pustulosis: role of cytotoxic T cells in pustule formation. Am J Pathol 2002; 161:2079.
  64. Mennicke M, Zawodniak A, Keller M, et al. Fulminant liver failure after vancomycin in a sulfasalazine-induced DRESS syndrome: fatal recurrence after liver transplantation. Am J Transplant 2009; 9:2197.
  65. Roujeau JC, Kelly JP, Naldi L, et al. Medication use and the risk of Stevens-Johnson syndrome or toxic epidermal necrolysis. N Engl J Med 1995; 333:1600.
  66. Fritsch PO, Sidoroff A. Drug-induced Stevens-Johnson syndrome/toxic epidermal necrolysis. Am J Clin Dermatol 2000; 1:349.
  67. Chung WH, Hung SI, Yang JY, et al. Granulysin is a key mediator for disseminated keratinocyte death in Stevens-Johnson syndrome and toxic epidermal necrolysis. Nat Med 2008; 14:1343.
  68. Macedo FI, Faris J, Lum LG, et al. Extensive toxic epidermal necrolysis versus acute graft versus host disease after allogenic hematopoietic stem-cell transplantation: challenges in diagnosis and management. J Burn Care Res 2014; 35:e431.
  69. Furudate S, Fujimura T, Kambayashi Y, Aiba S. Granulysin-Bearing Cells in the Skin Lesions of Acute Graft-versus-Host Disease: Possible Mechanisms for Hypohidrosis in Graft-versus-Host Disease. Case Rep Dermatol 2013; 5:93.
  70. Britschgi M, Steiner UC, Schmid S, et al. T-cell involvement in drug-induced acute generalized exanthematous pustulosis. J Clin Invest 2001; 107:1433.
  71. Keller M, Spanou Z, Schaerli P, et al. T cell-regulated neutrophilic inflammation in autoinflammatory diseases. J Immunol 2005; 175:7678.