Skip to main content
SpringerLink
Log in

Mechanisms of Drug Hypersensitivity

  • Chapter
  • First Online:
Drug Eruptions

Part of the book series: Updates in Clinical Dermatology ((UCD))

  • 445 Accesses

Abstract

Drug hypersensitivity (DH) is a growing problem worldwide. Although the exact mechanism is not well understood, it is considered immune-mediated. Drug hypersensitivity reactions are primarily classified into immediate or delayed type reactions and their presentation range from mild skin reactions [e.g., maculopapular exanthema (MPE) and urticaria] to severe life-threatening systemic reactions, such as drug reactions with eosinophilia and systemic symptoms (DRESS), Stevens–Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN), acute generalized exanthematous pustulosis (AGEP) and anaphylaxis. There are four postulated models to explain the interaction between drugs, human leukocyte antigens (HLA), and T cell receptors (TCR): (1) apten theory, (2) p–i concept, (3) altered peptide repertoire model, and the (4) altered T cell receptor (TCR) repertoire. Current pharmacogenomic studies have shown that pre-prescription screening of HLAs and drug-metabolizing enzymes variants may prevent severe cutaneous adverse reactions. The basic understanding of the mechanisms of DH would serve as a platform for future approaches to prevent and treat such diseases.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 249.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Abbreviations

ADR:

Adverse drug reactions

APC:

Antigen-presenting cells

CBZ:

Carbamazepine

CCL:

Chemokine (C–C motif) ligand

CTL:

Cytotoxic T lymphocytes

CXCL8 :

Chemotactic chemokine (C–X–C motif) ligand 8

CYP2C:

Cytochrome P450 2C

DH:

Drug hypersensitivity

DRESS:

Drug reaction with eosinophilia and systemic symptoms

FADD:

Fas-associated death domain

GM-CSF:

Granulocyte–macrophage colony-stimulating factor

HLA:

Human leukocyte antigen

IFN:

Interferon

IL:

Interleukin

LTG:

Lamotrigine

MCP:

Monocyte chemotactic protein

MPE:

Mild maculopapular exanthema

NK:

Nature killer

NSAIDs:

Nonsteroidal anti-inflammatory drugs

OXC:

Oxcarbazepine

OXP:

Oxypurinol

PHT:

Phenytoin

RANTES:

Regulated upon activation, normal T-cell expressed, and secreted

SAPLIP:

Saposin-like protein

SCAR:

Severe cutaneous adverse reactions

sFASL:

Soluble Fas ligand

SJS:

Stevens–Johnson syndrome

TCR:

T-cell receptors

TEN:

Toxic epidermal necrolysis

TNF-α:

Tumor necrosis factor-α

References

  • Abe R, et al. Toxic epidermal necrolysis and Stevens–Johnson syndrome are induced by soluble Fas ligand. Am J Pathol. 2003;162(5):1515–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Abe R, et al. Granulysin as a marker for early diagnosis of the Stevens–Johnson syndrome. Ann Intern Med. 2009;151(7):514–5.

    Article  PubMed  Google Scholar 

  • Belhadjali H, et al. Mercury-induced acute generalized exanthematous pustulosis misdiagnosed as a drug-related case. Contact Dermat. 2008;59(1):52–4.

    Article  Google Scholar 

  • Blanca-Lopez N, et al. Immediate hypersensitivity reactions to ibuprofen and other arylpropionic acid derivatives. Allergy. 2016;71(7):1048–56.

    Article  CAS  PubMed  Google Scholar 

  • Bots M, Medema JP. Granzymes at a glance. J Cell Sci. 2006;119(Pt 24):5011–4.

    Article  CAS  PubMed  Google Scholar 

  • Brockow K, et al. Skin test concentrations for systemically administered drugs—an ENDA/EAACI Drug Allergy Interest Group position paper. Allergy. 2013;68(6):702–12.

    Article  CAS  PubMed  Google Scholar 

  • Canto MG, et al. Selective immediate hypersensitivity reactions to NSAIDs. Curr Opin Allergy Clin Immunol. 2009;9(4):293–7.

    Article  CAS  PubMed  Google Scholar 

  • Caproni M, et al. Expression of cytokines and chemokine receptors in the cutaneous lesions of erythema multiforme and Stevens–Johnson syndrome/toxic epidermal necrolysis. Br J Dermatol. 2006;155(4):722–8.

    Article  CAS  PubMed  Google Scholar 

  • Chang CC, et al. Association of HLA-B*15:13 and HLA-B*15:02 with phenytoin-induced severe cutaneous adverse reactions in a Malay population. Pharmacogenom J. 2017;17(2):170–3.

    Article  CAS  Google Scholar 

  • Chantarangsu S, et al. HLA-B*3505 allele is a strong predictor for nevirapine-induced skin adverse drug reactions in HIV-infected Thai patients. Pharmacogenet Genom. 2009;19(2):139–46.

    Article  CAS  Google Scholar 

  • Chavez-Galan L, et al. Cell death mechanisms induced by cytotoxic lymphocytes. Cell Mol Immunol. 2009;6(1):15–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chen YC, et al. Human herpes virus reactivations and dynamic cytokine profiles in patients with cutaneous adverse drug reactions—a prospective comparative study. Allergy. 2015;70(5):568–75.

    Article  CAS  PubMed  Google Scholar 

  • Chen CB, et al. Risk and association of HLA with oxcarbazepine-induced cutaneous adverse reactions in Asians. Neurology. 2017;88(1):78–86.

    Article  CAS  PubMed  Google Scholar 

  • Cheung YK, et al. HLA-B alleles associated with severe cutaneous reactions to antiepileptic drugs in Han Chinese. Epilepsia. 2013;54(7):1307–14.

    Article  CAS  PubMed  Google Scholar 

  • Choi JH, et al. Association of TNF-alpha promoter polymorphisms with aspirin-induced urticaria. J Clin Pharm Ther. 2009;34(2):231–8.

    Article  CAS  PubMed  Google Scholar 

  • Choi MJ, et al. Clinicopathologic manifestations of 36 korean patients with acute generalized exanthematous pustulosis: a case series and review of the literature. Ann Dermatol. 2010;22(2):163–9.

    Article  PubMed  PubMed Central  Google Scholar 

  • Choquet-Kastylevsky G, et al. Increased levels of interleukin 5 are associated with the generation of eosinophilia in drug-induced hypersensitivity syndrome. Br J Dermatol. 1998;139(6):1026–32.

    Article  CAS  PubMed  Google Scholar 

  • Chung WH, Hung SI. Recent advances in the genetics and immunology of Stevens–Johnson syndrome and toxic epidermal necrosis. J Dermatol Sci. 2012;66(3):190–6.

    Article  CAS  PubMed  Google Scholar 

  • Chung WH, et al. Medical genetics: a marker for Stevens–Johnson syndrome. Nature. 2004;428(6982):486.

    Article  CAS  PubMed  Google Scholar 

  • Chung WH, et al. Granulysin is a key mediator for disseminated keratinocyte death in Stevens–Johnson syndrome and toxic epidermal necrolysis. Nat Med. 2008;14(12):1343–50.

    Article  CAS  PubMed  Google Scholar 

  • Chung WH, et al. Genetic variants associated with phenytoin-related severe cutaneous adverse reactions. JAMA. 2014;312(5):525–34.

    Article  PubMed  Google Scholar 

  • Chung WH, 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. 2015a;74(12):2157–64.

    Article  CAS  PubMed  Google Scholar 

  • Chung WH, et al. Oxypurinol-specific T cells possess preferential TCR clonotypes and express granulysin in allopurinol-induced severe cutaneous adverse reactions. J Investig Dermatol. 2015b;135(9):2237–48.

    Article  CAS  PubMed  Google Scholar 

  • Ciccacci C, et al. Association between CYP2B6 polymorphisms and nevirapine-induced SJS/TEN: a pharmacogenetics study. Eur J Clin Pharmacol. 2013;69(11):1909–16.

    Article  CAS  PubMed  Google Scholar 

  • Cornejo-Garcia JA, et al. Genetic variants of the arachidonic acid pathway in non-steroidal anti-inflammatory drug-induced acute urticaria. Clin Exp Allergy. 2012;42(12):1772–81.

    Article  CAS  PubMed  Google Scholar 

  • Correia O, et al. Increased interleukin 10, tumor necrosis factor alpha, and interleukin 6 levels in blister fluid of toxic epidermal necrolysis. J Am Acad Dermatol. 2002;47(1):58–62.

    Article  PubMed  Google Scholar 

  • Deng A, et al. Granulysin, a cytolytic molecule, is also a chemoattractant and proinflammatory activator. J Immunol. 2005;174(9):5243–8.

    Article  CAS  PubMed  Google Scholar 

  • Dona I, et al. Hypersensitivity reactions to non-steroidal anti-inflammatory drugs. Curr Pharm Des. 2016;22(45):6784–802.

    Article  CAS  PubMed  Google Scholar 

  • Ferrell PB Jr, McLeod HL. Carbamazepine, HLA-B*1502 and risk of Stevens–Johnson syndrome and toxic epidermal necrolysis: US FDA recommendations. Pharmacogenomics. 2008;9(10):1543–6.

    Article  CAS  PubMed  Google Scholar 

  • Finkelman FD, Khodoun MV, Strait R. Human IgE-independent systemic anaphylaxis. J Allergy Clin Immunol. 2016;137(6):1674–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fujiyama T, et al. Increased frequencies of Th17 cells in drug eruptions. J Dermatol Sci. 2014;73(1):85–8.

    Article  CAS  PubMed  Google Scholar 

  • Gatanaga H, et al. HLA-Cw8 primarily associated with hypersensitivity to nevirapine. AIDS. 2007;21(2):264–5.

    Article  PubMed  Google Scholar 

  • Genin E, et al. HLA-A*31:01 and different types of carbamazepine-induced severe cutaneous adverse reactions: an international study and meta-analysis. Pharmacogenom J. 2014;14(3):281–8.

    Article  CAS  Google Scholar 

  • Gueant JL, et al. HLA-DRA variants predict penicillin allergy in genome-wide fine-mapping genotyping. J Allergy Clin Immunol. 2015;135(1):253–9.

    Article  CAS  PubMed  Google Scholar 

  • Hashizume H, Fujiyama T, Tokura Y. Reciprocal contribution of Th17 and regulatory T cells in severe drug allergy. J Dermatol Sci. 2016;81(2):131–4.

    Article  CAS  PubMed  Google Scholar 

  • Hetherington S, et al. Genetic variations in HLA-B region and hypersensitivity reactions to abacavir. Lancet. 2002;359(9312):1121–2.

    Article  CAS  PubMed  Google Scholar 

  • Hung SI, et al. HLA-B*5801 allele as a genetic marker for severe cutaneous adverse reactions caused by allopurinol. Proc Natl Acad Sci USA. 2005;102(11):4134–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hung SI, et al. Genetic susceptibility to carbamazepine-induced cutaneous adverse drug reactions. Pharmacogenet Genom. 2006;16(4):297–306.

    Article  CAS  Google Scholar 

  • Hung SI, et al. Common risk allele in aromatic antiepileptic-drug induced Stevens–Johnson syndrome and toxic epidermal necrolysis in Han Chinese. Pharmacogenomics. 2010;11(3):349–56.

    Article  CAS  PubMed  Google Scholar 

  • Ikeda H, et al. HLA class I markers in Japanese patients with carbamazepine-induced cutaneous adverse reactions. Epilepsia. 2010;51(2):297–300.

    Article  PubMed  Google Scholar 

  • Illing PT, et al. Immune self-reactivity triggered by drug-modified HLA-peptide repertoire. Nature. 2012;486(7404):554–8.

    Article  CAS  PubMed  Google Scholar 

  • Johansson SG, et al. A revised nomenclature for allergy. An EAACI position statement f–rom the EAACI nomenclature task force. Allergy. 2001;56(9):813–24.

    Article  CAS  PubMed  Google Scholar 

  • Kabashima R, et al. Increased circulating Th17 frequencies and serum IL-22 levels in patients with acute generalized exanthematous pustulosis. J Eur Acad Dermatol Venereol. 2011;25(4):485–8.

    Article  CAS  PubMed  Google Scholar 

  • Kaniwa N, et al. HLA-B*1511 is a risk factor for carbamazepine-induced Stevens–Johnson syndrome and toxic epidermal necrolysis in Japanese patients. Epilepsia. 2010;51(12):2461–5.

    Article  CAS  PubMed  Google Scholar 

  • Kazeem GR, et al. High-resolution HLA genotyping and severe cutaneous adverse reactions in lamotrigine-treated patients. Pharmacogenet Genom. 2009;19(9):661–5.

    Article  CAS  Google Scholar 

  • Kim SH, et al. Genetic mechanism of aspirin-induced urticaria/angioedema. Curr Opin Allergy Clin Immunol. 2006;6(4):266–70.

    Article  CAS  PubMed  Google Scholar 

  • Kim SH, et al. HLA-B*5901 is strongly associated with methazolamide-induced Stevens–Johnson syndrome/toxic epidermal necrolysis. Pharmacogenomics. 2010;11(6):879–84.

    Article  CAS  PubMed  Google Scholar 

  • Kim SH, Lee KW, Song WJ, et al. Carbamazepine-induced msevere cutaneous reactions and HLA genotypes in Korea. Epilepsy Res. 2011;97:190–7.

    Google Scholar 

  • Kim SH, et al. A functional promoter polymorphism of the human IL18 gene is associated with aspirin-induced urticaria. Br J Dermatol. 2011a;165(5):976–84.

    Article  CAS  PubMed  Google Scholar 

  • Kim SH, et al. Carbamazepine-induced severe cutaneous adverse reactions and HLA genotypes in Koreans. Epilepsy Res. 2011b;97(1–2):190–7.

    Article  CAS  PubMed  Google Scholar 

  • Kim SK, et al. Upregulated RIP3 expression potentiates MLKL phosphorylation-mediated programmed necrosis in toxic epidermal necrolysis. J Investig Dermatol. 2015;135(8):2021–30.

    Article  CAS  PubMed  Google Scholar 

  • Kim D, et al. Targeted therapy guided by single-cell transcriptomic analysis in drug-induced hypersensitivity syndrome: a case report. Nat Med. 2020;26(2):236–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kishimoto TK, et al. Contaminated heparin associated with adverse clinical events and activation of the contact system. N Engl J Med. 2008;358(23):2457–67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Konvinse KC, et al. HLA-A*32:01 is strongly associated with vancomycin-induced drug reaction with eosinophilia and systemic symptoms. J Allergy Clin Immunol. 2019;144(1):183–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lanier LL. NK cell recognition. Annu Rev Immunol. 2005;23:225–74.

    Article  CAS  PubMed  Google Scholar 

  • Laroche D, et al. Anaphylactoid and anaphylactic reactions to iodinated contrast material. Allergy. 1999;54(Suppl 58):13–6.

    Article  PubMed  Google Scholar 

  • Littera R, et al. HLA-dependent hypersensitivity to nevirapine in Sardinian HIV patients. AIDS. 2006;20(12):1621–6.

    Article  CAS  PubMed  Google Scholar 

  • Locharernkul C, et al. Carbamazepine and phenytoin induced Stevens–Johnson syndrome is associated with HLA-B*1502 allele in Thai population. Epilepsia. 2008;49(12):2087–91.

    Article  PubMed  Google Scholar 

  • Lonjou C, et al. A European study of HLA-B in Stevens–Johnson syndrome and toxic epidermal necrolysis related to five high-risk drugs. Pharmacogenet Genom. 2008;18(2):99–107.

    Article  CAS  Google Scholar 

  • Mallal S, et al. Association between presence of HLA-B*5701, HLA-DR7, and HLA-DQ3 and hypersensitivity to HIV-1 reverse-transcriptase inhibitor abacavir. Lancet. 2002;359(9308):727–32.

    Article  CAS  PubMed  Google Scholar 

  • Mallal S, et al. HLA-B*5701 screening for hypersensitivity to abacavir. N Engl J Med. 2008;358(6):568–79.

    Article  PubMed  Google Scholar 

  • Martin AM, et al. Predisposition to nevirapine hypersensitivity associated with HLA-DRB1*0101 and abrogated by low CD4 T-cell counts. AIDS. 2005;19(1):97–9.

    Article  CAS  PubMed  Google Scholar 

  • McCormack M, et al. HLA-A*3101 and carbamazepine-induced hypersensitivity reactions in Europeans. N Engl J Med. 2011;364(12):1134–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Meier-Schiesser B, et al. Culprit drugs induce specific IL-36 overexpression in acute generalized exanthematous pustulosis. J Investig Dermatol. 2019;139(4):848–58.

    Article  CAS  PubMed  Google Scholar 

  • Mockenhaupt M, et al. HLA-B*57:01 confers genetic susceptibility to carbamazepine-induced SJS/TEN in Europeans. Allergy. 2019;74(11):2227–30.

    Article  PubMed  Google Scholar 

  • Montanez MI, et al. Epidemiology, mechanisms, and diagnosis of drug-induced anaphylaxis. Front Immunol. 2017;8:614.

    Article  PubMed  PubMed Central  Google Scholar 

  • Moon TC, Befus AD, Kulka M. Mast cell mediators: their differential release and the secretory pathways involved. Front Immunol. 2014;5:569.

    Article  PubMed  PubMed Central  Google Scholar 

  • Morel E, 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(3):703–10.

    Article  CAS  PubMed  Google Scholar 

  • Munoz-Cano R, et al. Mechanisms of anaphylaxis beyond IgE. J Investig Allergol Clin Immunol. 2016;26(2):73–82.

    Article  CAS  PubMed  Google Scholar 

  • Naisbitt DJ, et al. Hypersensitivity reactions to carbamazepine: characterization of the specificity, phenotype, and cytokine profile of drug-specific T cell clones. Mol Pharmacol. 2003;63(3):732–41.

    Article  CAS  PubMed  Google Scholar 

  • Nassif A, et al. Drug specific cytotoxic T-cells in the skin lesions of a patient with toxic epidermal necrolysis. J Investig Dermatol. 2002;118(4):728–33.

    Article  CAS  PubMed  Google Scholar 

  • Nassif A, et al. Evaluation of the potential role of cytokines in toxic epidermal necrolysis. J Investig Dermatol. 2004;123(5):850–5.

    Article  CAS  PubMed  Google Scholar 

  • Navarini AA, et al. Rare variations in IL36RN in severe adverse drug reactions manifesting as acute generalized exanthematous pustulosis. J Investig Dermatol. 2013;133(7):1904–7.

    Article  CAS  PubMed  Google Scholar 

  • Ng CY, et al. Impact of the HLA-B(*)58:01 allele and renal impairment on allopurinol-induced cutaneous adverse reactions. J Investig Dermatol. 2016;136(7):1373–81.

    Article  CAS  PubMed  Google Scholar 

  • Olteanu C, et al. The 10th international congress on cutaneous adverse drug reactions, Shimane, Japan, 2018: focus on new discoveries. Drug Saf. 2019;42(6):797–801.

    Article  PubMed  Google Scholar 

  • Ostrov DA, et al. Drug hypersensitivity caused by alteration of the MHC-presented self-peptide repertoire. Proc Natl Acad Sci USA. 2012;109(25):9959–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Oussalah A, et al. Genetic variants associated with drugs-induced immediate hypersensitivity reactions: a PRISMA-compliant systematic review. Allergy. 2016;71(4):443–62.

    Article  CAS  PubMed  Google Scholar 

  • Ozeki T, et al. Genome-wide association study identifies HLA-A*3101 allele as a genetic risk factor for carbamazepine-induced cutaneous adverse drug reactions in Japanese population. Hum Mol Genet. 2011;20(5):1034–41.

    Article  CAS  PubMed  Google Scholar 

  • Pacor ML, et al. Relationship between human leucocyte antigen class I and class II and chronic idiopathic urticaria associated with aspirin and/or NSAIDs hypersensitivity. Mediat Inflamm. 2006;2006(5):62489.

    Google Scholar 

  • Padovan E, et al. Penicilloyl peptides are recognized as T cell antigenic determinants in penicillin allergy. Eur J Immunol. 1997;27(6):1303–7.

    Article  CAS  PubMed  Google Scholar 

  • Pan RY, et al. Identification of drug-specific public TCR driving severe cutaneous adverse reactions. Nat Commun. 2019;10(1):3569.

    Article  PubMed  PubMed Central  Google Scholar 

  • Paquet P, et al. Macrophages and tumor necrosis factor alpha in toxic epidermal necrolysis. Arch Dermatol. 1994;130(5):605–8.

    Article  CAS  PubMed  Google Scholar 

  • Paquet P, et al. Immunoregulatory effector cells in drug-induced toxic epidermal necrolysis. Am J Dermatopathol. 2000;22(5):413–7.

    Article  CAS  PubMed  Google Scholar 

  • Pichler WJ. Pharmacological interaction of drugs with antigen-specific immune receptors: the p–i concept. Curr Opin Allergy Clin Immunol. 2002;2(4):301–5.

    Article  PubMed  Google Scholar 

  • Pichler WJ. Delayed drug hypersensitivity reactions. Ann Intern Med. 2003;139(8):683–93.

    Article  CAS  PubMed  Google Scholar 

  • Pinkoski MJ, et al. Granzyme B-mediated apoptosis proceeds predominantly through a Bcl-2-inhibitable mitochondrial pathway. J Biol Chem. 2001;276(15):12060–7.

    Article  CAS  PubMed  Google Scholar 

  • Qiao HL, Yang J, Zhang YW. Relationships between specific serum IgE, cytokines and polymorphisms in the IL-4, IL-4Ralpha in patients with penicillins allergy. Allergy. 2005;60(8):1053–9.

    Article  CAS  PubMed  Google Scholar 

  • Quiralte J, et al. Association of HLA-DR11 with the anaphylactoid reaction caused by nonsteroidal anti-inflammatory drugs. J Allergy Clin Immunol. 1999;103(4):685–9.

    Article  CAS  PubMed  Google Scholar 

  • Redwood AJ, et al. Single-cell transcriptomics reveal polyclonal memory T-cell responses in skin with positive abacavir patch test results. J Allergy Clin Immunol. 2019;144(5):1413–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rive CM, Bourke J, Phillips EJ. Testing for drug hypersensitivity syndromes. Clin Biochem Rev. 2013;34(1):15–38.

    PubMed  PubMed Central  Google Scholar 

  • Romano A, et al. Delayed hypersensitivity to aminopenicillins is related to major histocompatibility complex genes. Ann Allergy Asthma Immunol. 1998;80(5):433–7.

    Article  CAS  PubMed  Google Scholar 

  • Saag M, et al. High sensitivity of human leukocyte antigen-b*5701 as a marker for immunologically confirmed abacavir hypersensitivity in white and black patients. Clin Infect Dis. 2008;46(7):1111–8.

    Article  CAS  PubMed  Google Scholar 

  • Saito N, et al. An annexin A1-FPR1 interaction contributes to necroptosis of keratinocytes in severe cutaneous adverse drug reactions. Sci Transl Med. 2014;6(245):245ra95.

    Article  PubMed  Google Scholar 

  • Schaerli P, et al. Characterization of human T cells that regulate neutrophilic skin inflammation. J Immunol. 2004;173(3):2151–8.

    Article  CAS  PubMed  Google Scholar 

  • Schnyder B, Pichler WJ. Mechanisms of drug-induced allergy. Mayo Clin Proc. 2009;84(3):268–72.

    Article  PubMed  PubMed Central  Google Scholar 

  • Shepherd FA, et al. Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med. 2005;353(2):123–32.

    Article  CAS  PubMed  Google Scholar 

  • Shi YW, et al. Hla-B alleles and lamotrigine-induced cutaneous adverse drug reactions in the Han Chinese population. Basic Clin Pharmacol Toxicol. 2011;109(1):42–6.

    Article  CAS  PubMed  Google Scholar 

  • Somkrua R, et al. Association of HLA-B*5801 allele and allopurinol-induced Stevens–Johnson syndrome and toxic epidermal necrolysis: a systematic review and meta-analysis. BMC Med Genet. 2011;12:118.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Su SC, et al. Interleukin-15 is associated with severity and mortality in Stevens–Johnson syndrome/toxic epidermal necrolysis. J Investig Dermatol. 2017;137(5):1065–73.

    Article  CAS  PubMed  Google Scholar 

  • Subramanian H, Gupta K, Ali H. Roles of Mas-related G protein-coupled receptor X2 on mast cell-mediated host defense, pseudoallergic drug reactions, and chronic inflammatory diseases. J Allergy Clin Immunol. 2016;138(3):700–10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tangamornsuksan W, Lohitnavy M. Association between HLA-B*5901 and methazolamide-induced Stevens–Johnson syndrome/toxic epidermal necrolysis: a systematic review and meta-analysis. Pharmacogenom J. 2019;19(3):286–94.

    Article  CAS  Google Scholar 

  • Tangamornsuksan W, et al. Relationship between the HLA-B*1502 allele and carbamazepine-induced Stevens–Johnson syndrome and toxic epidermal necrolysis: a systematic review and meta-analysis. JAMA Dermatol. 2013;149(9):1025–32.

    Article  CAS  PubMed  Google Scholar 

  • Tanno LK, et al. The absence of CYP3A5*3 is a protective factor to anticonvulsants hypersensitivity reactions: a case-control study in Brazilian subjects. PLoS One. 2015;10(8):e0136141.

    Article  PubMed  PubMed Central  Google Scholar 

  • Tapia B, et al. Involvement of CCL27–CCR10 interactions in drug-induced cutaneous reactions. J Allergy Clin Immunol. 2004;114(2):335–40.

    Article  CAS  PubMed  Google Scholar 

  • Tassaneeyakul W, et al. Associations between HLA class I and cytochrome P450 2C9 genetic polymorphisms and phenytoin-related severe cutaneous adverse reactions in a Thai population. Pharmacogenet Genom. 2016;26(5):225–34.

    Article  CAS  Google Scholar 

  • Teraki Y, Fukuda T. Skin-homing IL-13-producing T cells expand in the circulation of patients with drug rash with eosinophilia and systemic symptoms. Dermatology. 2017;233(2–3):242–9.

    Article  CAS  PubMed  Google Scholar 

  • Tsai YG, et al. Increased type 2 innate lymphoid cells in patients with drug reaction with eosinophilia and systemic symptoms syndrome. J Investig Dermatol. 2019;139(8):1722–31.

    Article  CAS  PubMed  Google Scholar 

  • Valeyrie-Allanore L, Sassolas B, Roujeau JC. Drug-induced skin, nail and hair disorders. Drug Saf. 2007;30(11):1011–30.

    Article  CAS  PubMed  Google Scholar 

  • Viard I, et al. Inhibition of toxic epidermal necrolysis by blockade of CD95 with human intravenous immunoglobulin. Science. 1998;282(5388):490–3.

    Article  CAS  PubMed  Google Scholar 

  • Viard-Leveugle I, et al. TNF-alpha and IFN-gamma are potential inducers of Fas-mediated keratinocyte apoptosis through activation of inducible nitric oxide synthase in toxic epidermal necrolysis. J Investig Dermatol. 2013;133(2):489–98.

    Article  CAS  PubMed  Google Scholar 

  • Watkins S, Pichler WJ. Sulfamethoxazole induces a switch mechanism in T cell receptors containing TCRVβ20-1, altering pHLA recognition. PLoS One. 2013;8(10):e76211.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wedi B. Definitions and mechanisms of drug hypersensitivity. Expert Rev Clin Pharmacol. 2010;3(4):539–51.

    Article  CAS  PubMed  Google Scholar 

  • Wei CY, et al. Direct interaction between HLA-B and carbamazepine activates T cells in patients with Stevens–Johnson syndrome. J Allergy Clin Immunol. 2012;129(6):1562–9.

    Article  CAS  PubMed  Google Scholar 

  • Xiong H, et al. Comprehensive assessment of T cell receptor beta repertoire in Stevens–Johnson syndrome/toxic epidermal necrolysis patients using high-throughput sequencing. Mol Immunol. 2019;106:170–7.

    Article  CAS  PubMed  Google Scholar 

  • Yang J, Qiao HL, Dong ZM. Polymorphisms of IL-13 and IL-4-IL-13-SNPs in patients with penicillin allergies. Eur J Clin Pharmacol. 2005;61(11):803–9.

    Article  CAS  PubMed  Google Scholar 

  • Yang J, et al. HLA-DRB genotype and specific IgE responses in patients with allergies to penicillins. Chin Med J. 2006;119(6):458–66.

    Article  CAS  PubMed  Google Scholar 

  • Yang CW, et al. The interferon-gamma-induced protein 10/CXCR3 axis is associated with human herpesvirus-6 reactivation and the development of sequelae in drug reaction with eosinophilia and systemic symptoms. Br J Dermatol. 2020;183(5):909–19.

    Article  CAS  PubMed  Google Scholar 

  • Zhang FR, et al. HLA-B*13:01 and the dapsone hypersensitivity syndrome. N Engl J Med. 2013;369(17):1620–8.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Xiamen Chang Gung Hospital, School of Medicine, Medical Research Center and Xiamen Chang Gung Allergology Consortium, Xiamen, China

    Chih-Jung Chang

  2. Huaqiao University, Quanzhou, Fujian, China

    Chih-Jung Chang

  3. Chang Gung Memorial Hospital, Linkou, Taipei, Taiwan

    Chun-Bing Chen & Wen-Hung Chung

  4. Department of Dermatology, Drug Hypersensitivity Clinical and Research Center, Taoyuan, Taiwan

    Chun-Bing Chen & Wen-Hung Chung

Authors
  1. Chih-Jung Chang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Chun-Bing Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Wen-Hung Chung
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Department of Dermatology and Allergy Centre, Singapore General Hospital, Singapore, Singapore

    Haur Yueh Lee

  2. Department of Dermatology, King’s College Hospital, London, UK

    Daniel Creamer

Rights and permissions

Reprints and permissions

Copyright information

© 2022 Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Chang, CJ., Chen, CB., Chung, WH. (2022). Mechanisms of Drug Hypersensitivity. In: Lee, H.Y., Creamer, D. (eds) Drug Eruptions. Updates in Clinical Dermatology. Springer, Cham. https://doi.org/10.1007/978-3-031-09388-3_2

Download citation

  • DOI: https://doi.org/10.1007/978-3-031-09388-3_2

  • Published:

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-031-09387-6

  • Online ISBN: 978-3-031-09388-3

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation