A recent update of pharmacogenomics in drug-induced severe skin reactions.

In some adverse drug reactions (ADRs), genetic predisposition plays a significant role in pathogenesis, and the skin is the most frequently reported target. These severe cutaneous ADRs include bullous fixed drug eruptions (FDE), acute generalized exanthematous pustulosis (AGEP), drug-induced hypersensitivity syndrome (HSS), Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN). The putative contribution of individual effector cells in drug hypersensitivity is briefly mentioned. To trigger these drug hypersensitivities, certain class I HLA alleles (e.g., HLA-A and HLA-B alleles) and certain class II HLA alleles (e.g., HLA-DR alleles) have been recently found to be the genetic determinants. One of the best characterized examples mentioned in this article is HLA-B*1502 to determine the incidence of carbamazepine-induced SJS. How drugs are processed and presented by these HLA alleles to activate immune responses has been explained by several hypotheses. Further implication of pharmagenomic findings to prevent drug-induced severe skin reactions can be achieved by pre-screening putative risk HLA alleles before using drugs.

[1]  P. Henkart,et al.  Perforin and the granule exocytosis cytotoxicity pathway. , 2003, Current opinion in immunology.

[2]  P. Demoly,et al.  IL‐10 promoter and IL4‐Rα gene SNPs are associated with immediate β‐lactam allergy in atopic women , 2006 .

[3]  R. Stern,et al.  Clinical classification of cases of toxic epidermal necrolysis, Stevens-Johnson syndrome, and erythema multiforme. , 1993, Archives of dermatology.

[4]  T. Yamamura,et al.  NKT cells and autoimmune diseases: unraveling the complexity. , 2007, Current topics in microbiology and immunology.

[5]  Yuan-Tsong Chen,et al.  Granulysin is a key mediator for disseminated keratinocyte death in Stevens-Johnson syndrome and toxic epidermal necrolysis , 2008, Nature Medicine.

[6]  J. Tschopp,et al.  Inhibition of toxic epidermal necrolysis by blockade of CD95 with human intravenous immunoglobulin. , 1998, Science.

[7]  W. Pichler,et al.  In vitro detection of cytotoxic T and NK cells in peripheral blood of patients with various drug‐induced skin diseases , 2010, Allergy.

[8]  D. Grant,et al.  Characterization of the microsomal epoxide hydrolase gene in patients with anticonvulsant adverse drug reactions. , 1994, Pharmacogenetics.

[9]  H. Hengartner,et al.  The Role of Perforin in Infections and Tumour Surveillance , 2000, Experimental physiology.

[10]  T. Bellón,et al.  Involvement of CCL27-CCR10 interactions in drug-induced cutaneous reactions. , 2004, The Journal of allergy and clinical immunology.

[11]  T. Bellón,et al.  CD94/NKG2C is a killer effector molecule in patients with Stevens-Johnson syndrome and toxic epidermal necrolysis. , 2010, The Journal of allergy and clinical immunology.

[12]  M. Daly,et al.  HLA-B*5701 genotype is a major determinant of drug-induced liver injury due to flucloxacillin , 2009, Nature Genetics.

[13]  C. Joshi,et al.  Association of HLA-B*1502 allele and carbamazepine-induced Stevens-Johnson syndrome among Indians. , 2009, Indian journal of dermatology, venereology and leprology.

[14]  C. Brander,et al.  Characterization of lidocaine-specific T cells. , 1997, Journal of immunology.

[15]  Yuan-Tsong Chen,et al.  A marker for Stevens–Johnson syndrome , 2004 .

[16]  Eric Vivier,et al.  Functions of natural killer cells , 2008, Nature Immunology.

[17]  M. Pirmohamed,et al.  Generation and characterization of antigen-specific CD4+, CD8+, and CD4+CD8+ T-cell clones from patients with carbamazepine hypersensitivity. , 2007, The Journal of allergy and clinical immunology.

[18]  M. Pirmohamed,et al.  Characterization of drug-specific T cells in lamotrigine hypersensitivity. , 2003, The Journal of allergy and clinical immunology.

[19]  C. Sotozono,et al.  HLA-B locus in Japanese patients with anti-epileptics and allopurinol-related Stevens-Johnson syndrome and toxic epidermal necrolysis. , 2008, Pharmacogenomics.

[20]  N. Yawalkar.  Drug-induced exanthems. , 2005, Toxicology.

[21]  A. Berrebi,et al.  HLA class I/NK cell receptor interaction in early human decidua basalis: possible functional consequences. , 2005, Chemical immunology and allergy.

[22]  W. Pichler,et al.  Pharmacological interaction of drugs with immune receptors: the p-i concept. , 2006, Allergology international : official journal of the Japanese Society of Allergology.

[23]  Sang-Heon Cho,et al.  Carbamazepine-induced severe cutaneous adverse reactions and HLA genotypes in Koreans , 2011, Epilepsy Research.

[24]  Chen-Yang Shen,et al.  Carbamazepine-induced toxic effects and HLA-B*1502 screening in Taiwan. , 2011, The New England journal of medicine.

[25]  G. Griffiths,et al.  The role of the secretory immunological synapse in killing by CD8+ CTL. , 2003, Seminars in immunology.

[26]  C. Sotozono,et al.  HLA‐B*1511 is a risk factor for carbamazepine‐induced Stevens‐Johnson syndrome and toxic epidermal necrolysis in Japanese patients , 2010, Epilepsia.

[27]  R. Bleackley,et al.  Cytotoxic T lymphocytes: all roads lead to death , 2002, Nature Reviews Immunology.

[28]  M. Blanca,et al.  Natural killer–dendritic cell interaction in lymphocyte responses in hypersensitivity reactions to betalactams , 2010, Allergy.

[29]  Shui-Tein Chen,et al.  HLA-B*1502-bound peptides: implications for the pathogenesis of carbamazepine-induced Stevens-Johnson syndrome. , 2007, The Journal of allergy and clinical immunology.

[30]  L. Naldi,et al.  A European study of HLA-B in Stevens–Johnson syndrome and toxic epidermal necrolysis related to five high-risk drugs , 2008, Pharmacogenetics and genomics.

[31]  Jacqueline Adam,et al.  Delayed drug hypersensitivity: models of T-cell stimulation. , 2011, British journal of clinical pharmacology.

[32]  B. K. Park,et al.  Food , drug , insect sting allergy , and anaphylaxis Stimulation of human T cells with sulfonamides and sulfonamide metabolites , 2022 .

[33]  S. Lewitzky,et al.  OC-035 Elastography for the diagnosis of severity of fibrosis in chronic liver disease: a diagnostic test accuracy meta-analysis , 2010, Gut.

[34]  Yusuke Nakamura,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 , 2022 .

[35]  B. Sachs,et al.  Allergic and autoimmune reactions to xenobiotics: how do they arise? , 1998, Immunology today.

[36]  W. Pichler,et al.  Direct, MHC-dependent presentation of the drug sulfamethoxazole to human alphabeta T cell clones. , 1997, The Journal of clinical investigation.

[37]  T. Shiohara,et al.  Defective Regulatory T Cells In Patients with Severe Drug Eruptions: Timing of the Dysfunction Is Associated with the Pathological Phenotype and Outcome1 , 2009, The Journal of Immunology.

[38]  L. Kaer,et al.  NKT cells: what's in a name? , 2004, Nature Reviews Immunology.

[39]  D. Godfrey,et al.  Raising the NKT cell family , 2010, Nature Immunology.

[40]  M. Caligiuri,et al.  Biology and clinical impact of human natural killer cells , 2003, International journal of hematology.

[41]  Hailing Qiao,et al.  Specific serum IgE levels and FcɛRIβ genetic polymorphism in patients with penicillins allergy , 2004, Allergy.

[42]  C. Moore,et al.  Predisposition to nevirapine hypersensitivity associated with HLA-DRB1*0101 and abrogated by low CD4 T-cell counts , 2005, AIDS.

[43]  H. Neumann,et al.  Cytotoxic T lymphocytes in autoimmune and degenerative CNS diseases , 2002, Trends in Neurosciences.

[44]  K. Suphapeetiporn,et al.  Carbamazepine and phenytoin induced Stevens‐Johnson syndrome is associated with HLA‐B*1502 allele in Thai population , 2008, Epilepsia.

[45]  Dominic P. Williams,et al.  Toxicophores: investigations in drug safety. , 2006, Toxicology.

[46]  J. Strominger,et al.  CD1d-Restricted NKT Cells Express a Chemokine Receptor Profile Indicative of Th1-Type Inflammatory Homing Cells 1 , 2003, The Journal of Immunology.

[47]  T. Bauer,et al.  Penicilloyl peptides are recognized as T cell antigenic determinants in penicillin allergy , 1997, European journal of immunology.

[48]  C. Carcassi,et al.  HLA-dependent hypersensitivity to nevirapine in Sardinian HIV patients , 2006, AIDS.

[49]  H. Cheroutre,et al.  The many face-lifts of CD4 T helper cells. , 2010, Advances in immunology.

[50]  C. Benoist,et al.  CD1-restricted CD4+ T cells in major histocompatibility complex class II-deficient mice , 1995, The Journal of experimental medicine.

[51]  E. Andrès,et al.  CD56bright natural killer (NK) cells: an important NK cell subset , 2009, Immunology.

[52]  M. Wittmann,et al.  Interaction of keratinocytes with infiltrating lymphocytes in allergic eczematous skin diseases , 2006, Current opinion in allergy and clinical immunology.

[53]  Mads Hald Andersen,et al.  Cytotoxic T cells. , 2006, The Journal of investigative dermatology.

[54]  Martine Bagot,et al.  Drug specific cytotoxic T-cells in the skin lesions of a patient with toxic epidermal necrolysis. , 2002, The Journal of investigative dermatology.

[55]  W. Pichler,et al.  Transfection of Drug-Specific T-Cell Receptors into Hybridoma Cells: Tools to Monitor Drug Interaction with T-Cell Receptors and Evaluate Cross-Reactivity to Related Compounds , 2006, Molecular Pharmacology.

[56]  I. Barão,et al.  Human natural killer cells. , 1998, Archivum immunologiae et therapiae experimentalis.

[57]  M. Pirmohamed,et al.  Hypersensitivity reactions to carbamazepine: characterization of the specificity, phenotype, and cytokine profile of drug-specific T cell clones. , 2003, Molecular pharmacology.

[58]  M. Muramatsu,et al.  HLA Class I markers in Japanese patients with carbamazepine‐induced cutaneous adverse reactions , 2010, Epilepsia.

[59]  A. Romano,et al.  Delayed hypersensitivity to aminopenicillins is related to major histocompatibility complex genes. , 1998, Annals of allergy, asthma & immunology : official publication of the American College of Allergy, Asthma, & Immunology.

[60]  Hye‐Ryun Kang,et al.  HLA-B*5901 is strongly associated with methazolamide-induced Stevens-Johnson syndrome/toxic epidermal necrolysis. , 2010, Pharmacogenomics.

[61]  P. Woster,et al.  A role for bioactivation and covalent binding within epidermal keratinocytes in sulfonamide-induced cutaneous drug reactions. , 2000, The Journal of investigative dermatology.

[62]  M. Nelle,et al.  Toxic epidermal necrolysis and Stevens-Johnson syndrome: A review* , 2011, Critical care medicine.

[63]  S. Nutt,et al.  Functional subsets of mouse natural killer cells , 2006, Immunological reviews.

[64]  A. Romano,et al.  Gene–gene interactions of IL13 and IL4RA variants in immediate allergic reactions to betalactam antibiotics , 2006, Pharmacogenetics and genomics.

[65]  Smita Kulkarni,et al.  The Yin and Yang of HLA and KIR in human disease. , 2008, Seminars in immunology.

[66]  A. Lehuen,et al.  NKT cells: Friend or foe during viral infections? , 2009, European journal of immunology.

[67]  A. Romano,et al.  Association of tumor necrosis factor-α –308G>A polymorphism with IgE-mediated allergy to betalactams in an Italian population , 2008, The Pharmacogenomics Journal.

[68]  G. Griffiths,et al.  Secretory mechanisms in cell-mediated cytotoxicity. , 2007, Annual review of cell and developmental biology.

[69]  L. Naldi,et al.  Nevirapine and the risk of Stevens–Johnson syndrome or toxic epidermal necrolysis , 2001, AIDS.

[70]  S. Mallal,et al.  HLA-B*5701 screening for hypersensitivity to abacavir. , 2008, The New England journal of medicine.

[71]  H. Streeck,et al.  Cytolytic CD4+ T cells in viral immunity , 2010, Expert review of vaccines.

[72]  M. Pirmohamed,et al.  Activation of T cells by carbamazepine and carbamazepine metabolites. , 2006, The Journal of allergy and clinical immunology.

[73]  Arun T Pores-Fernando,et al.  Calcium influx and signaling in cytotoxic T‐lymphocyte lytic granule exocytosis , 2009, Immunological reviews.

[74]  D. Doherty,et al.  NKT Cells from Normal and Tumor-Bearing Human Livers Are Phenotypically and Functionally Distinct from Murine NKT Cells 1 , 2003, The Journal of Immunology.

[75]  David Nolan,et al.  Human leukocyte antigen class I-restricted activation of CD8+ T cells provides the immunogenetic basis of a systemic drug hypersensitivity. , 2008, Immunity.

[76]  Martine Bagot,et al.  Toxic epidermal necrolysis: effector cells are drug-specific cytotoxic T cells. , 2004, The Journal of allergy and clinical immunology.

[77]  A. Caton,et al.  CD4+CD25+ regulatory T cells in autoimmune arthritis , 2010, Immunological reviews.

[78]  A. Gaspari,et al.  Characterization of the Formation and Localization of Sulfamethoxazole and Dapsone-Associated Drug-Protein Adducts in Human Epidermal Keratinocytes , 2005, Journal of Pharmacology and Experimental Therapeutics.

[79]  S. Tiamkao,et al.  Association between HLA‐B*1502 and carbamazepine‐induced severe cutaneous adverse drug reactions in a Thai population , 2010, Epilepsia.

[80]  M. Pirmohamed,et al.  Genetic analysis of microsomal epoxide hydrolase in patients with carbamazepine hypersensitivity. , 1995, Biochemical pharmacology.

[81]  J. Roujeau,et al.  Blister fluid T lymphocytes during toxic epidermal necrolysis are functional cytotoxic cells which express human natural killer (NK) inhibitory receptors , 2000, Clinical and experimental immunology.

[82]  S. Jonjić,et al.  Immune evasion of natural killer cells by viruses. , 2008, Current opinion in immunology.

[83]  C. Christiansen.  Late-onset allergy-like reactions to X-ray contrast media , 2002, Current opinion in allergy and clinical immunology.

[84]  Lin He,et al.  Harvesting Candidate Genes Responsible for Serious Adverse Drug Reactions from a Chemical-Protein Interactome , 2009, PLoS Comput. Biol..

[85]  C. Moore,et al.  Association between presence of HLA-B*5701, HLA-DR7, and HLA-DQ3 and hypersensitivity to HIV-1 reverse-transcriptase inhibitor abacavir , 2002, The Lancet.

[86]  Yi‐Ying Huang,et al.  Presence of a novel subset of NKT cells bearing an invariant Vα19.1–Jα26 TCR α chain , 2002 .

[87]  T. Yamamura,et al.  Role of NK cells and invariant NKT cells in multiple sclerosis. , 2010, Results and problems in cell differentiation.

[88]  P. Kwan,et al.  Association between HLA‐B*1502 Allele and Antiepileptic Drug‐Induced Cutaneous Reactions in Han Chinese , 2007, Epilepsia.

[89]  E. Tomasello,et al.  Natural killer cells: detectors of stress. , 2008, The international journal of biochemistry & cell biology.

[90]  S. Jee,et al.  Genetic susceptibility to carbamazepine-induced cutaneous adverse drug reactions , 2006, Pharmacogenetics and genomics.

[91]  Yuan-Tsong Chen,et al.  Shared and restricted T-cell receptor use is crucial for carbamazepine-induced Stevens-Johnson syndrome. , 2011, The Journal of allergy and clinical immunology.

[92]  A. Lew,et al.  CD4 Help-Independent Induction of Cytotoxic CD8 Cells to Allogeneic P815 Tumor Cells Is Absolutely Dependent on Costimulation1 , 2000, The Journal of Immunology.

[93]  R. Brutkiewicz,et al.  CD1d-mediated antigen presentation to natural killer T (NKT) cells. , 2003, Critical reviews in immunology.

[94]  M. Gershwin,et al.  Stevens-Johnson syndrome and toxic epidermal necrolysis. , 2008, Autoimmunity reviews.

[95]  Yuan-Tsong Chen,et al.  HLA-B*5801 allele as a genetic marker for severe cutaneous adverse reactions caused by allopurinol. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[96]  M. Schumacher,et al.  A marker for Stevens-Johnson syndrome …: ethnicity matters , 2006, The Pharmacogenomics Journal.