Drug-induced epidermal necrolysis: Important new piece to end the puzzle
2011; Elsevier BV; Volume: 128; Issue: 6 Linguagem: Inglês
10.1016/j.jaci.2011.10.015
ISSN1097-6825
AutoresJean‐Claude Roujeau, Gabriel Bricard, Jean–François Nicolas,
Tópico(s)Autoimmune Bullous Skin Diseases
ResumoIn 1956, Alan Lyell reported, under the denomination of toxic epidermal necrolysis, the cases of 4 patients with acute necrosis and detachment of the superficial layers of the skin and mucous membrane. Over the years, it became obvious that Stevens-Johnson syndrome, which is also characterized by blisters affecting the skin and mucous membrane, was close to toxic epidermal necrolysis, and these 2 conditions are now considered severity variants of an identical process differing only in the extent of body surface involved.1Auquier-Dunant A. Mockenhaupt M. Naldi L. Correia O. Schröder W. Roujeau J.C. et al.Severe Cutaneous Adverse Reactions. Correlations between clinical patterns and causes of erythema multiforme majus, Stevens-Johnson syndrome, and toxic epidermal necrolysis: results of an international prospective study.Arch Dermatol. 2002; 138: 1019-1024Crossref PubMed Google Scholar Therefore it seems preferable to use a single designation encompassing Stevens-Johnson syndrome, toxic epidermal necrolysis, and overlapping forms: epidermal necrolysis or exanthematic necrolysis (EN).2Lyell A. Requiem for toxic epidermal necrolysis.Br J Dermatol. 1990; 122: 837Crossref PubMed Scopus (34) Google ScholarEN is rare, with about 1.5 to 2 cases per million inhabitants per year in most countries but about 3 times more cases in Taiwan.3Chung W.H. Hung S.I. Hong H.S. Hsih M.S. Yang L.C. Ho H.C. et al.A marker for Stevens-Johnson syndrome.Nature. 2004; 248: 486Crossref Scopus (1340) Google Scholar It is life-threatening, with an overall death rate close to 30% and ranging from 10% to 15% for Stevens-Johnson syndrome and 40% to 50% for toxic epidermal necrolysis. Most, but not all, cases (60% to 80%) are clearly related to an adverse drug reaction.1Auquier-Dunant A. Mockenhaupt M. Naldi L. Correia O. Schröder W. Roujeau J.C. et al.Severe Cutaneous Adverse Reactions. Correlations between clinical patterns and causes of erythema multiforme majus, Stevens-Johnson syndrome, and toxic epidermal necrolysis: results of an international prospective study.Arch Dermatol. 2002; 138: 1019-1024Crossref PubMed Google ScholarFor several decades, the physiopathology of EN was considered a mystery. Pathology slides showed a totally necrotic epidermis above a "silent" dermis, without significant cellular infiltrate, vascular lesions, or immune deposits and fitting with none of the usual pathways of tissue destruction through inflammatory processes.In the past 30 years, knowledge has improved slowly, with acceleration in the last years. The larger part of these recent advances was provided by the Taiwanese team authoring an article in the present issue of the Journal.4Ko T.-M. Chung W.-H. Wei C.-Y. Shih H.-Y. Chen J.-K. Lin C.-H. et al.Shared and restricted T-cell receptor use is crucial for carbamazepine-induced Stevens-Johnson syndrome.J Allergy Clin Immunol. 2011; 128 (e11): 1266-1276Abstract Full Text Full Text PDF PubMed Scopus (205) Google ScholarImportant pieces of information were initially obtained by studying the skin blister fluid. T lymphocytes were actually found abundantly in these fluids,5Correia O. Delgado L. Ramos J.P. Resende C. Torrinha J.A. Cutaneous T-cell recruitment in toxic epidermal necrolysis. Further evidence of CD8+ lymphocyte involvement.Arch Dermatol. 1993; 129: 466-468Crossref PubMed Scopus (190) Google Scholar comprising mostly CD8+ T cells5Correia O. Delgado L. Ramos J.P. Resende C. Torrinha J.A. Cutaneous T-cell recruitment in toxic epidermal necrolysis. Further evidence of CD8+ lymphocyte involvement.Arch Dermatol. 1993; 129: 466-468Crossref PubMed Scopus (190) Google Scholar and natural killer T cells.6Le Cleach L. Delaire S. Boumsell L. Bagot M. Bourgault-Villada I. Bensussan A. et al.Blister fluid T lymphocytes during toxic epidermal necrolysis are functional cytotoxic cells which express human natural killer (NK) inhibitory receptors.Clin Exp Immunol. 2000; 119: 225-230Crossref PubMed Scopus (134) Google Scholar CD8+ T cells extracted from the lesions were demonstrated to have classic cytotoxic functions: lysis of autologous lymphocytes or keratinocytes in an MHC class I–restricted and medication-dependent manner.7Nassif A. Bensussan A. Boumsell L. Deniaud A. Moslehi H. Wolkenstein P. et al.Toxic epidermal necrolysis: effector cells are drug-specific cytotoxic T-cells.J Allergy Clin Immunol. 2004; 114: 1209-1215Abstract Full Text Full Text PDF PubMed Scopus (316) Google Scholar Further investigations focused on the cytokines present in blister fluids, especially those inducing apoptosis. TNF-α, soluble Fas ligand, and TNF-related apoptosis-inducing ligand were successively proposed as the main cytokine responsible for amplifying the death of epidermal cells. It is now well established that the major role relies on granulysin contained in the cytolytic vesicles of cytotoxic T lymphocytes (CTLs), natural killer T cells, and macrophages.8Chung W.H. Hung S.I. Yang J.Y. Su S.C. Huang S.P. Wei C.Y. et al.Granulysin is a key mediator for disseminated keratinocyte death in Stevens-Johnson syndrome and toxic epidermal necrolysis.Nat Med. 2008; 14: 1343-1350Crossref PubMed Scopus (547) Google ScholarAnother clue was provided by the demonstration of the HLA-B∗1502 allele's association with 100% of EN cases related to carbamazepine (CBZ) in Han Chinese subjects, likely explaining most of the excess prevalence of EN in Taiwan.3Chung W.H. Hung S.I. Hong H.S. Hsih M.S. Yang L.C. Ho H.C. et al.A marker for Stevens-Johnson syndrome.Nature. 2004; 248: 486Crossref Scopus (1340) Google Scholar That association appeared both drug specific and phenotype specific,9Hung S.I. Chung W.H. Jee S.H. Chen W.C. Chang Y.T. Lee W.R. et al.Genetic susceptibility to carbamazepine-induced cutaneous adverse drug reactions.Pharmacogenet Genomics. 2006; 16: 297-306Crossref PubMed Scopus (566) Google Scholar but still, a minority of persons harboring HLA-B∗1502 had EN.The results presented by Ko et al4Ko T.-M. Chung W.-H. Wei C.-Y. Shih H.-Y. Chen J.-K. Lin C.-H. et al.Shared and restricted T-cell receptor use is crucial for carbamazepine-induced Stevens-Johnson syndrome.J Allergy Clin Immunol. 2011; 128 (e11): 1266-1276Abstract Full Text Full Text PDF PubMed Scopus (205) Google Scholar in this issue of the Journal demonstrate that the occurrence of EN requires both the relevant HLA allele and a relevant sequence within the variable part (CDR3 loop) of the β chain (VB-11-ISGSY) of the T-cell receptor (TCR). The authors demonstrate that oligoclonal drug-specific CD8+ T cells are expanded on drug stimulation, produce cytotoxic molecules, and exert cytotoxicity. A skewed T-cell repertoire was observed with a limited number of TCR clonotypes shared by the patients and accounting for most of the drug-specific T-cell repertoire. The predominant clonotypes (VB-11-ISGSY and VB-11-GLAGVDN) were detected ex vivo (without prior CBZ stimulation) in all blister cells tested and in circulating T cells of most of the patients tested (14/15) but not in blood cells of drug-tolerant HLA-B∗1502 carriers. Importantly, the VB-11 TCR clonotypes that permit the strongest CBZ recognition were detected by means of quantitative PCR in naive T cells from a minority of nonexposed control subjects carrying the HLA-B∗1502 allele and were predictive of in vitro reactivity to CBZ.With these findings, the gap has been considerably narrowed. The totality of cases is not yet explained because 2 of 19 patients had EN without VB identified as a major risk factor. It is also likely that not all persons with both relevant HLA and TCR polymorphisms would have EN if exposed to CBZ. From prior3Chung W.H. Hung S.I. Hong H.S. Hsih M.S. Yang L.C. Ho H.C. et al.A marker for Stevens-Johnson syndrome.Nature. 2004; 248: 486Crossref Scopus (1340) Google Scholar and present4Ko T.-M. Chung W.-H. Wei C.-Y. Shih H.-Y. Chen J.-K. Lin C.-H. et al.Shared and restricted T-cell receptor use is crucial for carbamazepine-induced Stevens-Johnson syndrome.J Allergy Clin Immunol. 2011; 128 (e11): 1266-1276Abstract Full Text Full Text PDF PubMed Scopus (205) Google Scholar articles, about 1% of the Taiwanese population is expected to harbor both HLA-B∗1502 (8%) and VB-11-ISGSY (14%), which is still superior to the risk of EN in CBZ-treated patients in Taiwan.This study has several important implications. It confirms that MHC class I–restricted CD8+ CTLs are involved in EN. It shows that T-cell recognition of CBZ is very similar to that of classical antigens, with a limited number of T-cell clones expressing unique TCR sequences to interact with MCH/peptide/drug complexes. The involvement of the variable part of the VB chain also rules out the hypothesis that the drug acts as a superantigen.It remains to be evaluated whether the above results also apply to other drugs, other populations, and other phenotypes of delayed reactions to medications.Concerning other EN-inducing drugs, a clear HLA association has been established for allopurinol and HLA-B∗5801. That should prompt further studies of the TCR repertoire in patients with allopurinol-induced EN.In European patients with CBZ-related EN, no association was found with HLA-B∗1502.10Lonjou C. Borot N. Sekula P. Ledger N. Thomas L. Halevy S. et al.A European study of HLA-B in Stevens-Johnson syndrome and toxic epidermal necrolysis related to five high-risk drugs.Pharmacogenet Genomics. 2008; 18: 99-107Crossref PubMed Scopus (510) Google Scholar However, one can hypothesize that similar mechanisms might also apply. Whether it involves the VB-11-ISGSY+ TCR should be evaluated in non–Han Chinese subjects. In such a case the public TCR clonotype reported here could be a more universal marker of CBZ-related EN. However, it is also possible that different pairs of biased TCRs and MHCs are used by other populations.Fortunately, EN is a rare variant of skin eruptions observed with CBZ. In Taiwan and in Europe maculopapular eruptions and hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms syndrome were not associated with HLA-B∗1502 but with HLA-A∗3101.9Hung S.I. Chung W.H. Jee S.H. Chen W.C. Chang Y.T. Lee W.R. et al.Genetic susceptibility to carbamazepine-induced cutaneous adverse drug reactions.Pharmacogenet Genomics. 2006; 16: 297-306Crossref PubMed Scopus (566) Google Scholar, 11McCormack M. Alfirevic A. Bourgeois S. Farrell J.J. Kasperavičiūtė D. Carrington M. et al.HLA-A∗3101 and carbamazepine-induced hypersensitivity reactions in Europeans.N Engl J Med. 2011; 364: 1134-1143Crossref PubMed Scopus (713) Google Scholar Exploration of the repertoire used by drug-specific T cells in such reactions will help us understand the determinants of phenotypic differences.CD8+ T cells were shown to be involved in all types of drug eruptions from maculopapular eruptions to EN.12Rozieres A. Vocanson M. Saïd B.B. Nosbaum A. Nicolas J.F. Role of T cells in nonimmediate allergic drug reactions.Curr Opin Allergy Clin Immunol. 2009; 9: 305-310Crossref PubMed Scopus (52) Google Scholar, 13Pichler W.J. Naisbitt D.J. Park B.K. Immune pathomechanism of drug hypersensitivity reactions.J Allergy Clin Immunol. 2011; 127: S74-S81Abstract Full Text Full Text PDF PubMed Scopus (126) Google Scholar How do we explain that a classical CD8+ CTL activation involving a limited number of clones leads to a disease as severe as EN? It is unlikely related to an unusually high number of specific T cells given the difficulties in providing evidence of such cells using conventional methods, such as the lymphocyte transformation test. We suggest the differentiation of more active CTLs, especially those capable of granulysin secretion. CTLs from both patients with EN and patients with maculopapular eruptions are able to produce granulysin. However, dramatic secretion of granulysin is only obtained by CTLs from patients with EN.8Chung W.H. Hung S.I. Yang J.Y. Su S.C. Huang S.P. Wei C.Y. et al.Granulysin is a key mediator for disseminated keratinocyte death in Stevens-Johnson syndrome and toxic epidermal necrolysis.Nat Med. 2008; 14: 1343-1350Crossref PubMed Scopus (547) Google Scholar Whether granulysin secretion by CTLs represents an ultimate activation state of drug-specific CTLs should be addressed. Full-blown T-cell activation should result from a strong signal that is likely provided by high avidity of the TCR for a CBZ/peptide/MHC complex.14Kedzierska K. La Gruta N.L. Stambas J. Turner S.J. Doherty P.C. Tracking phenotypically and functionally distinct T cell subsets via T cell repertoire diversity.Mol Immunol. 2008; 45: 607-618Crossref PubMed Scopus (39) Google Scholar Further investigations of the functional nature of binding interactions are clearly needed. Up to now, the CBZ link was detected with none of 13 HLA-B∗1502–bound peptides.15Yang C.W. Hung S.I. Juo C.G. Lin Y.P. Fang W.H. Lu I.H. et al.HLA-B∗1502-bound peptides: implications for the pathogenesis of carbamazepine-induced Stevens-Johnson syndrome.J Allergy Clin Immunol. 2007; 120: 870-877Abstract Full Text Full Text PDF PubMed Scopus (103) Google ScholarIn Taiwan testing for HLA-B∗1502 before prescribing CBZ proved highly effective in the prevention of EN,16Chen P. Lin J.J. Lu C.S. Ong C.T. Hsieh P.F. Yang C.C. et al.Carbamazepine-induced toxic effects and HLA-B∗1502 screening in Taiwan.N Engl J Med. 2011; 364: 1126-1133Crossref PubMed Scopus (535) Google Scholar with the limitation that most patients with positive results would have tolerated the drug. It might be tempting to use the double detection of HLA-B∗1502 and the shared TCR sequences to better identify subjects at high risk. However, the accuracy of such a PCR-based analysis of the TCR repertoire is limited to the T cells present in a blood sample and might result in false-negative results. Moreover, a few patients from the study by Ko et al4Ko T.-M. Chung W.-H. Wei C.-Y. Shih H.-Y. Chen J.-K. Lin C.-H. et al.Shared and restricted T-cell receptor use is crucial for carbamazepine-induced Stevens-Johnson syndrome.J Allergy Clin Immunol. 2011; 128 (e11): 1266-1276Abstract Full Text Full Text PDF PubMed Scopus (205) Google Scholar had EN without a detectable "specific" clonotypic TCR sequence. The practical issue would be totally different if the "permissive" TCR repertoire was similar in other populations in which no HLA marker was found.The breakthrough articles of the Taiwanese team, as with much prior research on EN, was funded only by public research grants. Research on one of the most severe reactions to drugs deserves more consideration and support from pharmaceutical companies. In 1956, Alan Lyell reported, under the denomination of toxic epidermal necrolysis, the cases of 4 patients with acute necrosis and detachment of the superficial layers of the skin and mucous membrane. Over the years, it became obvious that Stevens-Johnson syndrome, which is also characterized by blisters affecting the skin and mucous membrane, was close to toxic epidermal necrolysis, and these 2 conditions are now considered severity variants of an identical process differing only in the extent of body surface involved.1Auquier-Dunant A. Mockenhaupt M. Naldi L. Correia O. Schröder W. Roujeau J.C. et al.Severe Cutaneous Adverse Reactions. Correlations between clinical patterns and causes of erythema multiforme majus, Stevens-Johnson syndrome, and toxic epidermal necrolysis: results of an international prospective study.Arch Dermatol. 2002; 138: 1019-1024Crossref PubMed Google Scholar Therefore it seems preferable to use a single designation encompassing Stevens-Johnson syndrome, toxic epidermal necrolysis, and overlapping forms: epidermal necrolysis or exanthematic necrolysis (EN).2Lyell A. Requiem for toxic epidermal necrolysis.Br J Dermatol. 1990; 122: 837Crossref PubMed Scopus (34) Google Scholar EN is rare, with about 1.5 to 2 cases per million inhabitants per year in most countries but about 3 times more cases in Taiwan.3Chung W.H. Hung S.I. Hong H.S. Hsih M.S. Yang L.C. Ho H.C. et al.A marker for Stevens-Johnson syndrome.Nature. 2004; 248: 486Crossref Scopus (1340) Google Scholar It is life-threatening, with an overall death rate close to 30% and ranging from 10% to 15% for Stevens-Johnson syndrome and 40% to 50% for toxic epidermal necrolysis. Most, but not all, cases (60% to 80%) are clearly related to an adverse drug reaction.1Auquier-Dunant A. Mockenhaupt M. Naldi L. Correia O. Schröder W. Roujeau J.C. et al.Severe Cutaneous Adverse Reactions. Correlations between clinical patterns and causes of erythema multiforme majus, Stevens-Johnson syndrome, and toxic epidermal necrolysis: results of an international prospective study.Arch Dermatol. 2002; 138: 1019-1024Crossref PubMed Google Scholar For several decades, the physiopathology of EN was considered a mystery. Pathology slides showed a totally necrotic epidermis above a "silent" dermis, without significant cellular infiltrate, vascular lesions, or immune deposits and fitting with none of the usual pathways of tissue destruction through inflammatory processes. In the past 30 years, knowledge has improved slowly, with acceleration in the last years. The larger part of these recent advances was provided by the Taiwanese team authoring an article in the present issue of the Journal.4Ko T.-M. Chung W.-H. Wei C.-Y. Shih H.-Y. Chen J.-K. Lin C.-H. et al.Shared and restricted T-cell receptor use is crucial for carbamazepine-induced Stevens-Johnson syndrome.J Allergy Clin Immunol. 2011; 128 (e11): 1266-1276Abstract Full Text Full Text PDF PubMed Scopus (205) Google Scholar Important pieces of information were initially obtained by studying the skin blister fluid. T lymphocytes were actually found abundantly in these fluids,5Correia O. Delgado L. Ramos J.P. Resende C. Torrinha J.A. Cutaneous T-cell recruitment in toxic epidermal necrolysis. Further evidence of CD8+ lymphocyte involvement.Arch Dermatol. 1993; 129: 466-468Crossref PubMed Scopus (190) Google Scholar comprising mostly CD8+ T cells5Correia O. Delgado L. Ramos J.P. Resende C. Torrinha J.A. Cutaneous T-cell recruitment in toxic epidermal necrolysis. Further evidence of CD8+ lymphocyte involvement.Arch Dermatol. 1993; 129: 466-468Crossref PubMed Scopus (190) Google Scholar and natural killer T cells.6Le Cleach L. Delaire S. Boumsell L. Bagot M. Bourgault-Villada I. Bensussan A. et al.Blister fluid T lymphocytes during toxic epidermal necrolysis are functional cytotoxic cells which express human natural killer (NK) inhibitory receptors.Clin Exp Immunol. 2000; 119: 225-230Crossref PubMed Scopus (134) Google Scholar CD8+ T cells extracted from the lesions were demonstrated to have classic cytotoxic functions: lysis of autologous lymphocytes or keratinocytes in an MHC class I–restricted and medication-dependent manner.7Nassif A. Bensussan A. Boumsell L. Deniaud A. Moslehi H. Wolkenstein P. et al.Toxic epidermal necrolysis: effector cells are drug-specific cytotoxic T-cells.J Allergy Clin Immunol. 2004; 114: 1209-1215Abstract Full Text Full Text PDF PubMed Scopus (316) Google Scholar Further investigations focused on the cytokines present in blister fluids, especially those inducing apoptosis. TNF-α, soluble Fas ligand, and TNF-related apoptosis-inducing ligand were successively proposed as the main cytokine responsible for amplifying the death of epidermal cells. It is now well established that the major role relies on granulysin contained in the cytolytic vesicles of cytotoxic T lymphocytes (CTLs), natural killer T cells, and macrophages.8Chung W.H. Hung S.I. Yang J.Y. Su S.C. Huang S.P. Wei C.Y. et al.Granulysin is a key mediator for disseminated keratinocyte death in Stevens-Johnson syndrome and toxic epidermal necrolysis.Nat Med. 2008; 14: 1343-1350Crossref PubMed Scopus (547) Google Scholar Another clue was provided by the demonstration of the HLA-B∗1502 allele's association with 100% of EN cases related to carbamazepine (CBZ) in Han Chinese subjects, likely explaining most of the excess prevalence of EN in Taiwan.3Chung W.H. Hung S.I. Hong H.S. Hsih M.S. Yang L.C. Ho H.C. et al.A marker for Stevens-Johnson syndrome.Nature. 2004; 248: 486Crossref Scopus (1340) Google Scholar That association appeared both drug specific and phenotype specific,9Hung S.I. Chung W.H. Jee S.H. Chen W.C. Chang Y.T. Lee W.R. et al.Genetic susceptibility to carbamazepine-induced cutaneous adverse drug reactions.Pharmacogenet Genomics. 2006; 16: 297-306Crossref PubMed Scopus (566) Google Scholar but still, a minority of persons harboring HLA-B∗1502 had EN. The results presented by Ko et al4Ko T.-M. Chung W.-H. Wei C.-Y. Shih H.-Y. Chen J.-K. Lin C.-H. et al.Shared and restricted T-cell receptor use is crucial for carbamazepine-induced Stevens-Johnson syndrome.J Allergy Clin Immunol. 2011; 128 (e11): 1266-1276Abstract Full Text Full Text PDF PubMed Scopus (205) Google Scholar in this issue of the Journal demonstrate that the occurrence of EN requires both the relevant HLA allele and a relevant sequence within the variable part (CDR3 loop) of the β chain (VB-11-ISGSY) of the T-cell receptor (TCR). The authors demonstrate that oligoclonal drug-specific CD8+ T cells are expanded on drug stimulation, produce cytotoxic molecules, and exert cytotoxicity. A skewed T-cell repertoire was observed with a limited number of TCR clonotypes shared by the patients and accounting for most of the drug-specific T-cell repertoire. The predominant clonotypes (VB-11-ISGSY and VB-11-GLAGVDN) were detected ex vivo (without prior CBZ stimulation) in all blister cells tested and in circulating T cells of most of the patients tested (14/15) but not in blood cells of drug-tolerant HLA-B∗1502 carriers. Importantly, the VB-11 TCR clonotypes that permit the strongest CBZ recognition were detected by means of quantitative PCR in naive T cells from a minority of nonexposed control subjects carrying the HLA-B∗1502 allele and were predictive of in vitro reactivity to CBZ. With these findings, the gap has been considerably narrowed. The totality of cases is not yet explained because 2 of 19 patients had EN without VB identified as a major risk factor. It is also likely that not all persons with both relevant HLA and TCR polymorphisms would have EN if exposed to CBZ. From prior3Chung W.H. Hung S.I. Hong H.S. Hsih M.S. Yang L.C. Ho H.C. et al.A marker for Stevens-Johnson syndrome.Nature. 2004; 248: 486Crossref Scopus (1340) Google Scholar and present4Ko T.-M. Chung W.-H. Wei C.-Y. Shih H.-Y. Chen J.-K. Lin C.-H. et al.Shared and restricted T-cell receptor use is crucial for carbamazepine-induced Stevens-Johnson syndrome.J Allergy Clin Immunol. 2011; 128 (e11): 1266-1276Abstract Full Text Full Text PDF PubMed Scopus (205) Google Scholar articles, about 1% of the Taiwanese population is expected to harbor both HLA-B∗1502 (8%) and VB-11-ISGSY (14%), which is still superior to the risk of EN in CBZ-treated patients in Taiwan. This study has several important implications. It confirms that MHC class I–restricted CD8+ CTLs are involved in EN. It shows that T-cell recognition of CBZ is very similar to that of classical antigens, with a limited number of T-cell clones expressing unique TCR sequences to interact with MCH/peptide/drug complexes. The involvement of the variable part of the VB chain also rules out the hypothesis that the drug acts as a superantigen. It remains to be evaluated whether the above results also apply to other drugs, other populations, and other phenotypes of delayed reactions to medications. Concerning other EN-inducing drugs, a clear HLA association has been established for allopurinol and HLA-B∗5801. That should prompt further studies of the TCR repertoire in patients with allopurinol-induced EN. In European patients with CBZ-related EN, no association was found with HLA-B∗1502.10Lonjou C. Borot N. Sekula P. Ledger N. Thomas L. Halevy S. et al.A European study of HLA-B in Stevens-Johnson syndrome and toxic epidermal necrolysis related to five high-risk drugs.Pharmacogenet Genomics. 2008; 18: 99-107Crossref PubMed Scopus (510) Google Scholar However, one can hypothesize that similar mechanisms might also apply. Whether it involves the VB-11-ISGSY+ TCR should be evaluated in non–Han Chinese subjects. In such a case the public TCR clonotype reported here could be a more universal marker of CBZ-related EN. However, it is also possible that different pairs of biased TCRs and MHCs are used by other populations. Fortunately, EN is a rare variant of skin eruptions observed with CBZ. In Taiwan and in Europe maculopapular eruptions and hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms syndrome were not associated with HLA-B∗1502 but with HLA-A∗3101.9Hung S.I. Chung W.H. Jee S.H. Chen W.C. Chang Y.T. Lee W.R. et al.Genetic susceptibility to carbamazepine-induced cutaneous adverse drug reactions.Pharmacogenet Genomics. 2006; 16: 297-306Crossref PubMed Scopus (566) Google Scholar, 11McCormack M. Alfirevic A. Bourgeois S. Farrell J.J. Kasperavičiūtė D. Carrington M. et al.HLA-A∗3101 and carbamazepine-induced hypersensitivity reactions in Europeans.N Engl J Med. 2011; 364: 1134-1143Crossref PubMed Scopus (713) Google Scholar Exploration of the repertoire used by drug-specific T cells in such reactions will help us understand the determinants of phenotypic differences. CD8+ T cells were shown to be involved in all types of drug eruptions from maculopapular eruptions to EN.12Rozieres A. Vocanson M. Saïd B.B. Nosbaum A. Nicolas J.F. Role of T cells in nonimmediate allergic drug reactions.Curr Opin Allergy Clin Immunol. 2009; 9: 305-310Crossref PubMed Scopus (52) Google Scholar, 13Pichler W.J. Naisbitt D.J. Park B.K. Immune pathomechanism of drug hypersensitivity reactions.J Allergy Clin Immunol. 2011; 127: S74-S81Abstract Full Text Full Text PDF PubMed Scopus (126) Google Scholar How do we explain that a classical CD8+ CTL activation involving a limited number of clones leads to a disease as severe as EN? It is unlikely related to an unusually high number of specific T cells given the difficulties in providing evidence of such cells using conventional methods, such as the lymphocyte transformation test. We suggest the differentiation of more active CTLs, especially those capable of granulysin secretion. CTLs from both patients with EN and patients with maculopapular eruptions are able to produce granulysin. However, dramatic secretion of granulysin is only obtained by CTLs from patients with EN.8Chung W.H. Hung S.I. Yang J.Y. Su S.C. Huang S.P. Wei C.Y. et al.Granulysin is a key mediator for disseminated keratinocyte death in Stevens-Johnson syndrome and toxic epidermal necrolysis.Nat Med. 2008; 14: 1343-1350Crossref PubMed Scopus (547) Google Scholar Whether granulysin secretion by CTLs represents an ultimate activation state of drug-specific CTLs should be addressed. Full-blown T-cell activation should result from a strong signal that is likely provided by high avidity of the TCR for a CBZ/peptide/MHC complex.14Kedzierska K. La Gruta N.L. Stambas J. Turner S.J. Doherty P.C. Tracking phenotypically and functionally distinct T cell subsets via T cell repertoire diversity.Mol Immunol. 2008; 45: 607-618Crossref PubMed Scopus (39) Google Scholar Further investigations of the functional nature of binding interactions are clearly needed. Up to now, the CBZ link was detected with none of 13 HLA-B∗1502–bound peptides.15Yang C.W. Hung S.I. Juo C.G. Lin Y.P. Fang W.H. Lu I.H. et al.HLA-B∗1502-bound peptides: implications for the pathogenesis of carbamazepine-induced Stevens-Johnson syndrome.J Allergy Clin Immunol. 2007; 120: 870-877Abstract Full Text Full Text PDF PubMed Scopus (103) Google Scholar In Taiwan testing for HLA-B∗1502 before prescribing CBZ proved highly effective in the prevention of EN,16Chen P. Lin J.J. Lu C.S. Ong C.T. Hsieh P.F. Yang C.C. et al.Carbamazepine-induced toxic effects and HLA-B∗1502 screening in Taiwan.N Engl J Med. 2011; 364: 1126-1133Crossref PubMed Scopus (535) Google Scholar with the limitation that most patients with positive results would have tolerated the drug. It might be tempting to use the double detection of HLA-B∗1502 and the shared TCR sequences to better identify subjects at high risk. However, the accuracy of such a PCR-based analysis of the TCR repertoire is limited to the T cells present in a blood sample and might result in false-negative results. Moreover, a few patients from the study by Ko et al4Ko T.-M. Chung W.-H. Wei C.-Y. Shih H.-Y. Chen J.-K. Lin C.-H. et al.Shared and restricted T-cell receptor use is crucial for carbamazepine-induced Stevens-Johnson syndrome.J Allergy Clin Immunol. 2011; 128 (e11): 1266-1276Abstract Full Text Full Text PDF PubMed Scopus (205) Google Scholar had EN without a detectable "specific" clonotypic TCR sequence. The practical issue would be totally different if the "permissive" TCR repertoire was similar in other populations in which no HLA marker was found. The breakthrough articles of the Taiwanese team, as with much prior research on EN, was funded only by public research grants. Research on one of the most severe reactions to drugs deserves more consideration and support from pharmaceutical companies. Shared and restricted T-cell receptor use is crucial for carbamazepine-induced Stevens-Johnson syndromeJournal of Allergy and Clinical ImmunologyVol. 128Issue 6PreviewStevens-Johnson syndrome (SJS) and its related disease, toxic epidermal necrolysis (TEN), are life-threatening drug hypersensitivities with robust immune responses to drugs. Despite the strong HLA predisposition to drug hypersensitivities, such as HLA-B∗1502 to carbamazepine (CBZ)–induced SJS/TEN, it remains unknown whether particular T-cell receptors (TCRs) participate in recognition of small drug/peptide–HLA complexes. 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