Toxic epidermal necrolysis in the absence of circulating T cells: A possible role for resident memory T cells
Authors: Hisato Iriki, Takeya Adachi, Mariko Mori, Keiji Tanese, Takeru Funakoshi, Daiki Karigane, Takayuki Shimizu, Shinichiro Okamoto, Keisuke Nagao
Journal: Journal of the American Academy of Dermatology (2014)

To the Editor: Toxic epidermal necrolysis (TEN) is a life-threatening mucocutaneous disease with high mortality, mainly induced by drugs. Although the pathogenesis of TEN remains elusive, reports have suggested the importance of T lymphocytes.1Nassif A. Bensussan A. Dorothée G. Mami-Chouaib F. Bachot N. Bagot M. et al.Drug-specific cytotoxic T cells in the skin lesions of a patient with toxic epidermal necrolysis.J Invest Dermatol. 2002; 118: 728-733Crossref PubMed Scopus (248) Google Scholar, 2Pereira F.A. Mudgil A.V. Rosmarin D.M. Toxic epidermal necrolysis.J Am Acad Dermatol. 2007; 56: 181-200Abstract Full Text Full Text PDF PubMed Scopus (251) Google Scholar Here, we report a case of TEN that occurred in the absence of circulating leukocytes but in the presence of resident memory T cells (TRM), suggesting key role(s) for TRM in the pathogenesis of TEN.A 60-year-old Japanese man with natural killer cell leukemia underwent SMILE chemotherapy (dexamethasone, methotrexate, ifosfamide, L-asparaginase, etoposide). On day 19 after initiation of chemotherapy, erythema appeared on the whole body associated with a fever of 39°C. Targetoid lesions and erosions developed on the trunk and extremities. Erosions extended to the oral and genital mucosa, and covered more than 60% of the body surface by day 25 (Fig 1, A). Blood work on day 18 showed profound leukocytopenia (<1.0 × 102/μL, with absence of lymphocytes on blood smear), which persisted thereafter. Hemoglobin was 8.0 g/dL and platelet count was 2.1 × 103/μL. Histopathologic examination of a skin biopsy specimen on day 23 revealed interface dermatitis with individual cell necrosis (Fig 1, B). Infiltrating cells were mostly CD4+ and CD8+ T cells (Fig 2).Fig 2A to D, Two-color immunofluorescence images of frozen skin sections from the left arm were obtained for CD4/CD8 (green) and CD45RO/CD69 (red). The majority of CD4+ T cells and CD8+ T cells are costained with CD45RO and CD69. T cells that co-express both molecules (arrowheads). Scale bars: 20 μm.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Upon diagnosis of TEN, all drugs were either discontinued or changed. High-dose intravenous immunoglobulin (400 mg/kg/d) was given for 5 days and intravenous methylprednisolone (1000 mg/d) for 3 days followed by oral prednisone (2 mg/kg/d). Although the TEN subsided, he died of cerebral hemorrhage on day 39. The culprit drug remained undetermined.This case of TEN occurred in the absence of circulating T cells. As recently reported, skin contains a large number of TRM.3Clark R.A. Chong B. Mirchandani N. Brinster N.K. Yamanaka K. Dowgiert R.K. et al.The vast majority of CLA+ T cells are resident in normal skin.J Immunol. 2006; 176: 4431-4439Crossref PubMed Scopus (559) Google Scholar, 4Sathaliyawala T. Kubota M. Yudanin N. Turner D. Camp P. Thome J.J. et al.Distribution and compartmentalization of human circulating and tissue-resident memory T cell subsets.Immunity. 2013; 38: 187-197Abstract Full Text Full Text PDF PubMed Scopus (552) Google Scholar To determine whether TRM was involved, a necropsy skin specimen was analyzed via immunofluorescence microscopy for the expression of CD45RO (memory T-cell marker) and CD69 (resident T-cell marker).4Sathaliyawala T. Kubota M. Yudanin N. Turner D. Camp P. Thome J.J. et al.Distribution and compartmentalization of human circulating and tissue-resident memory T cell subsets.Immunity. 2013; 38: 187-197Abstract Full Text Full Text PDF PubMed Scopus (552) Google Scholar The majority of CD4+ and CD8+ T cells expressed CD45RO and CD69 (Fig 2). These results indicated that lesional T cells were of TRM phenotype, and because TRM were the only lesional T cells, it was suggested that they played a major role in the pathogenesis of this case. Expression of granzyme B indicated that lesional TRM were activated (data not shown).TRM in this patient's skin presumably arose in response to previous inflammatory events. Why such TRM with irrelevant antigen specificity attacked the epidermis in the presence of drugs to which the patient had not previously been exposed remains unclear. Interestingly, Ostrov et al5Ostrov D.A. Grant B.J. Pompeu Y.A. Sidney J. Harndahl M. Southwood S. et al.Drug hypersensitivity caused by alteration of the MHC-presented self-peptide repertoire.Proc Natl Acad Sci U S A. 2012; 109: 9959-9964Crossref PubMed Scopus (306) Google Scholar reported that abacavir binds to a major histocompatibility complex groove, which alters the repertoire of self-peptide ligands bound, thereby allowing self-reactivity of T cells. Application of this concept to our case would suggest that the culprit drug generated a self-peptide/drug/major histocompatibility complex as a neo-epitope on the keratinocytes. TRM then initiated cytotoxic responses against keratinocytes that resulted in epidermal necrolysis. Further analyses are needed to reveal the precise mechanisms.This case shows that TEN can be evoked even in the absence of circulating T cells, and emphasizes the importance of TRM during skin inflammation including drug hypersensitivity. To the Editor: Toxic epidermal necrolysis (TEN) is a life-threatening mucocutaneous disease with high mortality, mainly induced by drugs. Although the pathogenesis of TEN remains elusive, reports have suggested the importance of T lymphocytes.1Nassif A. Bensussan A. Dorothée G. Mami-Chouaib F. Bachot N. Bagot M. et al.Drug-specific cytotoxic T cells in the skin lesions of a patient with toxic epidermal necrolysis.J Invest Dermatol. 2002; 118: 728-733Crossref PubMed Scopus (248) Google Scholar, 2Pereira F.A. Mudgil A.V. Rosmarin D.M. Toxic epidermal necrolysis.J Am Acad Dermatol. 2007; 56: 181-200Abstract Full Text Full Text PDF PubMed Scopus (251) Google Scholar Here, we report a case of TEN that occurred in the absence of circulating leukocytes but in the presence of resident memory T cells (TRM), suggesting key role(s) for TRM in the pathogenesis of TEN. A 60-year-old Japanese man with natural killer cell leukemia underwent SMILE chemotherapy (dexamethasone, methotrexate, ifosfamide, L-asparaginase, etoposide). On day 19 after initiation of chemotherapy, erythema appeared on the whole body associated with a fever of 39°C. Targetoid lesions and erosions developed on the trunk and extremities. Erosions extended to the oral and genital mucosa, and covered more than 60% of the body surface by day 25 (Fig 1, A). Blood work on day 18 showed profound leukocytopenia (<1.0 × 102/μL, with absence of lymphocytes on blood smear), which persisted thereafter. Hemoglobin was 8.0 g/dL and platelet count was 2.1 × 103/μL. Histopathologic examination of a skin biopsy specimen on day 23 revealed interface dermatitis with individual cell necrosis (Fig 1, B). Infiltrating cells were mostly CD4+ and CD8+ T cells (Fig 2). Upon diagnosis of TEN, all drugs were either discontinued or changed. High-dose intravenous immunoglobulin (400 mg/kg/d) was given for 5 days and intravenous methylprednisolone (1000 mg/d) for 3 days followed by oral prednisone (2 mg/kg/d). Although the TEN subsided, he died of cerebral hemorrhage on day 39. The culprit drug remained undetermined. This case of TEN occurred in the absence of circulating T cells. As recently reported, skin contains a large number of TRM.3Clark R.A. Chong B. Mirchandani N. Brinster N.K. Yamanaka K. Dowgiert R.K. et al.The vast majority of CLA+ T cells are resident in normal skin.J Immunol. 2006; 176: 4431-4439Crossref PubMed Scopus (559) Google Scholar, 4Sathaliyawala T. Kubota M. Yudanin N. Turner D. Camp P. Thome J.J. et al.Distribution and compartmentalization of human circulating and tissue-resident memory T cell subsets.Immunity. 2013; 38: 187-197Abstract Full Text Full Text PDF PubMed Scopus (552) Google Scholar To determine whether TRM was involved, a necropsy skin specimen was analyzed via immunofluorescence microscopy for the expression of CD45RO (memory T-cell marker) and CD69 (resident T-cell marker).4Sathaliyawala T. Kubota M. Yudanin N. Turner D. Camp P. Thome J.J. et al.Distribution and compartmentalization of human circulating and tissue-resident memory T cell subsets.Immunity. 2013; 38: 187-197Abstract Full Text Full Text PDF PubMed Scopus (552) Google Scholar The majority of CD4+ and CD8+ T cells expressed CD45RO and CD69 (Fig 2). These results indicated that lesional T cells were of TRM phenotype, and because TRM were the only lesional T cells, it was suggested that they played a major role in the pathogenesis of this case. Expression of granzyme B indicated that lesional TRM were activated (data not shown). TRM in this patient's skin presumably arose in response to previous inflammatory events. Why such TRM with irrelevant antigen specificity attacked the epidermis in the presence of drugs to which the patient had not previously been exposed remains unclear. Interestingly, Ostrov et al5Ostrov D.A. Grant B.J. Pompeu Y.A. Sidney J. Harndahl M. Southwood S. et al.Drug hypersensitivity caused by alteration of the MHC-presented self-peptide repertoire.Proc Natl Acad Sci U S A. 2012; 109: 9959-9964Crossref PubMed Scopus (306) Google Scholar reported that abacavir binds to a major histocompatibility complex groove, which alters the repertoire of self-peptide ligands bound, thereby allowing self-reactivity of T cells. Application of this concept to our case would suggest that the culprit drug generated a self-peptide/drug/major histocompatibility complex as a neo-epitope on the keratinocytes. TRM then initiated cytotoxic responses against keratinocytes that resulted in epidermal necrolysis. Further analyses are needed to reveal the precise mechanisms. This case shows that TEN can be evoked even in the absence of circulating T cells, and emphasizes the importance of TRM during skin inflammation including drug hypersensitivity.