Immunological mechanisms of epidermal damage in toxic epidermal necrolysis

Tohyama, Mikiko; Hashimoto, Koji

doi:10.1097/aci.0b013e328355b865

Cited by 26 publications

(32 citation statements)

References 63 publications

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“…Taken together, lymphocyte-mediated cytotoxicity of individual keratinocytes appears as an early step in TEN lesion development in some dogs, which is consistent with the proposed pathogenesis of drug-or drug/peptide-specific T-lymphocyte and/or natural killer-cell initiation of TEN in humans. 25 Based on the histomorphology of our cases, progression of this early lymphocyte-mediated apoptosis lesion can vary considerably. In 1 dog, lesions progressed rapidly to full-thickness coagulation necrosis of the epidermis without significant leukocyte influx, similar to classic descriptions of TEN.…”

Section: Discussionmentioning

confidence: 89%

Clinical and Microscopic Characteristics of Canine Toxic Epidermal Necrolysis

et al. 2014

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Canine toxic epidermal necrosis (TEN), a rare and life-threatening cutaneous drug reaction, traditionally has been described as full-thickness devitalization of the epidermis with minimal dermal inflammation; however, few reports detail the histologic findings. We characterize the clinical features and histologic variations of 3 canine TEN patients. Clinically, irregular erythematous and purpuric macules evolved into widespread and severely painful erosions. The number of eroded mucosae varied; however, periocular and perilabial mucocutaneous junctions frequently were affected. Thirteen of 17 biopsies were evaluated. Apoptosis at multiple epidermal levels was the most common pattern of epidermal necrosis (12/13 biopsies, 92%). In contrast, full-thickness coagulation necrosis was present less often (7/13 biopsies, 52%). Lymphocytic interface dermatitis was the predominant inflammatory pattern, and intraepidermal lymphocytes, along with fewer histiocytes, were present to some degree in all samples along with lymphocytic satellitosis of apoptotic keratinocytes. The sequence of changes points to lymphocyte-mediated keratinocyte apoptosis as an early step in lesion development with subsequent variation in progression to coagulation necrosis among patients. Histopathologic changes overlapped with those reported for erythema multiforme, in contrast to traditional histologic descriptions of canine TEN. A specific algorithm for assessment of drug causality in epidermal necrolysis (ALDEN) was applied for each patient; carprofen was associated with a probable score for causality in 1 dog. Clinicians should be encouraged to take multiple biopsies in TEN suspect cases as nearly 25% of all biopsies lacked epithelium and were not diagnostic.

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Section: Discussionmentioning

confidence: 89%

Clinical and Microscopic Characteristics of Canine Toxic Epidermal Necrolysis

et al. 2014

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“…Serum granulysin levels directly relate to skin lesion severity, unlike FasL 37 . However, as noted with FasL, granulysin is not specific to TEN, and is also observed in other drug reactions 6 .…”

Section: Th17 Cellsmentioning

confidence: 75%

“…Furthermore, the cytotoxicity of sFasL is 1,000 times less than that of membrane-bound FasL 6,31 . Granulysin is a 9- .…”

Section: Th17 Cellsmentioning

confidence: 95%

“…One could assume that, in widespread epidermal necrosis, the amount of FasL would increase dramatically. However, this assumption is somewhat controversial, as the lymphocytes in TEN blisters do not express high levels of FasL, in contrast to the substantial perforin/granzyme increases observed 6 . Indeed, in a study by Nassif et al, the cytotoxicity of TEN blister lymphocytes was attenuated when perforin/granzyme lysis was inhibited.…”

Section: Th17 Cellsmentioning

confidence: 99%

“…granules such as perforin-granzyme and granulysin, tumor necrosis factor α (TNFα) 6 , annexin, microRNA (miR)-18a-5p, and drug metabolites are all thought to be involved. The proposed mechanisms of apoptosis can be divided into 2 groups: the extrinsic and intrinsic pathways.…”

Section: T-cells (T-reg Cells) T Helper 17 (Th17) Cells Cytotoxicmentioning

confidence: 99%

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A Review of the Pathogenesis of Toxic Epidermal Necrolysis

Kinoshita

Saeki

2016

J Nippon Med Sch

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Toxic epidermal necrolysis (TEN) is a rare skin condition, most often drug-induced, known for its skin detachment and high mortality. In general, acute TEN is considered a T-cell mediated, type IV hypersensitivity disorder. It mostly results from a cumulative effect of risks from the drug structure, drug metabolism, HLA alleles and T cell clonotypes. However, the precise mechanism of TEN is still unknown.Apoptosis or necroptosis causes keratinocytes to lose their shape and adhesion, and necrosis predominates within a few days. Total epidermal necrosis separates the epidermis from the dermis. TEN is regarded as an immune reaction with predominantly CD8+ T lymphocytes, monocytes/macrophages, and natural killer cells. Impaired regulatory T-cells, T-helper 17 cells, cytotoxic granules such as perforingranzyme and granulysin, tumor necrosis factor α, annexin, microRNA-18a-5p, and drug metabolites are all thought to be involved. From what is known, it can be assumed their mechanism is complex, and there is still much to be investigated. New findings will contribute to the identification of effective active methods of intervention. (J Nippon Med Sch 2016; 83: 216 222)

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Adverse Immunological Reactions to Drugs

Ardern‐Jones

2024

Rook's Textbook of Dermatology

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Cutaneous eruptions caused by drug hypersensitivity reactions have been the subject of great interest to dermatologists for more than half a century. The precise molecular pathways involved in their pathogenesis are becoming clearer but there remain many areas that are poorly understood. Close delineation of the mechanistic pathways has been possible for some reactions including those where a close association with a specific human leukocyte antigen (HLA) type has been demonstrated. This work was led by the discovery that abacavir directly binds the HLA‐B*5701 major histocompatibility complex (MHC) peptide groove thereby altering the repertoire of self‐peptides that can be expressed in the MHC. Such novel self‐peptides are targeted T cells, which results in cytokine inflammation and induces clinical features typical of a drug hypersensitivity syndrome. HLA associations with severe cutaneous adverse reactions have now been shown for many different drugs. Despite the initial enthusiasm of this approach, it has become apparent that some drug–HLA associations have a lower odds ratio than others. This underscores the interpretation that other individual factors are at play as well as HLA sequence. Indeed, drug/HLA/clinical phenotype do not always correlate. For example, carbamazepine hypersensitivity is associated with both HLA‐B*1502 and HLA‐A*3101, yet genetic studies show that the former only predisposes to Stevens–Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) although the latter associates with exanthems, systemic hypersensitivity and SJS/TEN. In TEN, multiple molecular mechanisms of keratinocyte death have been postulated but two predominate including: (i) FasL upregulation and induction of Fas‐mediated keratinocyte cell death; and (ii) cytotoxic granulysin production by T, natural killer (NK) and NKT cells. Whether these act independently or synergistically remains to be established.

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Immunological mechanisms of epidermal damage in toxic epidermal necrolysis

Cited by 26 publications

References 63 publications

Clinical and Microscopic Characteristics of Canine Toxic Epidermal Necrolysis

Clinical and Microscopic Characteristics of Canine Toxic Epidermal Necrolysis

A Review of the Pathogenesis of Toxic Epidermal Necrolysis

Adverse Immunological Reactions to Drugs

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