Introduction 

Toxic Epidermal Necrolysis (TEN) is a rare, potentially life-threatening skin condition attributed to widespread keratinocyte apoptosis (a form of cell death)  and presents with rashes, skin blistering, and peeling. Although the prevalence of TEN is only 0.4-7 cases per 1 million annually,¹ those affected can rapidly progress from flu-like symptoms to a fatal skin condition within days. With a mortality rate of up to 40%,¹ rapid diagnosis and effective treatment are important in the management of TEN. In most cases, the condition is caused by the inappropriate activation of the immune system in response to certain drugs or their metabolites, and studies have also identified a genetic association with its progression.  

The condition is diagnosed by an epidermal detachment area of greater than 30% and is normally managed in burn intensive care units to promote the process of healing.² Despite advancements in supportive care, variability in clinical presentation and identifying high-risk individuals remains challenging. Understanding the immune mechanisms driving TEN is therefore essential to improve outcomes through targeted therapeutic interventions that go beyond supportive care. 

At a molecular level, TEN arises due to a combination of innate and adaptive immune mechanisms. It is proposed to be triggered by three key immune mediators: Fas/Fas-ligand (FasL), perforin/granzyme b, and granulysin.³

Pathogenesis 

Drug hypersensitivity 

Hypersensitivity refers to the abnormal activation of the immune system in response to a harmless antigen. TEN is considered a T cell-mediated, type-IV hypersensitivity reaction in response to certain medications or their metabolites. There are three pathways by which a drug or metabolite can activate the immune response, all of which result in the activation of cytotoxic T cells. 

Firstly, the hapten/pro-hapten model refers to the binding of a drug to a protein, forming an immune complex,  which is processed and presented to T cells. Secondly, the pharmacological interaction pathway suggests that some drugs interact with immune receptors, triggering T-cell activation. Finally, the altered peptide pathway suggests that certain drugs can modify the peptides presented to T cells, thereby triggering an immune response.³ Collectively, these pathways all lead to inappropriate immune activation and result in keratinocyte apoptosis, which consequently triggers epidermal necrolysis.

The most common drugs known to trigger TEN are:¹

• Antibiotics are used to treat bacterial infections
• Anticonvulsants are used to treat seizures
• Allopurinol are used to treat kidney stones or gout
• Non-steroidal anti-inflammatory drugs (NSAIDs) are used to reduce pain and inflammation.

Genetic association

Genome-wide association studies have identified strong associations between the expression of specific human leukocyte antigen (HLA) alleles and the risk of drug hypersensitivity. There are many forms of the same HLA gene, termed allelic variants, that vary between individuals, allowing the immune system to recognise and respond to a wide range of foreign proteins. HLA molecules play an essential role in presenting peptides to T cells and promoting effector T cell responses. The most common variant associated with TEN occurs in the HLA-B gene.¹ 

Immune mechanisms and molecular mediators 

The immunopathogenesis of TEN is a result of the combination of genetic susceptibility and both innate and adaptive immune mechanisms, contributing to keratinocyte apoptosis and epidermal necrosis. Several studies have identified high concentrations of CD8+ cytotoxic T cells and natural killer (NK) cells in the blister fluid and epidermis of TEN lesions.⁴ 

Innate and adaptive immunity

An antigen-presenting cell initiates the immune responses seen in TEN. Exposure to the triggering drug or metabolite promotes antigen presentation via HLA molecules to naive T cells in the lymph node. This triggers T cell specialisation to both CD4+ T helper cells and CD8+ cytotoxic T cells, which expand and migrate to the skin epidermis. 

CD4+ T helper cells

CD4+ T helper cells play a key role in amplifying the immune response by producing proinflammatory mediators, called cytokines. By sustaining the inflammatory environment, they also promote the recruitment of additional immune cells. CD4+ T cells in TEN lesions specialise into the Th1 and Th17 effector subsets, producing the cytokines interferon-gamma (IFNy) and interleukin 17 (IL-17) respectively. IFNy drives the growth and specialisation of CD8+ T cells, while IL-17 sustains inflammation.^3,4 

CD8+ cytotoxic T cells

CD8+ cytotoxic T cells are the main cell type responsible for keratinocyte apoptosis and, consequently, epidermal necrosis. They act through three main effector pathways:

• Fas-FasL pathway 

FasL is secreted by CD8+ T cells and binds to Fas, the receptor, on the cell surface of the keratinocyte, promoting apoptosis. The subsequent activation of the intracellular signalling cascade involves the recruitment and activation of caspases, which results in the breakdown of target cells.⁴

• Perforin and granzyme B

CD8+ T cells contain cytotoxic mediators, which are released when they directly contact a target cell. Perforin is a mediator that attaches itself to the cell membrane of the target and forms pores. Granzymes are able to enter the target cell (the keratinocyte in the case of TEN) via perforin-induced channels, and cleave caspases to induce apoptosis.^3,4

• Granulysin 

Granulysin is a negatively charged cytotoxic protein that binds to the positively charged cell membrane of the target keratinocyte. The consequent disruption in charge damages the mitochondria, an organelle involved in apoptosis, by the release of specific proteins.⁴

NK cells

NK cells play an important role in triggering apoptosis by recognising stressed keratinocytes through specific activating receptors. Like CD8+ cytotoxic T cells, they express FasL on their membrane and secrete potent cytotoxic mediators (granulysin, perforin, and granzyme B).⁵ 

Unlike T cells, NK cells don’t require priming in the lymph node and are therefore activated earlier, enhancing the inflammatory environment and promoting widespread necrosis due to the death of keratinocytes.⁶ 

Macrophages 

Monocytes/macrophages are also abundant in the epidermis and dermoepidermal junction of TEN skin lesions.⁴ They promote the growth and cytotoxicity of CD8+ T cells through specific systems, as well as contributing to keratinocyte apoptosis by the release of proinflammatory cytokines such as tumour necrosis factor-alpha (TNF-a).^1,5,6 

Regulatory T cells

Regulatory T cells (Tregs) have a role in maintaining the balance between inflammation and regulation. They suppress the immune response, maintain tolerance to self-proteins, and promote tissue repair. In TEN, Tregs are found to be functionally impaired, and some studies have identified high levels of non-Tregs in skin lesions, which secrete pro-inflammatory cytokines rather than suppressive ones, thereby enhancing epidermal injury.³ 

Keratinocytes 

As the target of apoptosis in TEN, keratinocytes express not only the receptor Fas, but also FasL on their surface, and secrete soluble FasL.^3,4 Although not normally cytotoxic, in TEN lesions, they are able to target neighbouring keratinocytes for apoptosis.^3,5 In response to stress, they release danger signals and cytokines, which recruit and activate additional immune cells, promoting the inflammatory cycle and further tissue damage. 

Cytokines: soluble mediators 

As part of the inflammatory cascade, immune cells secrete proinflammatory cytokines that recruit additional immune cells and promote differentiation of cells to an inflammatory phenotype. Alongside the cytotoxic mediators, CD8+ T cells, NK cells, macrophages, and keratinocytes in TEN lesions predominantly secrete IFN-γ and TNFa,⁴ which promote systemic inflammation. Overactivation of the immune system leads to epidermal necrosis. 

Therapeutic implications 

Understanding the immune cells and mechanisms involved in the progression of TEN has allowed for the development of targeted therapies, which is a step forward from supportive care. 

First-line treatments for TEN

• Systemic corticosteroids are frequently used to reduce inflammation by suppressing the immune system, however, the associated increased risk of secondary infection has sparked uncertainty^7,8 
• Anti-TNFa antibodies, such as etanercept, aim to inhibit several inflammatory pathways initiated by this proinflammatory cytokine and promote healing. Clinical trials have shown successful wound healing with minimal side effects⁹ 

Second-line treatments for TEN

• Intravenous immunoglobulin (IVIg) therapy is the focus of recent trials. By pooling antibodies (immunoglobulins) that are extracted from healthy donors together, it aims to suppress type IV hypersensitivity. Studies have shown a reduction in CD8+ T cell activation and the number of NK cells in the blood. It is also suggested that they block the Fas receptor, thereby protecting keratinocytes from apoptosis¹⁰
• Plasmapheresis is a method by which metabolites are removed from the bloodstream on an alternate-day basis, thereby reducing the levels of early mediators. Although the safety profile is favourable, the invasiveness of the technique limits its use⁷ 

Summary 

TEN is an immune-mediated skin condition that progresses through a combination of immune mechanisms. Drug hypersensitivity and genetic factors are the main triggers of TEN and promote the overactivation of the immune system, leading to epidermal necrolysis. Clinically, this acute condition presents with rashes and epidermal detachment, forming the basis of diagnosis. The involvement of key cell types of the innate and adaptive immune response, most importantly CD8+ T cells and NK cells, promotes the release of proinflammatory and cytotoxic mediators. Not only do these mediators amplify the immune response by recruiting additional cells, but they also trigger keratinocyte apoptosis both directly and indirectly. The inflammatory mediators form the basis of targeted therapeutic approaches, and several clinical trials are underway to investigate treatment options which combat this life-threatening condition.