Stevens-Johnson syndrome pathophysiology
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief:
Overview
SJS, like toxic epidermal necrolysis and erythema multiforme, are characterized by confluent epidermal necrosis with minimal associated inflammation. The acuity is apparent from the (normal) basket weave-like pattern of the stratum corneum.
Pathophysiology
Pathogenesis
- The exact pathogenesis of SJS/TEN is not completely understood
- However, It is believed that SJS/TEN is immune mediated and the result of a MHC Class-I restricted T-cell mediated cytotoxic reaction to drug antigens in keratinocytes leading to apoptosis[1]
- Drug antigens bind to MHC-I and T cell Receptors (TCR) leading to the clonal proliferation of the drug specific cytotoxic T cells
- On the activation of these T cells, various cytotoxic signals, including Fas/Fas ligand , perforin/granzyme B , and granulysin, are known to be responsible for mediating the damages in skin lesions and the subsequent worsening of the disease as explained below.
- T lymphocytes found in bisters were CD8+, HLA-DR+, CLA+ (cutaneous lymphocyte antigen), CD56+ and were shown to be strongly immunoreactive for granzyme B suggesting perforin/granzyme mediated cytotoxicity[2]
- There is also beleived to be some involvement of the soluble FasL (sFasL) in keratinocyte apoptosis in SJS and TEN. sFasL is secreted by peripheral bood mononuclear cells (PBMC's) and interacts with the Fas that is expressed on keratinocyte leading to apoptosis. Higher serum levels of sFasL may be seen in patients with suspicion of SJS/TEN[3]
- Recent studies suggest that the Granulysin, which is a cytotoxic protein released from cytotoxic T cells or natural killer (NK) cells, is a key mediator for disseminated keratinocyte apoptosis in SJS/TEN[4] and is identified by gene expression profiling as the highly cytotoxic molecule and confirmed by PCR and immunohistochemistry. Granulysin concentrations in blister fluid were found to be 2x to 4x more than the Perforin/Granzyme B/sFasL thus making it the most important cytotoxic molecule in SJS/TEN pathogenesis[5]
- Other cytokines that may be associated with trafficking, activation and proliferation of Cytotoxic T cells and other immune cells include IFN-Y(gamma), TNF-aplha, IL-2, IL-5, IL-6, IL-10, IL-13. IL-15 was one of the cytokines that was seen in the highest amount and also correlated with disease severity and mortality.Studies also suggest that IL-15 is important in mentaining long-lasting cytotoxic T lymphocyte responses as well as generating and mentaining Nk cells. It is also responsible for enhancing MHC-I antigen presentation thus has an important contribution in SJS/TEN pathogenesis[6]
Genetics
[Disease name] is transmitted in [mode of genetic transmission] pattern.
OR
Genes involved in the pathogenesis of [disease name] include:
- [Gene1]
- [Gene2]
- [Gene3]
OR
The development of [disease name] is the result of multiple genetic mutations such as:
- [Mutation 1]
- [Mutation 2]
- [Mutation 3]
Associated Conditions
Gross Pathology
On gross pathology, [feature1], [feature2], and [feature3] are characteristic findings of [disease name].
Microscopic Pathology
On microscopic histopathological analysis, [feature1], [feature2], and [feature3] are characteristic findings of [disease name].
References
- ↑ Correia O, Delgado L, Ramos JP, Resende C, Torrinha JA (1993). "Cutaneous T-cell recruitment in toxic epidermal necrolysis. Further evidence of CD8+ lymphocyte involvement". Arch Dermatol. 129 (4): 466–8. PMID 8466217.
- ↑ Nassif A, Bensussan A, Boumsell L, Deniaud A, Moslehi H, Wolkenstein P; et al. (2004). "Toxic epidermal necrolysis: effector cells are drug-specific cytotoxic T cells". J Allergy Clin Immunol. 114 (5): 1209–15. doi:10.1016/j.jaci.2004.07.047. PMID 15536433.
- ↑ Abe R, Shimizu T, Shibaki A, Nakamura H, Watanabe H, Shimizu H (2003). "Toxic epidermal necrolysis and Stevens-Johnson syndrome are induced by soluble Fas ligand". Am J Pathol. 162 (5): 1515–20. doi:10.1016/S0002-9440(10)64284-8. PMC 1851208. PMID 12707034.
- ↑ Chung WH, Hung SI (2012). "Recent advances in the genetics and immunology of Stevens-Johnson syndrome and toxic epidermal necrosis". J Dermatol Sci. 66 (3): 190–6. doi:10.1016/j.jdermsci.2012.04.002. PMID 22541332.
- ↑ Chung WH, Hung SI, Yang JY, Su SC, Huang SP, Wei CY; et al. (2008). "Granulysin is a key mediator for disseminated keratinocyte death in Stevens-Johnson syndrome and toxic epidermal necrolysis". Nat Med. 14 (12): 1343–50. doi:10.1038/nm.1884. PMID 19029983.
- ↑ Su SC, Mockenhaupt M, Wolkenstein P, Dunant A, Le Gouvello S, Chen CB; et al. (2017). "Interleukin-15 Is Associated with Severity and Mortality in Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis". J Invest Dermatol. 137 (5): 1065–1073. doi:10.1016/j.jid.2016.11.034. PMID 28011147.