Neutrophil-driven and interleukin-36γ-associated ocular surface inflammation in chronic Stevens–Johnson syndrome

Document Type

Article

Publication Title

Allergy: European Journal of Allergy and Clinical Immunology

Abstract

Purpose: This study aims to elucidate the tear proteome and understand the underlying molecular mechanisms involved in the ocular complications following Stevens–Johnson syndrome/toxic epidermal necrolysis (SJS/TEN). Methods: Mass spectrometry (MS) was performed to quantify the tear fluid proteins from chronic SJS/TEN patients (n = 22 eyes) and age- and gender-matched controls (n = 22 eyes). The candidate proteins were validated using ELISA (n = 80 eyes) in tear samples and immunohistochemistry (IHC; n = 12) in eyelid margin specimens. These proteins were compared for significant differences based on age, gender, disease duration, and ocular severity. Results: A total of 1692 tear fluid proteins were identified, of which 470 were significantly differentially regulated in chronic SJS/TEN. The top 10 significantly upregulated proteins were neutrophil secretions including neutrophil elastase (p <.0001), defensin (p <.0001), and matrix metalloproteinase 8 (p <.0001). The presence of neutrophils was confirmed by the upregulation of IL-8 (p <.001) in tears, a key cytokine known for recruiting neutrophils. Additionally, positive expression of myeloperoxidase was observed in the keratinized eyelid margins of SJS/TEN to validate the presence of neutrophils. Among 41 unique proteins identified by MS, IL-36γ (p <.01) was expressed in three SJS/TEN patients and was confirmed in SJS/TEN tears and eyelid margins by ELISA and IHC, respectively. IL-36γ was specifically expressed in the superficial layers of eyelid margin keratinized conjunctiva. The majority of the significantly downregulated proteins were lacrimal gland secretions such as lacritin (p <.0001) and opiorphin (p <.002). Neutrophil elastase (p <.02) was significantly elevated in patients with severe eyelid margin keratinization. Conclusion: Our observations indicate a clear correlation between eyelid margin keratinization and the expression of IL-36γ, potentially mediated by neutrophils recruited via IL-8. Future experimental studies are needed to test the role of therapies targeting IL-8 and/or IL-36γ in reducing eyelid margin keratinization and its associated ocular complications in SJS/TEN.

DOI

10.1111/all.16126

Publication Date

1-1-2024

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