Immune Mechanisms of Chronic Ocular Damage after Acute Exposure to Nitrogen Mustard - PROJECT SUMMARY / ABSTRACT
Mustard agents, in particular sulfur mustard and nitrogen mustard, can pose potent threats to both Service
Members and civilians by penetrating exposed tissues and resulting in devastating effects on myriad organs,
among which the ocular surface is the most vulnerable. Exposed victims can develop severe chronic corneal
sequelae termed mustard gas keratopathy (MGK) that impairs corneal transparency and visual function.
Chronic MGK is characterized by corneal epithelial lesions, stromal edema and limbal stem cell deficiency.
The current post-exposure management for mustards is very limited and largely ineffective in preventing
development of MGK. Once MGK develops, there is no cure beyond palliative treatment. To date, the precise
underlying pathogenesis of MGK remains largely unknown. We have recently established a mouse model of
nitrogen mustard (NM) exposure induced MGK which exhibits persistent corneal epitheliopathy and loss of
limbal stem cells, along with corneal haze and nerve damage. In light of potential involvement of chronic
inflammation in driving long-term sequelae of mustard exposure, we have performed immune characterization
in our chronic MGK model and demonstrated a robust local T-helper 17 (Th17) response, which has been
similarly reported in mustard exposure-induced chronic pulmonary disease. However, the role of these Th17
cells in mustard-induced chronic organ damages remains elusive.
In the current proposal, we hypothesize that ocular exposure to NM leads to rapid release of inflammatory
factors by stressed corneal epithelium, resulting in activation of corneal antigen-presenting cells (APC) that
subsequently migrate to eye-draining lymphoid tissues, and mount a robust local Th17 response, which
persists for a long time and principally mediates the development of MGK. The main objectives of this project
are to (i) determine the mechanisms of Th17 activation and their pathogenic functions during the course of
MGK development; and (ii) assess the therapeutic strategies targeting Th17 in preventing the development
of MGK. To achieve these objectives, two specific aims have been developed: Aim 1: We will test our
hypothesis that acute innate corneal response after mustard exposure, primarily involving corneal epithelium
and APC, promotes the subsequent Th17 activation; and Aim 2: We will test our hypothesis that activated
Th17 immunity mediates the development of persistent tissue and cell damage at the ocular surface primarily
through secreting the cytokine IL-17. Successful completion of this project will provide novel knowledge at
both the mechanistic and translational levels, which will facilitate the discovery of specific targets in mitigating
mustard agents-induced chronic ocular disease.
