In systemic autoimmune diseases like Sj"gren's syndrome (SS), exocrinopathy of the lacrimal gland leads to an aqueous-deficient dry eye that is among the most common and debilitating clinical manifestations. As dry eye disease progresses, it initiates a multi-step, immune-mediated process that includes two pathological characteristics (1) transdifferentiation a nonkeratinized, mucosal ocular surface to a keratinized, "skin-like" epithelium;and (2) disruption of ocular surface and goblet cell mucins. This process, known as squamous metaplasia (SQM), is a devastating, end-stage consequence of dry eye disease that can cause considerable morbidity as advanced keratinzation couples with subepithelial fibrosis to cause corneal opacification and blindness. While immune-mediated inflammation has been implicated in the pathogenesis of SQM, little is known about the precise immunopathogenic mechanisms, leaving us with treatment strategies that are limited, costly and largely palliative. The goal of our research is to decipher how autoimmune-mediated inflammation provokes vision-threatening SQM. Using three model systems, (i) human patients with SS;(ii) a validated mouse model of spontaneous autoimmune exocrinopathy and keratopathy that mimics the clinical characteristics of SS;and (iii) in vitro studies of cultured corneal epithelial cells, our previous work demonstrated an essential role for autoreactive CD4+ T cells and their interplay with the proinflammatory cytokine IL-1 in the pathogenesis of SQM. Yet, the specific mechanism whereby CD4+ T cells and IL-1 promote SQM in autoimmune dry eye remains unknown. To deepen our understanding of the molecular and cellular pathogenic mechanism of immune-mediated SQM, and to identify possible targets for treatment, we seek to (i) determine how CD4+ cells work together with IL-1 to provoke SQM;and (ii) how IL-1 promotes transdifferentiation of the ocular surface epithelium to one that is mucin-depleted and pathologically keratinized. We hypothesize that autoantigen-primed CD4+ T cells work in collaboration with infiltrating monocytes to promote the local release of proinflammatory mediators (e.g., IL-1) that establish and sustain a chronic inflammatory state at the ocular surface. Once established, the local inflammatory response causes ocular surface damage and promotes SQM by disrupting, PAX6, the master regulator of ocular mucosal phenotype and altering the glycosylation and expression of ocular mucins. To test this hypothesis we will (Aim 1) explore infiltrating mononuclear cells as potential cellular intermediate linking antigen-primed CD4+ T cells to the local production of IL-1;
(Aim 2) define how IL-1 directs the early stages of pathological keratinization, by studying its effects on the master gene controlling corneal phenotype, Pax6;
and (Aim 3) characterize the mechanisms whereby IL-1 alters ocular mucins by identifying key genes regulating glycoconjugate biosynthesis. The overall impact of this work will include a better understanding of the immunopathology of SQM in autoimmune disease that is likely to uncover key events that aid in its early diagnosis and/or treatment.

Public Health Relevance

Autoimmune diseases like Sjgren's syndrome cause a severe dry eye that is highly recalcitrant to treatment. Despite powerful immunosuppressive and immunomodulatory therapy, autoimmune dry eye can progress to complete corneal opacification and blindness through a process known as squamous metaplasia. Little is known about the pathogenesis of squamous metaplasia and there is no cure. A better understanding of the underlying disease process would open the possibility of developing novel treatments to prevent corneal blindness.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY016203-07
Application #
8316282
Study Section
Anterior Eye Disease Study Section (AED)
Program Officer
Mckie, George Ann
Project Start
2004-12-01
Project End
2014-08-31
Budget Start
2012-09-01
Budget End
2013-08-31
Support Year
7
Fiscal Year
2012
Total Cost
$386,250
Indirect Cost
$136,250
Name
University of California San Francisco
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
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