Desiccating stress-induced disruption of ocular surface immune tolerance drives dry eye disease

Abstract

SummaryDry eye is an allegedly autoimmune disorder for which the initiating mechanisms and the targeted antigens in the ocular surface are not known, yet there is extensive evidence that a localized T helper type 1 (Th1)/Th17 effector T cell response is responsible for its pathogenesis. In this work, we explore the reconciling hypothesis that desiccating stress, which is usually considered an exacerbating factor, could actually be sufficient to skew the ocular surface's mucosal response to any antigen and therefore drive the disease. Using a mouse model of dry eye, we found that desiccating stress causes a nuclear factor kappa B (NF-jB)-and time-dependent disruption of the ocular surface's immune tolerance to exogenous ovalbumin. This pathogenic event is mediated by increased Th1 and Th17 T cells and reduced regulatory T cells in the draining lymph nodes. Conversely, topical NF-jB inhibitors reduced corneal epithelial damage and interleukin (IL)-1b and IL-6 levels in the ocular surface of mice under desiccating stress. The observed effect was mediated by an augmented regulatory T cell response, a finding that highlights the role of mucosal tolerance disruption in dry eye pathogenesis. Remarkably, the NF-jB pathway is also involved in mucosal tolerance disruption in other ocular surface disorders. Together, these results suggest that targeting of mucosal NF-jB activation could have therapeutic potential in dry eye.

Goblet cell loss abrogates ocular surface immune tolerance

“…Loss of immune tolerance has been implicated in the immune-based conjunctival inflammation that develops in dry eye (10,11). Tolerance to antigens, such OVA, topically applied to the ocular surface has been reported to develop through anergy induction and generation of antigen-specific Tregs (10,11,24).…”

“…Loss of immune tolerance has been implicated in the immune-based conjunctival inflammation that develops in dry eye (10,11). Tolerance to antigens, such OVA, topically applied to the ocular surface has been reported to develop through anergy induction and generation of antigen-specific Tregs (10,11,24). Guzman and associates found that induction of tolerance to topically applied OVA antigen was lost after 3 days of experimental dry eye induced by pharmacological suppression of tear secretion and exposure to a desiccating environment, a model in which GC loss occurs (10).…”

“…Tolerance to antigens, such OVA, topically applied to the ocular surface has been reported to develop through anergy induction and generation of antigen-specific Tregs (10,11,24). Guzman and associates found that induction of tolerance to topically applied OVA antigen was lost after 3 days of experimental dry eye induced by pharmacological suppression of tear secretion and exposure to a desiccating environment, a model in which GC loss occurs (10). Loss of tolerance in the dry eye group was confirmed by increased DTH to OVA antigen, reduced T cell suppression of antigen-specific T cell proliferation, and increased generation of IFN-γ-and IL-17-positive CD4 + T cells (10).…”

“…One theory for the generation of autoreactive CD4 + T cells is that dry eye disrupts ocular surface immune tolerance. Loss of immune tolerance to antigens topically applied to the eye surface has been found in experimental models of dry eye induced by systemic cholinergic blockade and exposure to a desiccating environment, lacrimal gland excision, or topical administration of the detergent benzylkonium chloride (9)(10)(11). Similar to human dry eye, significant conjunctival GC loss has been documented in these mouse models (5,12).…”

“…Spdef-KO mice that lack GCs have been previously reported to develop ocular surface inflammation and dry eye disease (17). Additionally, loss of ocular surface immune tolerance has been observed in experimentally induced mouse dry eye models where GC loss occurs (9,10). Based on these findings and the altered distribution of APCs in the conjunctiva of the Spdef-KO mice, we compared the ability to induce tolerance to topically applied OVA antigen in WT and Spdef-KO mice using a previously reported protocol with cutaneous delayed type hypersensitivity (DTH) response as the readout ( Figure 4A).…”