When Clarity Is Crucial: Regulating Ocular Surface Immunity

Abstract

The ocular surface is a unique mucosal immune compartment in which anatomical, physiological, and immunological features act in concert to foster a particularly tolerant microenvironment. These mechanisms are vital to the functional competence of the eye, a fact underscored by the devastating toll of excessive inflammation at the cornea - blindness. Recent data have elucidated the contributions of specific anatomical components, immune cells, and soluble immunoregulatory factors in promoting homeostasis at the ocular surface. We highlight research trends at this distinctive mucosal barrier and identify crucial gaps in our current knowledge.

Figure 1. Anatomical and functional characteristics of the ocular mucosal surface

The ocular surface comprises the cornea, limbus and conjunctiva and is protected by a non-keratinized, stratified epithelium. The epithelium constitutively expresses a range of immunomodulatory factors, including cell surface molecules (such as FasL and PDL-1) and secreted molecules (such as soluble VEGF decoy receptors [sVEGFRs] and PEDF). The epithelium is bathed in tear film, which consists of three distinct layers–an outer lipid layer (secreted by Meibomian glands in the eyelids), a middle aqueous layer (secreted by the main and accessory lacrimal glands) and an inner mucous layer (secreted by goblet cells). Secretory IgA (sIgA) is the predominant immunoglobulin in the tears, and acts in concert with a wide variety of antimicrobial molecules to facilitate cytolysis/limit the growth of pathogenic organisms. The high molecular weight heavily glycosylated membrane-associated mucins of the glycocalyx facilitate the maintenance of the tear film on the ocular surface, in addition to limiting bacterial adhesion and promoting the removal of debris via the lacrimal puncta. Corneal nerves form networks that penetrate the epithelium and stroma–these include the sub-basal and anterior stromal nerve plexuses. Neuropeptides such as CGRP and VIP moderate both innate and adaptive immunity. The stroma contains collagen-synthesizing keratocytes as well as immature CD11b⁺ antigen-presenting cells. The corneal endothelium is posterior to the stroma, and expresses a wide variety of immunoregulatory factors, including GITR and PD-L1.

Figure 2. Distribution of DCs at the ocular surface

The highest density of DCs is found in the conjunctiva, and their density decreases from the limbus to the central cornea. Langerhans cells are found in the conjunctiva and peripheral corneal epithelium. DC-SIGN⁺ DCs have been identified in the conjunctiva and peripheral anterior stroma. CD11b⁺ DCs are found in the conjunctiva and posterior stroma. Immature DCs are distributed throughout the anterior corneal stroma–these cells mature in response to inflammation with enhanced expression of MHC class II and costimulatory molecules CD80, CD86 and CD40.

Figure 3. Dominant immune pathways in ocular surface alloimmunity and autoimmunity

Antigen presenting cells stimulate naïve CD4⁺ cells to differentiate into effector cells. The rejection of corneal allografts is principally driven by Th1 cells, which are generated in the presence of the cytokine IL-12. In contrast, a Th17 effector response predominates in ocular surface autoimmunity, with TGF-β, IL-6 and IL-23 inducing Th17 generation. Regulatory T cells modulate effector CD4⁺ T cell responses in both alloimmunity and autoimmunity.