The eye is directly exposed to the surrounding environment with this interface providing an external surface for the establishment of a local microbiome. As such, the host response to infection of the eye is complex as the organ must rid itself of invading environmental pathogens while minimizing immunologically driven pathology from the self or the nonpathogenic microbiota. The combination of the tear film contents (e.g., IgA, Lactoferrin, defensins, and growth factors) and the continuous washing by tears produced by the lacrimal gland serve to remove infectious agents, limit uncontrolled and unregulated inflammatory damage, provide a physical barrier to the surrounding environment, and promote the healing of the ocular surface to reduce the risk of ocular infection [17]. These antimicrobial compounds and barriers alone, however, are insufficient to protect the eye from pathogen invasion. Relatively similar barriers can be found within the retina and posterior segment [18].

Once physical barriers are breached on or within the eye, innate immune mechanisms serve to rapidly identify the pathogen. While the overall immunological response of the eye may slightly differ compared to that of other sites, innate immune sensors are expressed throughout the eye [19,20,21,22,23]. Much like those found in other tissues, Toll-like receptors (TLRs) and other innate sensors recognize conserved pathogen-associated molecular patterns and activate Myeloid differentiation primary response protein (MyD)88-dependent and -independent pathways following complex interactions with other inflammatory receptors [24,25]. NF-κB-related pathways and/or type I interferon (IFN) pathways are preferentially activated by these innate immune sensors [22,26]. Activation of these pathways leads to local innate immune responses including the production of chemokines to facilitate leukocyte trafficking and priming of the more pathogen-specific adaptive immune response [26]. The interplay between many of these pathways will be further highlighted below regarding specific pathogens within distinct areas of the eye.

To further complicate matters, certain parts of the eye are considered “immune privileged” and respond immunologically in ways not seen in other tissues and organs. This is due in part to blood–aqueous and blood–retinal barriers that prohibit the egress of macromolecules into the eye, limiting the exposure of ocular tissue, including local innate immune cells, to circulating pathogens and toxins [27]. Retinal pigment epithelial cells also upregulate T regulatory responses and suppress effector T cell activation [28,29]. This ocular anti-inflammatory milieu with an atypical response known as anterior chamber-associated immune deviation (ACAID) is a phenomenon within the eye in which antigens injected into the anterior chamber induce tolerance whereas the host develops a muted or abolished systemic response to the antigen. While the process is not completely understood, the generation of antigen-specific, antigen-presenting B cells within the spleen following antigen exposure intracamerally results in the development of T regulatory cells and interleukin (IL)-10 production in a relatively immunosuppressive microenvironment within the anterior chamber [30,31,32,33]. γδ T cells and IFN-γ production also appear to be important in this response as their loss does not allow ACAID to develop [34,35]. Subretinal exposure to antigens has been shown to induce a similar response to that induced by ACAID [36]. While different cells, cytokines, and chemokines have all been implicated, ACAID is still not completely understood and it is unclear if this is simply a mouse phenomenon or if it is seen in humans.

The hallmark of immune privilege and immune deviation within the eye is epitomized by the exceptionally high rates of success of corneal transplantation compared to those of other tissues and organs despite the lack of preoperative HLA typing [37]. The success of corneal transplantation appears to be related to the unique nature of the eye in which physical and cellular barriers of the cornea, ACAID-induced by T regulatory cells, and the immunosuppressive microenvironment of the anterior chamber reduce inflammatory reactions, promote immune privilege, and thereby reduce graft failure [37,38,39,40]. However, immune privilege and corneal transplant rejection can be overridden by severing corneal nerves and this rejection process appears to be driven by minor H alloantigens and the loss of regulatory T cells [41,42,43]. Ocular immune privilege is tightly controlled and can be overcome with relatively innocuous changes to eye anatomy.