Autoimmunity at the ocular surface: pathogenesis and regulation

Abstract

A healthy ocular surface environment is essential to preserve visual function, and as such the eye has evolved a complex network of mechanisms to maintain homeostasis. Fundamental to the health of the ocular surface is the immune system, designed to respond rapidly to environmental and microbial insults, whereas maintaining tolerance to self-antigens and commensal microbes. To this end, activation of the innate and adaptive immune response is tightly regulated to limit bystander tissue damage. However, aberrant activation of the immune system can result in autoimmunity to self-antigens localized to the ocular surface and associated tissues. Environmental, microbial and endogenous stress, antigen localization, and genetic factors provide the triggers underlying the immunological events that shape the outcome of the diverse spectrum of autoimmune-based ocular surface disorders.

Figure 1

Immunoregulation on the ocular surface: (a) the ocular surface tissues contain a variety of soluble and cellular factors to reduce inflammation-induced pathology in the lacrimal functional unit. Those implicated in immunoregulation within the ocular surface tissues include: (1) nTregs (e.g., CD4+, CD8+, γδ, and NKT cells), which include many of the conjunctival intraepithelial lymphocytes, are thought to dampen or inhibit the inflammatory/autoimmune response on the ocular surface. (2) The anti-inflammatory cytokine transforming growth factor (TGF)-β is present on the ocular surface, and has profound suppressive affects on resident dendritic cell (DC) maturation in the cornea, autoreactive T-cell proliferation, differentiation, and survival, and Treg differentiation and maintenance. The activity of the potent acute response proinflammatory cytokine interleukin (IL)-1 is modulated by the IL-1 receptor antagonist (IL-1RA), expressed and secreted by corneal and conjunctival epithelial cells. Vasoactive intestinal peptide (VIP) also seems to be protective; VIP secreted by sensory nerve endings in the cornea increases production of TGF-β and IL-10 and inhibits expression of the proinflammatory cytokines/chemokines, IL-1 β, tumor necrosis factor (TNF)-α, interferon (IFN)-γ, and CXCL2. Hormones are also implicated in curbing inflammation and maintaining homeostasis. In addition, the corneal epithelium also expresses vascular endothelium growth factor (VEGF) receptor-1 to sequester VEGF and reduce neovascularization. (3) APCs bearing self-antigen derived at the ocular surface may migrate to the regional lymph nodes to induce antigen-specific Tregs (iTregs). (b) Immunoregulation in the lymphoid organs: nTregs may exert their immunosuppressive function by (1) releasing soluble factors (e.g., TGF-β, IL-10), (2) cell–cell contact, which disables pathogenic effector T cells (Teff) and/or APCs, and/or (3) competing for soluble factors (e.g., IL-2). (4) Inducible Tregs (iTregs) may use similar mechanisms to inhibit cells bearing or responding to autoantigens. It is possible that these Treg-dependent mechanisms may also function within the ocular surface tissues. (c) Other peripheral immunoregulatory mechanisms: additional mechanisms also limit access and effector function of autoreactive T cells within the ocular surface tissues: (1) TGF-β and (2) nTregs and iTregs are suggested to suppress infiltrating autoreactive lymphocytes and (3) low-level expression of integrins in the healthy ocular surface endothelial cells, coupled with expression of the programmed death ligand-1 (PD-L1), negatively regulates activated T cells within the ocular surface tissues.

Figure 2

The immunopathogenesis of Dry Eye disease. (a) Afferent autoimmune response: stress to the ocular surface triggers the initial events suggested to initiate autoimmunity. (1) Induction of proinflammatory factors (cytokines, chemokines, and matrix metalloproteinases (MMPs)) is a hallmark of ocular surface autoimmunity and may be initiated by stress signal transduction pathways or possibly by Toll-like receptor (TLR) signaling (after microbial infection or aberrant endogenous activation). Acute response cytokines, such as interleukin (IL)-1 α, IL-1 β, tumor necrosis factor (TNF)-α, and IL-6 are elevated in patients with Dry Eye. IL-1 and TNF-α amplify inflammation on the ocular surface through processes, such as activation of APCs. (2) Evidence suggests that APCs internalize autoantigen, for example, type III muscarinic receptor (M₃R), Kallikrein (Klk)13, process and present immunogenic epitopes on MHCII, upregulate expression of costimulatory molecules, for example, CD80, and CD86 and (3) the chemokine receptor, CCR7, which directs the activated APCs to the draining cervical lymph node. (b) Efferent activation of autoreactive lymphocytes: the local cytokine milieu influences T-cell differentiation. (1) IL-12 present within the ocular surface tissues and produced by mature APCs, combined with interferon (IFN)-γ likely influences the activation and differentiation of autoreactive Th1 cells. (2) By contrast, elevated IL-6 in the presence of transforming growth factor (TGF)-β and IL-23 may skew differentiation toward Th17 cells. (3) B cells are also predicted to have a role in Dry Eye as shown in Sjögren's syndrome. In this scenario, Th2 cells provide help to autoreactive B cells and promote clonal expansion, somatic hypermutation, isotype switching, affinity maturation and plasma cell differentiation into autoantibody-secreting cells. Alternatively, B cells may be activated independently of T cells, for example, TLR and BAFF signaling. Efferent trafficking of autoreactive T cells to the ocular surface tissues is widely thought to be directed by adhesion molecules (e.g., LFA-1, VLA-4) and chemokine receptors (e.g., CCR5 and CXCR3) that respond to cognate ligands expressed on the ocular surface (e.g., ICAM-1, CCL5, and CXCL10). (c) Efferent effector function of autoreactive lymphocytes: Autoreactive Th1 and Th17 cells present during the immunopathogenesis of Dry Eye potentiate the chronic autoimmune response and have pathological consequences. For example, Th1 cells stimulate APCs to secrete proinflammatory cytokines and are a prominent source of interferon (IFN)-γ, which induces expression of a multitude of proinflammatory factors, pro-apoptotic proteins and causes direct tissue destruction. IFN-γ alters mucins on corneal epithelial cells that have devastating effects on ocular surface integrity. IFN-γ is linked to (1) epithelial cell apoptosis, (2) reduced goblet cell density, and (3) squamous metaplasia. IL-17 produced by infiltrating Th17 cells increases MMP3/9 expression and induces corneal epithelial barrier dysfunction. Furthermore, autoantibodies may bind to target antigens causing direct tissue destruction.

Figure 3

The immunopathogenesis of ocular cicatricial pemphigoid (OCP). (a) Afferent autoimmune response. (1) An environmental trigger, that is, stress to the ocular surface tissues in the context of genetic predisposition may initiate the events leading to autoimmunity. Induction of proinflammatory factors (cytokines, chemokines, and matrix metalloproteinases (MMPs)) sets the stage for (2) autoantigen (epitopes from example, β4 integrin, putative 45, and 168 kDa antigens) presentation on major histocompatibility complex (MHC)II by APCs, upregulation of costimulatory molecules and (3) migration to the draining cervical lymph node. (b) Efferent activation of autoreactive B and T cells. (1) T cells may provide help to B cells to undergo clonal expansion, somatic hypermutation, isotype switching, affinity maturation, and differentiation into autoantibody-secreting plasma cells. (2) Alternatively, autologous B-cell activation (e.g., TLR, BAFF signaling) may activate B cells (independently of T cells) to become autoantibody-secreting plasma cells. (c) Efferent effector function of autoantibodies, T cells, and cytokines. (1) Plasma cells secrete autoantibodies that (2) bind to their target self-antigens (e.g., β4 integrin, and/or putative 45 and168 kDa antigens) to promote complement component 3 (C3) deposition and tissue destruction. (3) Overabundance of anti-inflammatory factors, namely transforming growth factor (TGF)-β, produced by ocular surface epithelial cells and innate effectors also contributes directly to pathology. Excessive TGF-β favors production and accumulation of extracellular matrix proteins and overt tissue fibrosis. Interleukin (IL)-13 has recently been shown to be an important contributor to conjunctival fibrosis and inflammation in ocular cicatricial pemphigoid (OCP). Together these factors cause tissue scarring, which ultimately leads to blindness.