Jiawu Zhao1, Naomi Oxberry1, Nikita Balachandran1
1 Swansea Medical School, Swansea University, Swansea, UK
Introduction
Ocular immune-privilege (IP) is a reduced or altered immune response to an immunogen in the eye. It is believed that ocular IP is essential to prevent collateral damage from inflammatory responses and retain the clarity of the visual axis through the cornea and retina (1). IP is achieved through two mechanisms: unique anatomical structure and the immunosuppressive microenvironment of the eye. Anatomical structure that supports IP includes a limited lymphatic system, non-fenestrated endothelium with supportive cells such as pericytes, astrocytes, Müller cells and perivascular macrophages, and tight junctions formed by retinal pigment epithelial cells. The immunosuppressive microenvironment within the eye is created by soluble factors (e.g. α-MSH, TGF-β2) in the aqueous humour and membranous molecules (e.g. FasL, PD-L1, CD200) of cells in the intraocular compartment (2, 3). In addition, tolerogenic Antigen Presenting Cells (APC) and homeostatic microbiome-induced regulatory T cells (Treg) also contribute to the immunosuppressive microenvironment (3, 4). However, such IP is always threatened by physiological changes and pathological processes within the body. This short article will discuss common mechanisms which disrupt our ocular IP.
Mechanisms by which ocular immune-privilege is disrupted
The process of aging compromises the unique anatomical structure of the eye, particularly the blood-retinal barrier. It has been shown that aging can cause loss of endothelial cells, morphological changes of retinal pigment epithelial cells and tissue injury caused by para-inflammation. In addition, the aging process causes reduced expression of CD200, TGF-β2 and several other immunosuppressive factors. This lowers the threshold of the local inflammatory response (3). The defence mechanism in the eye is also compromised with the aging process. For example, microglia, the macrophage in the eye, has reduced phagocytic function. There is also a reduction in expression of complement inhibitors. As a result, oxidative damage within the retinal neurons weakens the regulatory control over microglial activation. This raises the local inflammatory level (3). Furthermore, recurrent systemic inflammation is common with increasing age. Such systemic inflammation can potentially alter the character of tolerogenic APC and homeostatic microbiome-induced Treg, and can ultimately reduce ocular IP.
Corneal infection and inflammation can lead to the disruption of ocular IP by promoting lymph and blood vessel development. The cornea is normally avascular and this supports ocular IP. It has been noticed that corneal HSV-1 infection can induce lymphangiogenesis which is driven by VEGF-A/VEGFR2 signalling. The study showed that the corneal lymphatics persist long after the resolution of the corneal infection (5). A similar phenomenon has been observed in conditions like keratitis sicca (dry eye disease). Low grade corneal inflammation caused by dry eye disease can induce lymphangiogenesis, but interestingly no angiogenesis (6). Therefore, infection and inflammation can disrupt ocular IP by changing the unique anatomical structure of the eye.
Sympathetic loss of immune privilege (SLIP) is where injury in one eye can lead to loss of IP in the other. Studies have shown that nerve injury in one eye can sharply increase neuropeptide substance P (SP) in both eyes. SP plays a pivotal role in converting naive CD11c+ cells into contrasuppressor cells (CSC) which can disable Treg, and thus lose full control of the immune response (7). A similar phenomenon had been noticed long ago by the ancient Greeks (8). The reason why nerve injury in one eye could alter pathophysiology in the other is still not fully understood. Interestingly, studies have shown that simple suturing or X-shaped incisions in one eye did not have any effect to the corneal allografts in the other. However, circular incision in one eye led to significant more rejection of the allograft in the opposite (9). Hence, it is believed that only severe insult can terminate ocular IP in the unaffected eye to protect it against life-threatening risk via an anticipatory mechanism. For example, HSV keratitis sets off a T-cell dependent immune response in the eye, potentially sacrificing vision to defend against a life-threatening sequelae like viral encephalitis. A similar response overriding IP will be observed in the remaining eye as the body ‘anticipates’ similar danger to eventually befall the uninfected eye (7).
Primary autoimmune conditions such as birdshot chorioretinopathy, age-related macular degeneration (AMD) and autoimmune retinopathy can impact ocular IP. Studies of these primary autoimmune conditions revealed that eyes are capable of developing cell-mediated immunity. Autoimmune conditions can disrupt ocular IP by different mechanisms as the eye manifestations vary from condition to condition (10). For example, 95% patients with birdshot chorioretinopathy have HLA-A29 genes which can present autoantigens to T cells (11). In AMD, there is an accumulation of degenerative outer segments of photoreceptors which cause chronic inflammation in the eye (12). In addition, studies have shown that some microbial antigens can induce autoantibody production against retinal photoreceptor protein through molecular mimicry (13). These molecular changes seen in autoimmne conditions can increase local inflammation disrupt ocular IP.
Conclusion
Loss of ocular IP can be caused by disruption in the normal anatomical structure of the eye and the ocular immunosuppressive microenvironment. This can be caused by aging, infection, SLIP and autoimmunity. IP disruption can lead to unwanted inflammation, particularly for the elderly, and negatively impact intraocular drug delivery. Understanding how ocular IP is disrupted can help us prevent unnecessary inflammation and to develop novel therapies to restore its function.
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