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Clear vision is of paramount importance in the survival of the vertebrates, including humans. Intraocular inflammation through the invasion of cells, proteins, the formation of flare and the possible corneal and retinal damage can lead to cloudiness of the visual axis which may results in severe visual impairment.
This is why complex mechanisms are presents in the eye to allow protection towards different pathogens and other extraocular threats while avoiding the mounting of an excessive immune response.
The highly controlled intraocular environment is dominated by a huge variety of anti-inflammatory molecules, immunomodulators and specialised cells with the role of suppressing and regulating immune reactions. The entire range of these "processes that work to minimize expression of immunopathology" in the eye is known as immune privilege 1.
The first study which described this concept was conducted by Medewar in 1948 2. He reported the limited immune reaction in the intraocular environment after an allograft was positioned into the anterior chambers of rabbits. After noticing that the rejection of the allograft followed the formation of new vessels, he assumed that the poor inflammatory response was due an "immunological ignorance" of the eye. In his opinion, this was secondary on the one hand to the lack of lymphatic drainage from the eye and, on the other hand, to the blockage of inflammatory cells recruitment at vascular level.
This apparently passive role of the ocular system in the control of immune reactions was then contradicted by Kaplan and Streilein's studies which demonstrated how the presence of an antigen into the anterior chamber results in an active suppression of the immune response 3.
This essay concentrates on the description of the mechanisms involved in the immune privilege of the eye, outlining the elements contributing to its maintenance.
Vascular supply, blood-ocular barrier and lymphatic drainage
Multiple mechanisms contribute to the immune privilege of the eye. These range from macroscopic structures to a variety of microscopic elements which possess an immunosuppressive function.
To the first group belongs the absence of vessels in some ocular structures such as the lens and the cornea. Their nutritional needs are satisfied through diffusion of oxygen, glucose and other metabolites from the adjacent tissues. The vascularisation of the cornea leads to the disruption of the immune privilege in this tissue, resulting in an increased rejection rate after allogenic transplantation 4.
Limiting the penetration of inflammatory cells and factors into the eye which could potentially promote an immune reaction is another mechanism which contributes to the privileged immunity of this organ. This is accomplished by the presence of an efficient blood-ocular barrier. While in the iris this barrier consists of a dense connective tissue formation surrounding the vessels, in other structures like the retina, this is realized by the presence of tight junctions which seal the intercellular spaces between the retinal pigment epithelial cells and between the vascular endothelial cells. The initiation of an inflammatory reaction (i.e. in uveitis), however, causes the disruption of the blood-ocular barrier, facilitating the penetration into the eye of inflammatory cells and cytokines.
Finally, the absence of a lymphatic drainage to transport antigens from the intraocular eye structures to the local lymph nodes was believed for many years to be one of the key factors in the maintenance of a limited immune response within the eye. However, this was disputed by the discovery of the uveoscleral pathway which was found to drain ca. 10% of the aqueous humor out of the eye 5. Part of this fluid was then transported via the lymphatic vessels into head and neck lymph nodes 6.
Elements that induce immune tolerance towards ocular antigens
The injection of an antigen into the anterior chamber leads to a highly regulated immune reaction which results in the activation of Treg cells (CD4 and CD8). These cells suppress pro-inflammatory effectors including Th1/Th2 cells without influencing non-complement fixing antibodies and cytotoxic T-cells 7. This process is known as anterior chamber associated immune diviation (ACAID) and allows a relatively effective protection towards external pathogens avoiding the raise of strong immune reaction which may endanger fundamental eye's structures (figure 1) 8.
Figure 1: schematic representation of ACAID 8.
In ACAID, after an antigen is placed into the anterior chamber, this is phagocysed by F4/80 macrophages which function as antigen presenting cells (APC). F4/80 is an essential protein in the induction of immune tolerance. In fact, F4/80-deficient mice fail to generate an ACAID response 14. F4/80 shows a hybrid configuration involving structures from two different protein superfamilies (figure 2) 15: epidermal growth factor (EGF) and seven span transmembrane (TM7) 16.
Figure 2: schematic representation of an F4/80 molecule which consists of the combination of EGF and TM7 derived proteins.
APCs are mainly derived from the iris stroma and ciliary body. These cells express CD1d 8, a MHC class 1-like molecule 15, and present a low concentration of CD40 on their plasma membranes 15.
After phagocytosis, the antigen is presented on MHC 1 and 2 of the APCs inducing the expression of co-stimulatory molecules such as B7-1 and B7-2 and the secretion of TGF-Î²2 7. The latter and other factors which are present in the aqueous humour such as Î±-MSH and CGRP play a central role in the action of ocular F4/80 APCs. In addition to suppress the release of pro-inflammatory molecules and the activation of Th1 cells by APC, aqueous humour factors also provoke the secretion of immunosuppressive cytokines 9, 10.
Following antigen phagocytosis, APCs leave the eye via the trabecular meshwork and enter the bloodstream before reaching the marginal zone of the spleen (figure 1). In this organ, APCs attract NKT cells (Natural Killer T cells) through the action of the secreted MIP-2. NKT cells, after the identification of the CD1d molecules present on the surface of APCs, bind them to form NKT - APC complexes. The subsequent secretion of activated cytokines from aggregates of B-cells, NKT and APCs, attracts antigen-specific T cells which, after further modification, are transformed into CD4 and CD8 Treg cells 8, 11, 12.
While CD4 cells inhibit the activation of the immune response (afferent), CD8 cells limit the action of the already stimulated inflammatory cells (efferent) 15. Two types of CD4 cells have been described recently: CD4 CD25+ and CD4 CD25- cells 25. The programmed death-1 molecule (PD-1) expressed on CD4 Treg was shown to play a role in the regulation of ACAID 26. On the other hand, CD8 cells cultivated in vitro following contact with APCs developed the ability to activate genes linked to TGF-Î² secretion while inhibiting the expression of genes which are believed to limit the production of this anti-inflammatory molecule 27. In addition to TGF-Î², CD8 cells also secrete other factors such as IL-10 15.
The generation of ACAID requires the presence of the spleen until four days after the placement of the antigen into the anterior chamber. In addition, the eye should not be removed before 48 hours after injection 13.
In summary, the essential role of ACAID consists in the presentation of a specific antigen to the immune system with the aim of achieving a certain degree of tolerance. The future occurrence of the same antigen in the eye will therefore cause a controlled intraocular immune reaction which will preserve the integrity of the delicate eye structures and the clarity of the media present along the visual axis.
Elements affecting the ocular adaptive immunity
The intraocular environment manifests its ability to limit adaptive immunity acting at two different levels: through the expression of immunosuppressive molecules by various types of cells and through the anti-inflammatory action of soluble factors present mainly in the aqueous humour 8.
Pigment epithelium cells of the iris and of the ciliary body as well as retinal pigment epithelium cells of the retina, have been shown to convert T cells into Treg cells 15. The involved mechanisms include the binding with B7 and CTLA 4 molecules 17 in addition to the expression of Fas ligands (FasL) 18. The expression of the latter occurs in some of the cells present in the retina, iris, ciliary body and cornea which are involved in the barrier function against the systemic immune system 18. The interaction of FasL on the ocular cells with the Fas molecules induces programmed cell death of the target cells (apoptosis). In contrast to necrosis, apoptosis does not cause inflammation which may endanger the clarity of vision.
Moreover, corneal cells manifest on their surface specific molecules which have been demonstrated to induce apoptosis (CD95L) as well as to reduce complement activation (CD46, CD55, CD59) 19.
In addition to non-soluble molecules localised in the cells' plasma membranes, a multiplicity of immunosuppressive factors is present in the aqueous humour. These include transforming growth factor beta (TGF-Î²2), melanocyte-stimulating hormone (Î±-MSH), calcitonin gene related peptide (CGRP), vasoactive intestinal peptide (VIP), somatostatin (SOM), indoleamine 2,3 deoxygenase (IDO), migration inhibitory factor (MIF), ...
It has been known for many years that aqueous humour limits the expansion of lymphocytes 20. The addition of aqueous humour to IFN-Î³ secreting T cells in vitro was recently shown to cause a blockage in the IFN-Î³ production while inducing the release of TGF-Î²2 21. Similar results have been obtained after treatment of T cells with a solution containing TGF-Î²2 and Î±-MSH 22. These factors retain also the ability to change the property of T cells from hypersensitivity mediator cells to regulatory T cells, leading to an overall suppression of their pro-inflammatory role 23. In addition, TGF-Î²2 was shown to completely block T-cells expansion while Î±-MSH was reported to decrease IFN-Î³ and IL-4 secretion in stimulated T-cells 8. The ability of the aqueous humour and its soluble factors to suppress inflammation was also confirmed in "in vivo" studies. In one of them hypersensitivity-mediating T cells and their antigens injected into the anterior chamber of the eye failed to raise an inflammatory reaction 24.
However, aqueous humour does not possess the capacity of totally block the innate immunity components present in the eye. In fact, cytotoxic T cells and non complement-fixing antibodies cannot be inhibited and maintain their respective roles, lysing cell and binding antigens 19. This balance is essential to guarantee a certain degree of immunological protection while minimising the risks of a potentially damaging severe immune response.
Nevertheless, the activation of complement factors is limited by molecules which block the binding of C1q to IgG antibodies. Factors which inhibit the conversion of C3 to C3b are also present 8.
Elements affecting the innate ocular immunity
Under others, a study published by J.W. Niederkorn undoubtedly confirmed the inhibition of the innate immune system in the eye 28. Firstly, he injected tumor cells into the flank of mice, provoking an NK cells driven immune reaction which resulted in the elimination of the tumor cells. However, the placement of the same cell line into the anterior chamber of mice with a defect adaptive immune system did not cause an inflammatory response but the continuous growth of the tumor cells.
Such a protection towards the innate immune system may be necessary given the potential vulnerability of some ocular structures to its action. Corneal endothelial cells, for example, possess a low level of MHC 1 molecules, making them easily identified and destroyed by NK cells 8. In addition, corneal endothelial cells express CD14 receptors where LPS can bind initiating the recruitment of inflammatory cells. Finally, they are highly susceptible to oxygen products like NO 8.
Moreover, ocular parenchymal cells were shown to possess a high concentration of CD95 ligands and TNF-Î± receptors 8. While the former induce the secretion of cytokines from inflammatory cells, the latter make parenchymal cells an easy target for the harmful TNF-Î± 8.
These are some of the reasons why in the anterior chamber of the eye regulatory mechanisms exist to limit the range of action of the innate ocular immunity. Migratory inhibitory factor (MIF), for example, rapidly inhibits the activity of NK cells 29 while TGF-Î²2 was shown to possess a delayed restraining function on this type of cells 8. In addition, TGF-Î²2, Î±-MSH and FasL limit the recruitment of macrophages into the eye 30, 31. Moreover, Î±-MSH and calcitonin gene related peptides (CGRP) were reported to block the secretion of cytokines from macrophages 9. Finally, molecules like CD 46, CD55, and CD 59 which are expressed on the plasma membranes of the cornea endothelial cells are able to suppress the induction of the complements' system 19.
Ocular immune privilege in practice
The evolutionary reason why the eye is an immune privileged site is the need to keep under strict control any inflammatory process which may otherwise damage the delicate intraocular structures and impair vision.
Some clinical examples of the significance of the immune privilege are represented by allogenic corneal transplant, sympathetic ophthalmia and uveitis.
Many studies showed how the abolishment of the immune privilege is linked to a considerably decreased secretion of anti-inflammatory factors which results in the development of an uncontrolled inflammatory response 32. This is one of the reasons for the higher rejections' rate of corneal allografts in the presence of a vascularised cornea. On the other hand, from an immunological point of view, corneal allograft transplant is an extremely successful procedure when immune privilege is maintained.
In sympathetic ophthalmia, a potentially blinding uveitis against retinal antigens occurs in one eye, following a penetrating trauma in the contralateral eye. It is currently believed that the release of ocular antigens into the system after the injury induces an immune response against the retina of the contralateral eye. However, only a small number of patients develop this disease after an eye trauma. This may be due to ACAID activation and the induction of immune tolerance against the ocular antigens which, in most cases, prevents the development of an immune reaction 8.
A final example is represented by recurrent herpes uveitis. The resolution of an ocular herpes virus infection is achieved through the action of CD4 T cells 8. In mice, the suppression of the CD4 T cells activity in the early stage of an HSV infection reduces corneal complications, suggesting a positive role of immune privilege in this disease. In humans, however, herpes uveitis is a recurrent disease which very often proves difficult to eradicate. This might be due to the immune tolerance induced by ACAID towards HSV antigens 8. If this assumption is correct, this could be considered as an unsuccessful contribution of the immune privilege towards the maintenance of intact eye's structures and good vision.
In summary, the immune privilege in the eye is achieved through the coordination of different mechanisms. These include the lack of vascularisation in some ocular structures and the presence of a blood-ocular barrier; the anti-inflammatory action of molecules expressed by intraocular cells which inhibit the systemic inflammatory cells and promote the conversion of T cells to Treg cells; the immunoregulatory activity of factors present in the aqueous humour which promote immunotolerance via the ACAID system and maintain immunosuppression.
The reason for the presence of an immune privilege in the eye is the need for a strict control of inflammations which may potentially damage the delicate eye structures, leading to visual impairment. Microorganisms and tumor cells can in some cases only be eliminated through the activation of a stronger immune reaction which cannot be achieved in the immunologically suppressed intraocular environment. This is why immune privilege can be seen as a biological compromise to avoid visual impairment through a complex regulation of the immune response 8.