BLOG: Just what is ocular immune privilege?

Lately we have had a rash of iritis cases in our clinic, so I thought this month would be a good time to talk about ocular immunology.

As we know, inflammation can be a double-edged sword, allowing immune cells to swarm to a tissue to fight infection, but bringing with them the possibility of local tissue destruction. Nowhere is this more dangerous than in the eye, where scar tissue production within the visual axis would have devastating consequences.

We are taught that this is the reason why the eye has “immune privilege” – but what specifically does that mean? The answer is more complicated than we thought, and it is changing each year as researchers uncover more about this fascinating system.

Let’s begin by reviewing what happens in an immune response in most parts of the body. The immune system can be broken down into two parts: the innate and the adaptive systems. The innate system involves things such as barriers, that is, our skin or lysozymes in our tears. It also generates inflammation, which is a nonspecific response designed to increase blood flow into the affected (or infected) tissue. With inflammation comes nonspecific inflammatory cells such as macrophages and polymorphonuclear leukocytes (PMNLs), which phagocytose a wide variety of foreign microorganisms and eliminate them.

The innate system also includes the complement system, which comprises proteins (such as C-reactive protein and interferon, among others) that circulate in the blood and facilitate (or complement) the destruction of cells by marking them in large numbers for the adaptive immune system.

The adaptive system is very specific compared to the innate system. It remembers. The adaptive system is broken down into two parts: cellular and humoral immune responses. The cellular response is mediated by T cells and antigen-presenting cells (APCs). It works by having APCs present an antigen to a helper T cell, which is made to recognize a certain surface receptor. This helper T cell identifies the antigen to the rest of the immune system, especially killer T cells, which then destroy antigen cells. The humoral response involves the B cells, which are antibodies to entire cells, not just a certain receptor. Specific and individual B cells are created (by plasma cells) from past exposures to antigens.

Of course, it’s much more complicated than that. And, of course, it’s helpful that the eye (specifically the cornea) is privileged from some of that immune system.

So, what is ocular immune privilege? First, the lack of a vascular supply in the lens and the central cornea prevents the innate and adaptive immune systems from interfering. Roving PMNLs, B cells and T cells can’t respond to a random antigen that may be in the corneal stroma, for instance.

Second, the presence of a vascular barrier in the eye also helps to keep the eye clear from inflammation. We know this barrier as the blood-ocular barrier, which consists of tight-junctions in the capillary endothelial cells of the iris, ciliary body and retinal pigmented epithelial cells.

Third, 90% of our aqueous humor does not drain directly to a lymph node; it drains out to our vasculature via Schlemm’s canal. Lymphatic vessels typically channel antigens to lymph nodes, where they are trapped and bound to APCs and B cells, initiating an immune response. Only 10% of aqueous drains to lymph nodes (via the uveoscleral pathway), allowing for a tampered down reaction. This is one reason why patients on prostaglandin therapy have larger inflammatory reactions.

Fourth, the ocular immune privilege comes from the scarcity of APCs. Specifically, the central cornea has nearly zero APCs, and there are few found in the iris and ciliary body. This means, again, that although some antigens may be found and destroyed in these areas, there is less likelihood of a large inflammatory response.

In addition to these factors of immune privilege, the eye has also developed something known as anterior chamber-associated immune deviation, which impairs the immune system’s ability to mount a delayed-type hypersensitive reaction to a specific antigen. This is a large reason why corneal grafts are successful and why ocular autoimmunity is low, but it also unfortunately hinders T cells from detecting tumor cells and is one of the reasons why ocular tumors can grow unchecked.

There is also an immunosuppressive property of aqueous humor itself, which has been shown to inhibit lymphocyte reactions and cytokine production.

Keeping the fragile visual axis clear is not an easy task, given the destructive potential of immune inflammation. Thus, we are not surprised to learn how complex the ocular immune privilege is, given the consequence of its failure.

References:

Koevary SB. Ocular Immunology in Health and Disease. Boston, MA: Butterworth Heinemann; 1999.

Pleyer U, et al. Uveitis and Immunological Disorders. Berlin: Springer; 2007.

Streilein JW. J Leukoc Biol. 2003;74(2):179-185.

Taylor AW. Eye. 2009;23:1885-1889. doi:10.1038/eye.2008.382.

Zhou R, et al. F1000 Biology Reports. 2010; 2:3. doi:10.3410/B2-3.