Regulación inmune en el ojo

Review

Immune regulation and the eye
Joan Stein-Streilein
Schepens Eye Research Institute, 20 Staniford Street, Boston, MA02114, USA

The eye is an immune privileged site that is styled to
maintain the visual pathway while at the same time
provide defense against invading organisms. The eye
does this by selecting immune responses that function
in the absence of inflammation. Immuneregulation by
the eye takes the form of several active processes including a local immunosuppressive environment, the
contribution of soluble factors, Fas-FasL-induced apoptosis and unique suppressive mechanisms used by pigment epithelial cells in the eye. These processes are so
effective that antigens encountered in the eye result in
specific systemic tolerization; a phenomenon akin togut-induced oral tolerance. This review discusses the
cellular and molecular basis of tolerance induction by
the eye and notes the parallels to gut-induced peripheral
tolerance.
Regional specialization of immune responses
The immune response seems to be customized to the organ
in which it is initiated, as well as being specialized for the
region in which it has to function. Thus, it is not surprisingthat there are differences in responses to antigen depending on the route of its administration. Immunologists
working in the field know these facts and therefore select
the route of immunization to bias the response to their
desired outcome. For instance, injection of antigen into the
eye or gut is used in animal models to induce tolerance and
a subcutaneous route used to produceinflammation.
The eye and the gut are immunization routes classically
used for inducing peripheral tolerance. However, the eye is
far more well-studied as a model of immune privilege.
Immune privileged sites are known for their acceptance
of foreign tissue grafts. Indeed, in humans, mismatched
cadaver cornea grafts are accepted 60–70% of the time,
whereas 50% are rejected in eyes with preexistinginflammation [1]. The mechanisms of immune privilege in the eye
are multiple and overlapping, but what is not generally
recognized is that other tissues share some of the mechanisms used to down-regulate inflammation and induce
tolerance in their own environments. Thus, what is learned
from ocular immunology studies might be generally
applicable to other tissues.
Every location within the eye isimmune privileged
(Figure 1). In other words, antigen injected into the
anterior chamber [2], vitreous [3] or sub-retinal space [4]
induces peripheral tolerance to that antigen. Furthermore,
parts of the eye like the cornea are considered to be
intrinsically immune privileged tissues because when
transplanted to sites perfectly capable of rejecting foreign
antigens, they enjoy acceptance. Forinstance, a cornea is
Corresponding author: Stein-Streilein, J. (joan.stein@schepens.harvard.edu).

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accepted when transplanted under the kidney capsule, a
site that is not immune privileged [5,6].
Mechanisms of immune privilege in the eye
To understand the eye’s immune response one has to
consider the multiple overlapping mechanisms that contribute to the establishment and maintenanceof privilege.
First, the eye is filled with immunosuppressive factors
including neuropeptides, aMSH (melanocyte stimulating
hormone), somatostatin, vasoactive intestinal peptide, calcitonin gene related peptide [7,8], cytokines (e.g. TGFb-2),
complement inhibitors [9], and an inhibitor of NK cell
activity (macrophage inhibitory factor) [10]. Second, the
low expression of MHC class II in theeye limits antigen
presentation. Third, stromal cells from the iris, ciliary body
and retina of the eye are able to convert immune T cells to
regulatory (Treg) cells [11–15] (also see Figure 1). Furthermore retinal pigment epithelial (RPE) cells that line the
borders of the eye are able to directly inhibit primed T cells
[16]. Fourth, death inducing molecules like PDL-1 and
FasL are...