Page 1030 - Clinical Immunology_ Principles and Practice ( PDFDrive )

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Immunological Ocular Disease

James T. Rosenbaum, Phoebe Lin

The immune system can induce disease in virtually any portion triggers apoptosis of the Fas-bearing cell. FasL is constitutively
of the eye. Examples include conjunctivitis, keratitis, keratocon- expressed within the eye, being detected in normal cornea, anterior
junctivitis, uveitis, scleritis, optic neuritis, and orbital inflam- uvea, and retina. The importance of FasL to ocular immune
mation. The anatomy of the eye is depicted schematically in privilege has been demonstrated primarily in experimental models
Fig. 74.1. Uveitis is defined as inflammation of the uveal tract, of ocular inflammation. Corneal allografts from FasL-negative
which is the middle layer of the eye, divided into the anterior mice into recipients of normal phenotype are rejected in all
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uvea (iris, ciliary body) and posterior uvea (choroid). The uvea cases, whereas approximately half of FasL-positive grafts survive.
is sandwiched between an outer layer (sclera) and an inner layer When injected into the eyes of FasL-deficient mice, herpes simplex
(retina). The anterior segment is separated from the posterior virus (HSV) causes a severe invasive infection. A similar procedure
segment by the lens. Two relatively common immunologically in normal phenotype control animals results in relatively minor
mediated ocular diseases, discussed elsewhere in this volume, inflammation. Levels of FasL in the aqueous humor during human
are sicca secondary to Sjögren syndrome (Chapter 54) and anterior acute anterior uveitis are capable of inducing apoptosis in Fas-
ischemic optic neuropathy secondary to giant cell arteritis positive lymphoid cells. In this self-limiting condition, as well
(Chapter 59). Before considering the various ocular inflammatory as in relevant rodent models, apoptosis of infiltrating T cells is
disorders, it is critical to review some unique considerations observed early in the course of the inflammation. In addition
related to ocular immunology. to FasL, the local expression of tumor necrosis factor (TNF)–
related apoptosis inducing ligand (TRAIL) by corneal endothelium
OCULAR IMMUNE PRIVILEGE also contributes to enhanced apoptosis and immune privilege
within the eye. 2
Many of the mechanisms that drive inflammation in the eye
are identical to those operating at other tissue sites. The major
difference between the immunopathology of intraocular inflam- CYTOKINES, NEUROPEPTIDES, AND COMPLEMENT
mation and that of systemic inflammatory disease relates to the IN THE PROMOTION AND REGULATION OF
fact that the eye, like the brain and the testis, is an immuno- OCULAR INFLAMMATION
logically privileged site. During uveitis, keratitis, and scleritis,
as well as following corneal transplantation, a variety of local The aberrant immune activation that occurs in uveitis appears to
immunosuppressive mechanisms act to limit the damage caused be caused by a combination of environmental triggers and genetic
by infiltrating leukocytes and, consequently, to influence the risk factors that tip the balance away from immune regulation
patient’s clinical course. One of the most important factors and toward inflammation. Inflammatory pathways of the adaptive
is the constitutive expression of Fas ligand (FasL) within the immune system that play a role in the pathogenesis of uveitis
eye. In addition, normal ocular tissues produce relatively high include T-helper 1 (Th1) lymphocytes (that produce interferon-γ
levels of immunomodulatory cytokines and immunosuppressive [IFN-γ], interleukin-2 [IL-2], and IL-12), and IL-23-responsive
neuropeptides, as well as complement. Other factors include the Th17 lymphocytes (that produce IL-17, IL-22, and IL-6).
blood–aqueous and blood–retinal anatomical barriers, limited An example of a subgroup of immune cells that keep the
major histocompatibility complex (MHC) expression, a paucity immune system in check are regulatory T cells (Tregs). Tregs
of lymphatic drainage channels within the eye, and, in the case produce antiinflammatory cytokines, such as IL-10, transforming
of the cornea, the complete absence of blood vessels. The term growth factor (TGF)-β, and IL-35. Tissues in both the anterior
anterior chamber–associated immune deviation (ACAID) describes and the posterior segments of the human eye constitutively
the suppression of a cell-mediated immune response when soluble express TGF-β. The concentration of TGF-β in the aqueous
antigen is directly injected into the aqueous humor. All of the humor is sufficient to inhibit T-cell activation and proliferation
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above factors contribute to ACAID. in a variety of assays. As might be anticipated, significantly
lower levels of this activated cytokine are measured in the aqueous
FAS LIGAND humor of patients with a variety of uveitis syndromes compared
with levels present in normal eyes. Another antiinflammatory
Most immune cells, including neutrophils, monocytes, macro- cytokine, IL-27, is produced constitutively by resident cells in
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phages, and lymphocytes, express Fas (CD95) on their surface. the retina, including retinal ganglion and photoreceptor cells.
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The interaction between Fas and its receptor FasL (CD95L) IL-27 is upregulated by IFN-γ and suppresses Th17 cells.
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