The Eye
Vision, which is essential for the survival of most vertebrates, can be easily impaired by inflammation within the eye. Various anatomic and physiologic features have evolved to minimize the likelihood of immune responses and inflammation in the eye. Many of these features are analogous to those that underlie the partial immune privilege in the brain. The retina is anatomically an extension of the CNS and is protected by a blood-retinal barrier with many of the same vascular wall properties as the blood brain barrier. The anterior chamber of the eye is the fluid-filled space between the transparent cornea in front and the iris and lens behind. Inflammation in this chamber could lead to opacification of the transparent cornea and lens, with loss of sight. The fluid in this space, aqueous humor, is biochemically similar to CSF, and in terms of access to the immune system, is analogous to lymph, in that it drains into veins or into conjunctival lymphatics. Despite this access, the anterior chamber of the normal eye maintains a significant degree of immune privilege. Anatomic features of the anterior chamber that contribute to immune privilege include the tight junctions of the epithelial layer and resistance to leakiness of blood vessels in the tissues adjacent to the anterior chamber, and the avascular nature of the cornea. Several soluble factors have immunosuppressive and antiinflammatory properties in the aqueous humor that fills the anterior chamber, including neuropeptides (α-melanocyte-stimulating hor mone, vasoactive intestinal peptide, somatostatin), TGF-β, and indolamine 2,3-dioxygenase (IDO, discussed later). Cells lining the anterior chamber, including the epithelium of the iris and the endothelium, constitutively express FAS ligand and PD-L1, which can induce death or inactivation of T cells, respectively.
One liability of the sequestration of self antigens in the eye is that immune tolerance to these antigens is not induced. This lack of tolerance becomes a problem only when trauma exposes the eye antigens to the immune system. A striking example of this is sympathetic ophthalmia, in which trauma to one eye causes release of eye antigens leading to autoimmune disease in both the injured eye and the uninjured eye. Presumably, although self antigens in the normal eye are inaccessible to the extraocular immune system to induce either autoimmunity or tolerance, activated immune effector cells and antibodies that are generated in the periphery when one eye is injured have access to and cause injury to the normal eye.
An experimental phenomenon called anterior chamber associated immune deviation occurs when an antigen placed in the anterior chamber of a mouse eye results in systemic immune tolerance to that antigen. A similar phenomenon has been described when the antigen is placed in the brain. Several different mechanisms have been proposed, but the relevance of this phenomenon to immune privilege is unclear.
The Testis
Immune privilege in the testis serves to limit inflammation that may impair male fertility. Many self antigens in the adult testis are first expressed at the time of puberty, well after the development of a competent immune system, so it is unlikely that lymphocytes specific for these antigens are deleted during development. Therefore, immune privilege in the testis may also serve to prevent autoimmunity. The testis, like the eye and brain, has a blood-tissue barrier that limits delivery of cells and molecules to the sites of spermatogenesis. This barrier is not formed by endothelial cells but rather by Sertoli cells, which line the outer layer of the seminiferous tubules where spermatogenesis takes place. The hormonal milieu of the testis, which is rich in androgens, has an antiinflammatory influence on macrophages. TGF-β is produced by Leydig, Sertoli, and peritubular cells and likely contributes to local immune suppression.
