Eyeassociated Lymphoid Tissue As An Entrance Site For Immunological Events

Some organs of the human body (anterior eye chamber, brain, placenta, testicle) are characterized by a special immunological state of reduced activation of the specific and nonspecific immune systems. This condition of local immune suppression, termed the immune privilege, is expressed in delayed or totally suppressed rejection of allogenic transplantations in these organs (17,18); this is illustrated by maintenance of the immunophenotypically immature placenta in the maternal organism as well as in survival of corneal transplants and the immuno-logical acceptance of intraocular lenses. The biological functions of the immune privilege are evident: tolerance of a foreign antigen is obviously better in some organs than its rejection, and this can be achieved only at the expense of T-cell-mediated cytolysis of local cells. Such cell loss is not replaceable in poorly regenerative, postmitotic, or highly differentiated tissues. Therefore, some viruses survive in the central nervous system, as their elimination by T effector cells would certainly lead to neural cell death with severe neurological deficits or even individual death. A similar situation applies in the anterior eye chamber (19) and testicles. Such immune suppression is not necessary in regenerative organs like the liver or skin, since all cells needed for the process are capable of proliferation and redifferentiation.

The mechanisms that maintain the immune privilege are not uniform in different organs and are not understood in detail. Besides the classical concept of mechanical tissue barriers (i.e., the blood-brain, blood-testis and blood-retina barriers), we must consider the expression of so-called death ligands (CD95, TRAIL, TNF), that induce apoptosis of potentially dangerous T cells as well as a special form of antigen presentation that produces immune tolerance. Such immune deviation was first described in the anterior eye chamber (20). Injection of foreign antigen into the chamber does not lead—as at other locations of the body—to a local T-cell reaction (type IV immune reaction), but rather produces systemic tolerance of the inoculated antigen. The antigens are thus not attacked in the anterior eye chamber, in turn protecting the sensitive visual system against inflammatory damage. Thus, the immune privilege of the anterior eye chamber allows transplantation of allogenic lenses, artificial intraocular lenses, and cornea.

Such tolerance is known to be transferable by means of injection into a second animal of splenocytes from an animal primed by antigen inoculation, demonstrating that antigens from the anterior eye chamber receive a signal developed by regulatory T cells that mediates immune deviation. In contrast to the spleen, the cervical lymph nodes do not play a critical role in the induction of immune deviation, as demonstrated in rats by Yamagami and Dana (21). Nevertheless, the drainage routes of the antigens from the anterior eye chamber, the location of their origin, and the passage of the corresponding antigen-presenting cells all remain unclear. In particular, it is not clear what role is played by the conjunctiva and the nasolacrimal ducts and their associated lymphoid tissues [CALT (6,7,14,22-24) and TALT (10-12,15)] in the immune privilege of the anterior chamber of the eye.

Egan et al. (25) demonstrated in mice that potent immunologic tolerance can be achieved by exposure of antigen (ovalbumin) through the conjunctival mucosa. They identified the submandibular lymph node as the principal lymph node in which antigen-bearing antigen presenting cells are located and in which antigen-specific T-cell clonal expansion occurs following conjunctival application of antigen. Clonal expansion was maintained at an elevated level and the T cells were responsive in vitro during a 10-day period of daily ovalbumin application to the conjunctiva. However, in spite of the continuous antigen application, the number of antigen-specific T cells steadily declined over the 10-day period, and by day 14, the remaining ovalbumin-specific T cells were refractory to secondary challenge with ovalbumin, indicating that they had become anergic in vivo. Egan et al. (25) concluded that the fact that antigen-presenting cells presenting ovalbumin were found only in the submandibular lymph node and not in other lymph nodes, spleen, or nasal-associated lymphoid tissue (NALT) rules out the likelihood that tolerance in this system was due to drainage of antigen through the efferent tear ducts and association with NALT or gastrointestinal-associated lymphoid tissue (GALT).

Figure 3 Antigen uptake by an M cell (Mc) (for details see text). Abbreviations: e, epithelial cell; T, T lymphocyte; B, B lymphocyte; mp, macrophage; dc, dendritic cell; tj, tight junction.

However, one important point is lacking in the suggestions of Egan et al. (25). It has not yet been taken into consideration that antigens that are drained by the tear fluid itself and not injected intraconjunctivally would be able to induce immune deviation via CALT and/or TALT. With regard to protection of the cornea against inflammatory destruction, this would be plausible and analogous to the process in the nervous system and the anterior eye chamber (20). It is as yet not known how antigen is translocated across the epithelium of conjunctiva and the nasolacrimal duct. M cells, highly specialized epithelial cells that facilitate uptake and transcytosis of macromolecules and microorganisms (Fig. 3), are present in the dome-associated epithelium of peyer's patches. Following transcytosis, antigens to cells of the immune system are released in lymphoid aggregates beneath the epithelium, where antigen processing and presentation and stimulation of specific B and T lymphocytes are achieved (26,27). Whereas epithelial cells of the conjunctiva, which show morphological features of M-cells have been demonstrated in several animal species, no such cells could be demonstrated in humans. The mechanisms of conjunctival antigen uptake and transport remain unclear.

According to a definition by Isaacson (5) for MALT of the gut wall (i.e., Peyer's patches), MALT comprises four components (Fig. 4): (i) organized mucosa-associated lymphoid tissue, (ii) a lamina propria, (iii) intraepithelial lymphocytes, and (iv) an associated lymph node. Circulation of the lymphoid cells in these four components enables their homing to their original and other mucosal sites, where they exert the effector function. Such a response may be dominated by sIgA release and may include cytotoxic T-lymphocyte action (27). In this regard, the submandibular lymph node found by Egan et al. (25) could be the "associated lymph node" of CALT and TALT but not of NALT.

Associated lymph nodes

Figure 4 Organization and components of MALT. Abbreviations: HEV, high endothelial venules; MALT, mucosa-associated lymphoid tissue.

Associated lymph nodes

Figure 4 Organization and components of MALT. Abbreviations: HEV, high endothelial venules; MALT, mucosa-associated lymphoid tissue.

Activation of T lymphocytes has been observed in dry eye, leading to frequent occurrence of abnormal (pathological) apoptosis in terminally differentiated acinar epithelial cells of the lacrimal gland (28). Tears, now secreted to the ocular surface, will contain pro-inflammatory cytokines and will inflame the tissues of the ocular surface. Abnormal apoptosis has also been detected within the epithelial cells and lymphocytes of the ocular surface (28). This ocular surface inflammatory response consists of inflammatory cell infiltration, activation of the ocular surface epithelium, with increased expression of adhesion molecules, inflammatory cytokines, and pro-apoptotic factors, increased concentrations of inflammatory cytokines in the tear fluid, and increased activity of matrix-degrading enzymes in the tear fluid. It has been suggested that the reduction of circulating androgens plays a role in these processes (29,30). Treatment with locally applied cyclosporin A eye drops interferes with interleukin (IL) metabolism, especially that of IL-6, and thus creates a new treatment option that leads to remarkable improvement of the irritation symptoms and ocular surface signs, especially in severe cases of ker-atoconjunctivitis sicca.

All these findings lead to the conclusion that CALT and TALT may play a role in the pathogenesis of dry eye. One can imagine that misdirected stimulation of EALT can result in a misguided form of immune deviation at the ocular surface.

Within the scope of this event, apoptosis no longer hinders T-cell autoimmunity induction, completing the picture of dry eye.

It should be mentioned, however, that a recently published article has put our understanding of the functional significance of MALT in a different light. Alpan et al. (31) demonstrated that a systemic immune response to orally administered soluble antigens does not depend on the presence of functional MALT of the gastrointestinal tract, but more likely on initiation of immune response by gut-conditioned dendritic cells. This finding suggests that MALT is not necessary to initiate a primary immune response to antigens that have entered the body. However, if present it seems to act in two ways: (i) It produces plasma cell precursors which later migrate into the neighboring mucosa, mature to plasma cells, and produce sIgA for mucosal protection. (ii) It allows uptake of antigens by specialized epithelial cells and presentation of these antigens to virgin T and B cells to initiate a primary immune response. Thus, MALT could represent a second pathway (a kind of safeguard of the adaptive immune system) for initiation of an immune response to antigens that have been incorporated into the mucus layer and, in the case of CALT or TALT, have entered the ocular surface and are drained with tear fluid.

It can be concluded that the development of EALT is a common feature frequently occurring in symptomatically normal conjunctiva and nasolacrimal ducts. Whether special types of bacteria, viruses, or other factors, e.g., immune deviation, are responsible for the development of EALT in humans requires further investigation in prospective and experimental studies.

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