In Immune Mediated Dry Eye Disease

The starting point of immune mediated inflammation in the conjunctiva, similar to events in the lacrimal gland in Sjogren's syndrome, may lie in an alteration of the epithelial cells. In the case of the conjunctiva, this is caused by destructions that are observed in all kinds of dry eye due to mechanical abrasion via increased

Fig. 6.6. Common mechanisms in immune mediated dry eye disease. Different types of dry eye disease share an immune modulated inflammatory process that can similarly occur in the lacrimal gland (e.g. in Sjogren's syndrome) and at the ocular surface. It appears to start from epithelial defects resulting in a loss of immunological tolerance. Epithelial cells produce inflammatory cytokines (e.g. TNF-a, IL-i, IL-6, IFN-g), upregulate MHC class II and co-stimulatory molecules on their surface and allow uncontrolled antigen (AG) influx through defects. Together this leads to an uncontrolled activation of normal resident mucosal T cells into the inflammatory Thi type that also pro-

duces inflammatory cytokines and hence amplifies the inflammatory cytokine milieu in the tissue. Further events include an impairment of innervation with a decrease of glandular secretion, and an activation of matrix metalloproteinases that results in a degenerative remodelling of the tissue with loss of function (e.g. destruction of secretory acini in the lacrimal gland or squamous metaplasia in the conjunctiva) and the risk of further epithelial defects. The events involved here can hence result in a vicious circle of tissue destruction (solid arrows indicate production of molecules; interrupted arrows indicate action of molecules or movement of cells)

Fig. 6.6. Common mechanisms in immune mediated dry eye disease. Different types of dry eye disease share an immune modulated inflammatory process that can similarly occur in the lacrimal gland (e.g. in Sjogren's syndrome) and at the ocular surface. It appears to start from epithelial defects resulting in a loss of immunological tolerance. Epithelial cells produce inflammatory cytokines (e.g. TNF-a, IL-i, IL-6, IFN-g), upregulate MHC class II and co-stimulatory molecules on their surface and allow uncontrolled antigen (AG) influx through defects. Together this leads to an uncontrolled activation of normal resident mucosal T cells into the inflammatory Thi type that also pro-

duces inflammatory cytokines and hence amplifies the inflammatory cytokine milieu in the tissue. Further events include an impairment of innervation with a decrease of glandular secretion, and an activation of matrix metalloproteinases that results in a degenerative remodelling of the tissue with loss of function (e.g. destruction of secretory acini in the lacrimal gland or squamous metaplasia in the conjunctiva) and the risk of further epithelial defects. The events involved here can hence result in a vicious circle of tissue destruction (solid arrows indicate production of molecules; interrupted arrows indicate action of molecules or movement of cells)

friction of the eyelids on the ocular surface (Fig. 6.6). In addition, cell damage can also be caused by hyperosmolarity of the tear film [14]. In the case of the lacrimal gland, epithelial alterations may arise after viral infection [52].

If alteration of the epithelial barrier occurs due to such damage, antigens can achieve uncontrolled access to the tissue, which may be the dominating effect in the conjunctiva; or epithelial cells gain the ability to present autoantigens as observed in the lacrimal gland. In both affections the mucosal immune tolerance is likely to fail. Resident T-helper cells of the physiological mucosal immune system in the subepithelial connective tissue can then be activated and im-munological reactions shifted towards inflam mation [59], resulting in the further elevation of proinflammatory cytokines. Additional new T-cell can immigrated via an upregulation of adhesion molecule on the vascular endothelium. Similar events have been shown in inflammatory bowel disease (IBD) [34], which represents an inflammatory mucosal condition of the intestine where a large body of information is already acquired. At the ocular surface, the production of these cytokines is as yet mainly attributed to the epithelial cells. This may be due to the fact that the presence of a resident population of lymphocytes and plasma cells constituting a physiologic mucosal immune system at the normal ocular surface (EALT) was unknown until recently because lymphoid cells in general were erroneously believed to be "inflammatory". However, in the intestine where the presence of a physiologic mucosal immune system has been accepted for a longer time, it has been verified that TNFa and IL-1P are also secreted by activated lamina propria lymphocytes promoting an inflammatory reaction and resulting in the production of matrix metalloproteinases by stromal cells [34]. A shift of the cytokine profile towards a TH-1 response has been reported in several inflammatory ocular surface diseases, as similarly found in IBD, and both disorders are reported to respond to immunosuppressive treatment.

Novel Therapeutic Approaches to Dry Eye Disease

Combining these results, it can be noted that the widespread dry eye syndrome is increasingly being recognized to include an inflammatory component [47,59] and it thus resembles disorders in other mucosal organs which are governed by lymphocytes of the mucosal immune system [34]. Hence, the resident lymphatic population localized in the eye-associated lym-phoid tissue of the ocular surface (EALT), which represents a potent source of professional cyto-kine producing cells, may also act as an important regulator of inflammatory ocular surface disease. Consequently the activation of T cells, which can be inhibited by different immuno-suppressive strategies, is an interesting target for new therapeutic approaches [47].

Some compounds that interfere with the process of lymphocyte activation (Fig. 6.4), and hence act more specifically than for example glucocorticoids, are known from immunosup-pression after transplantation of solid organs where they are administered systemically. An important step in lymphocyte activation is the production of IL-2 in T cells that is necessary for full activation. Cyclosporin A (CsA), like another agent (tacrolimus also known as FK506), prevents the transcription of the IL-2 gene by binding to the transcription factor calcineurin. Another compound, rapamycin, acts later in the activation cascade and blocks IL-2 peptide after production in the lymphocytes. Therefore CsA or FK506 can act synergistically in combination with rapamycin.

In inflammatory ocular surface disease, topical administration of immunosuppressive drugs has been attempted in order to achieve a high local concentration and to avoid systemic side effects. CsA has been the focus of interest in recent years. A CsA ophthalmic oil-in-water emulsion that was previously only available for veterinary use is now also approved for human therapy and has been tested in multicentre studies. It proved to be significantly better than placebo in reducing objective findings (corneal staining, Schirmer's test) and subjective symptoms when it was applied twice daily over a period of 3-6 months, with the best results at a concentration of 0.05% CsA [54].

Other approaches successfully improved the underlying androgen deficiency, which increases susceptibility to ocular inflammation and negatively affects the secretion of ocular glands, with topical androgen therapy in animal [60] and human trials [65].

Summary for the Clinician

• Different types of dry eye disease all contain an underlying immune modulated inflammatory component that is mediated by a deregulation of the physiological and normally protective mucosal immune system

• New causative topical treatment options are now available for a therapeutic approach to the immune mediated inflammation in moderate to severe dry eye disease

• Immunosuppression with CsA 0.05-0.1% eyedrops, given twice daily for several months, is an effective treatment as tested in multicentre studies

• Topical androgen acts as a trophic and anti-inflammatory factor and normalizes glandular function. It was successfully used in animal models and tested in a case report on a human patient

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