Insights gained from animal models of ocular autoimmunity

The questions outlined above are being studied in animal models of ocular autoimmunity (Table 1). The best studied is experimental autoimmune uveo-retinitis (EAU), which serves as a model for human posterior uveitic disease that is most likely to result in impairment of vision. EAU can be induced in various species of rodents and in primates by any of several defined retinal antigens injected in emulsion with complete Ereund's adjuvant (CFA). A number of uveitogenic proteins derived from the photoreceptor cell layer have been identified (Table 2). EAU is characterized by destruction of the photoreceptor cells of the retina, where the eliciting antigen(s) are located (Figure 1), and is usually accompanied by autoimmune inflammation of the pineal gland ('third eye'), which shares ocular-specific antigens with the retina.

A dictum which clearly emerges from studies in animal models is that mere exposure to an ocular antigen is insufficient to elicit ocular autoimmunity. Use of adjuvants is mandatory to elicit uveitis in experimental animals, and a concomitant microbial infection has been implicated in cases of SO in humans. Bacterial components and toxins are particularly efficient in promoting induction of EAU, possibly because of their effects in promoting a TH1 -type response to the uveitogen. Depending on the species, the adjuvant effect can be provided by mycobacterial components (CFA), and/or by products of gram-negative bacteria such as Bordetella pertussis toxin or Klebsiella pneumoniae capsular lipopolvsac-charide. Some studies indicate that microbial

Table 2 Uveitogenic photoreceptor-derived proteins

Protein

Biological function

Location

Retinal soluble antigen (S-Ag, arrestin) 48

Interphotoreceptor retinoid-binding protein 140 (IRBP)

Rhodopsin (and its illuminated form, opsin) 40

Recoverin 40

Phosducln 33

Phototransduction cascade Intracellular

Transport of vitamin A derivatives between the Extracellular photoreceptor and the retinal pigment epithelium

Rod visual pigment Intracellular

Calcium-binding protein Intracellular

Phosphoprotein Intracellular components may do more than simply provide an adjuvant effect. Sequence similarities have been found between a uveitopathogenic site of S-Ag, Escherichia coli protein and yeast histone C3. Moreover, rats immunized with synthetic peptides containing these microbial sequences develop typical EAU and demonstrate lymphocyte responses cross-reactive with the corresponding peptide sequence derived from S-Ag. These findings suggest that under some circumstances molecular mimicry might play a role in induction of ocular autoimmunity. In this context, of note are the reports that, in human anterior uveitis associated with rheumatoid disease and HLA-B27, a gram-negative bacterial infection precedes the onset of symptoms. A homology of six amino acids was found between HLA-B27 and K. pneumoniae nitrogenase, with antibodies against this residue being found in a high proportion of the patients.

A central role for T cells in human uveitis is indicated by the dramatic response of some of these diseases to the T cell targeting agent cyclosporine. The immunopathogenic mechanisms of EAU, as studied in both rats and mice, indicate a central involvement of T lymphocytes in this experimental disorder. Thus, EAU can be adoptively transferred with long-term T cell lines and clones, and is suppressed by therapy that targets T cells, including cyclosporine, monoclonal antibodies to T cell markers, and interleukin 2 (IL-2) receptor targeting therapy with monoclonal antibodies and chimeric toxins. A number of uveitogenic epitopes for rats and mice have now been elucidated, and research aimed at characterizing the T cell receptors of uveitogenic cells is under way. Analyses of the lymphokine profile of uveitogenic T cell lines and clones have uniformly indicated that the pathogenic lymphocyte produces high levels of the lymphokine interferon y (IFNy), or in some cases both IFNy and IL-4, characteristic of a THl-type or a TH0-type cell. In contrast, some types of protective responses (e.g. tolerance induced by oral administration of antigen) are characterized by a concomitant induction of IL-10, IL-4 and trans forming growth factor (3 (TGF(3), suggesting that the putative regulatory lymphocyte may be of the Tn2 phenotype. Thus, immunotherapy designed to direct an ongoing autoimmune response towards the T, ,2 differentiation pathway could potentially divert the response from a pathogenic to a nonpathogenic one. This basic research may eventually lead to the development of novel therapeutic strategies, targeting the specific lymphocytes and processes involved in ocular autoimmunity.

Similarly to human uveitis, EAU shows a strong genetic association. In the mouse EAU model, im-munogenetic studies done in congenic strains indicate that susceptibility is connected to the MHC haplotype, presumably due to recognition of the appropriate (pathogenic) epitopes. However, quantitative aspects of the disease are strongly modulated by background, non-MHC genes, whose effects can be sufficiently strong to render the bearer of a 'susceptible' MHC haplotype resistant to disease. The mechanisms for most of these genetic effects remain obscure, but at least one is connected to a propensity to mount a T| [1-dominated immune response. The susceptible genetic background in both rats (Lewis) and mice (C57/BL) is one that supports development of an IFNy-dominated response to the uveitogen, whereas resistant strains tend to mount an lFNy-low (but not necessarily an IL-4-high, i.e. T, ,2-dominated) response. Thus, while susceptibility may depend on a dominant TH1 response, it appears that resistance may be achieved through more than one regulatory pathway. It is unclear at this time whether these findings have a parallel in genetic susceptibility and resistance to ocular autoimmunity in humans.

Although a number of studies in the EAU model have indicated a role for regulatory (TH2-type?) cells in downregulation of disease, it is still an open question whether such regulatory cells exist before the onset of ocular autoimmunity and have a role in its prevention. It was believed in the past that because the immune system never comes in contact with ocular antigens, development of such active regulation is both unlikely and unnecessary. It is clcar

Figure 1 Histopathology of experimental and clinical uveitis. (A). Section through a healthy mouse eye. Note ordered structure of tissue layers and absence of inflammation. V: vitreous body; G: ganglion cell layer (cell bodies and nuclei); P: photoreceptor cell layer (nuclei and outer segments); rpe: retinal pigment epithelium; c: choroid; s: sclera, b: retinal blood vessel. (B). Section through a mouse eye with experimental autoimmune uveitis induced with IRBP. Note disrupted ocular architecture; cells and debris in the vitreous, vasculitis, retinal folds and retinal detachment, subretinal hemorrhage, subretinal granuloma, disrupted retinal pigment epithelium, infiltrated and thickened choroid. (C). Section through a human eye with uveitic disease. This patient has ocular sarcoid. Note similarity in histological appearance to experimental uveitis in the mouse.

Figure 1 Histopathology of experimental and clinical uveitis. (A). Section through a healthy mouse eye. Note ordered structure of tissue layers and absence of inflammation. V: vitreous body; G: ganglion cell layer (cell bodies and nuclei); P: photoreceptor cell layer (nuclei and outer segments); rpe: retinal pigment epithelium; c: choroid; s: sclera, b: retinal blood vessel. (B). Section through a mouse eye with experimental autoimmune uveitis induced with IRBP. Note disrupted ocular architecture; cells and debris in the vitreous, vasculitis, retinal folds and retinal detachment, subretinal hemorrhage, subretinal granuloma, disrupted retinal pigment epithelium, infiltrated and thickened choroid. (C). Section through a human eye with uveitic disease. This patient has ocular sarcoid. Note similarity in histological appearance to experimental uveitis in the mouse.

today that this view is no longer tenable. Recent work has shown that by using the sensitive PCR technique, messenger RNA for ocular antigens is detectable in the thymus. The proteins themselves, however, are not readily detectable by conventional laboratory techniques and it is not clear whether their level of expression (if indeed they are expressed) is sufficient to contribute to induction of tolerance. However, easily detectable ievels of uveitogenic proteins such as S-Ag and interphotoreceptor retinoid-binding protein (IRBP) are present in the pineal gland (third eye), which has no blood-organ barrier. Furthermore, numerous studies indicated that antigens placed in the anterior chamber of the eye (AC]) do reach and are recognized by the immune system. In some cases (depending on the antigen), a deviant form of immunity is elicited, appropriately known as anterior chamber-associated immune deviation (ACAID). ACA1D is characterized by suppressed delayed-type hypersensitivity responses, together with normal, or supernormal, induction of cytotoxic T lymphocytes and (noncomplcmcnt-binding) antibodies. Some researchers suggest that ocular antigens escaping from the AC into the circulation through the trabecular meshwork (facilitated by inflammation?) may naturally elicit an ACAID-like response, which would prevent, rather than promote, induction of uveitis. Under experimental conditions, ACAID induced to a uveitogenic retinal antigen can protect mice and rats from EAU induced by a subsequent immunization with the same antigen. It is unclear, however, whether a natural equivalent of this experimental phenomenon exists and plays a role in preventing ocular autoimmune disease.

Irrespective of the existence of putative systemic protective responses, the eye has several locally acting mechanisms that might help to curb autoimmune responses if and when the integrity of the blood-retinal barrier is breached. These mechanisms are also believed to contribute to ocular immune privilege. The ocular fluids contain immunosuppressive factors and cytokines, among them various neuropeptides and TGFß. More recently, high levels of Fas ligand were identified in ocular tissues. Lymphocytes infiltrating the AC underwent a Fas-mediated programmed cell death by apoptosis, and were prevented from causing tissue damage. In addition, ocular resident cells are able to suppress activation and clonal expansion of uveitogenic T cells through what is apparently a Fas-unrelated mechanism. For example, retinal glial cells (Müller cells) and ciliary body cells were shown to suppress activation and clonal expansion of uveitogenic T lymphocytes in an in vitro system derived from the rat EAU model, and chemical depletion of retinal Miiller cells caused a normally EAU-resistant rat strain to develop disease. Interestingly, the potent lymphocyte inhibitory function of these ocular resident cells was found to mask an underlying capacity to act as antigen-presenting cells. It is an intriguing notion that locally acting suppression mechanisms of this type might have evolved to prevent organ-resident cells, with the potential to present autoantigens, from initiating and perpetuating autoimmunity.

In summary, currently available evidence points to the notion that central mechanisms involving the thymus may have a limited role in maintaining a state of functional tolerance to ocular antigens. That ocular autoimmunity is the exception, rather than the rule, may be attributable to the effectiveness of the blood-ocular barrier and the various local and peripheral immunosuppressive mechanisms in curtailing immunologic processes that would lead to ocular autoimmune disease.

See also: Adjuvants; Autoimmune diseases; Autoimmunity; Eye infections; Privileged sites.

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