Barbara Detrick

Expression of Ia antigen on retinal pigment epithelium in experimental autoimmune uveoretinitis

Recently, human retinal pigment epithelial (RPE) cells have been demonstrated to express class II, HLA-DR, antigens both in vivo and in vitro. HLA-DR antigens were detected on RPE cells from patients with uveitis and retinitis pigmentosa. In addition, in vitro studies revealed that not only does this cell express HLA-DR antigen but also that this antigen can be modulated by the lymphokine, interferon (IFN)-gamma. In this study we evaluated the development of the murine class II, Ia, antigens on RPE cells in experimental autoimmune uveoretinitis (EAU). Ia antigen was evaluated with the avidin-biotin-peroxidase technique. Ia antigen was not detected on RPE cells from normal rats. However, Ia antigen was detected on the surface of RPE cells from EAU rats four days prior to the development of clinical and histopathological EAU. Moreover, the expression of Ia antigen on RPE cells from EAU rats continued to persist until one and one-half months after immunization. This study demonstrates that during the course of EAU the RPE cell is activated to express Ia antigens. This antigen expression may be important in the initiation and/or perpetuation of immune reactivity in the eye.

Expression of HLA-DR Antigen on Retinal Pigment Epithelial Cells in Retinitis Pigmentosa

Class II (HLA-DR) antigens are cell surface molecules that play a major role in the initiation and perpetuation of immune responses. Although most cells do not constitutively express class II antigens, selected cells can be stimulated to do so in some immunologically mediated disorders. When retinal pigment epithelial cells were evaluated by either immunoperoxidase or immunofluorescent staining of frozen eye sections from normal individuals, HLA-DR antigens were not detected. In contrast, retinal pigment epithelial cells from two patients with retinitis pigmentosa did express HLA-DR antigens. These findings demonstrated that at some time during the course of retinitis pigmentosa, the retinal pigment epithelial cell is activated to express HLA-DR.

Retinal vascular endothelium expresses fibronectin and class II histocompatibility complex antigens in experimental autoimmune uveitis.

To analyze the role of the retinal vascular endothelial cells in the development of experimental autoimmune uveitis (EAU), we studied the presence of Ia antigen and FN in retinal vessels of Lewis rats immunized with retinal S antigen. Immunopathologic studies were performed on frozen tissues obtained during various stages of the disease. Our results show that Ia antigen was not present in the normal rat retina, and there was very little FN present in a few retinal vessels. One to two days prior to the histologic and clinical onset of EAU, FN was found to be increased in the retinal vessels. Ia antigen was found to be present in the retinal vessels coincident with the first signs of cellular infiltration. During the stage of maximal cellular infiltration, FN was present diffusely throughout the retina, as well as in the subretinal space, and Ia antigen was found diffusely in the cellular infiltrate. Therefore, FN and Ia antigen reflect the immunomodulation of vascular endothelial cells in EAU, which may be very important in the pathogenesis of retinal S antigen-induced uveitis. Two possible mechanisms for the role of the activation of the retinal vascular endothelium in the development of retinal inflammation in uveitis are discussed.

Evaluation of la expression in rat ocular tissues following inoculation with interferon-gamma

It is becoming increasingly clear that IFN-gamma is a potent immunoregulatory protein which influences MHC class II (Ia) antigen expression and cellular functions of B cells, T cells, NK cells and macrophages. During the past 5 yr our laboratory has provided evidence that IFN-gamma modulates class II antigens on retinal cells (retinal pigment epithelial cells, endothelial cells) and is localized within the eye during human inflammatory conditions. In this study we evaluate the direct effect of IFN-gamma on ocular tissue. Lewis rats were inoculated intravitreally or under the retina with either recombinant IFN-gamma (20,000 U) or saline. At 2 hr, 1, 2 and 6 days postinoculation, the eyes were removed and frozen sections were evaluated by immunocytochemical staining with monoclonal anti-Ia antibodies and an irrelevant monoclonal anti-T cell antibody. Saline treated tissue and tissue removed 2 hr after IFN-gamma inoculation showed no significant staining for Ia antigens. However, eyes evaluated 24 hr after IFN-gamma inoculation revealed Ia expression on a variety of ocular cells localized in the conjunctiva and anterior segment, such as conjunctival epithelium, keratocytes, iris epithelium, ciliary epithelium and choroidal cells. In the retina, retinal pigment epithelial (RPE) cells were Ia positive only when IFN-gamma was injected directly under the retina. In conjunction with Ia expression, two striking changes were noted. An iritis was seen and infiltrating cells were detected in the inner retinal layers. Both of these phenomena have been observed in certain inflammatory eye diseases. These studies clearly substantiate the concept that IFN-gamma can regulate class II antigens in the eye and thus may perpetuate immune reactivity in this site.

Retinopathies Associated with Antiretinal Antibodies

The identification of autoantibodies during the course of a disease has been shown to be useful in making a diagnosis, understanding mechanisms of pathogenesis, identifying therapeutic strategies, and monitoring treatments. Numerous examples of the utility of autoantibody detection are seen in both

Anti-la antibody diminishes ocular inflammation in experimental autoimmune uveitis

An experimental model of inflammatory eye disease, experimental autoimmmune uveitis (EAU), was established by injecting rats in the footpad with S-antigen in complete Freunds adjuvant. This model system was used to evaluate the role of major histocompatibility complex (MHC) class II antigens (la) in the pathogenesis of this T cell mediated disease. One day prior to S-antigen priming, rats were injected with either anti-la antibodies or with mouse ascites. Clinical and histopathological analysis of eyes from rats treated with anti-la antibody showed less ocular inflammation as well as a delay in onset of EAU when compared to controls (p=0.01). Furthermore, immunocytochemical evaluation demonstrated that tissue obtained from animals receiving anti-la therapy also expressed less la antigen, as well as a diminution in the number of infiltrating macrophages and lymphocytes. These data show that anti-la treatment significantly modifies the course of EAU in the rat. In addition, this study suggests that MHC cla...

Experimental coronavirus retinopathy (ECOR): Retinal degeneration susceptible mice have an augmented interferon and chemokine (CXCL9, CXCL10) response early after virus infection

Abstract Mouse hepatitis virus induces a biphasic disease in BALB/c mice that consists of an acute retinitis followed by progression to a chronic retinal degeneration with autoimmune reactivity. Retinal degeneration resistant CD-1 mice do not develop the late phase. What host factors contribute to the distinct responses to the virus are unknown. Herein, we show that IFN-α, IFN-β and IFN-γ act in concert as part of the innate immune response to the retinal infection. At day 2, high serum levels of IFN-γ, CXCL9 and CXCL10, were detected in BALB/c mice. Moreover, elevated levels of CXCL9 and CXCL10 gene expression were detected in retinal tissue. Although IFN-γ and the chemokines were detected in CD-1 mice, they were at significantly lower levels compared to BALB/c mice. These augmented innate responses observed correlated with the development of autoimmune reactivity and retinal degeneration and thus may contribute to the pathogenic processes.

Retinopathy following intravitreal injection of mice with MHV strain JHM.

The causes of many human degenerative and inflammatory diseases of the retina are unknown. Some are genetic in origin; others are preceded by viral infections (Ryan and Maumenee, 1972; Annesley et al., 1973; Fitzpatrick and Robertson, 1973; Bos and Deutman, 1975; Wright et al., 1978). These diseases are difficult to study since eye tissue from patients is rarely available. Thus, animal models are considered useful for understanding their pathogenesis.

Chapter 57 – Infections Associated with Retinal Autoimmunity

Abstract Autoimmune reactivity and autoimmune disease in the eye is a rapidly expanding area of research and therapy. We present evidence implicating three distinct classes of infectious agents in the development of an autoimmune process within the retina. We highlight two human diseases triggered by Onchocerca volvulus or Toxoplasma gondii and an experimental model of retinal degenerative disease, referred to as experimental coronavirus retinopathy (ECOR). Analysis of these systems revealed distinct pathogenic mechanisms involved in the induction of autoimmunity triggered by each organism. In T. gondii infections, the chronic reactivation is probably responsible for the presentation of sequestered retinal epitopes of the immune system. In O. volvulus infections, molecular mimicry between the organism and the human RPE protein may contribute to retinal pathology. In ECOR, differences in time of induction, duration, and intensity of innate immune reactivity may contribute to autoimmune reactivity in BALB/c mice.