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Age-related macular degeneration (AMD) is a leading causes for vision loss in industrialized countries. Different types of translational research indicate that chronic inflammation drives the disease in the outer retina affecting photoreceptors, retinal pigment epithelium (RPE) and the choroid. Along with this, genetic analysis identified genes of components of the complement system with risk association for AMD. Polymorphisms in the complement gene C9, which’s gene product is part of the terminal complement complex (TCC), showed risk association and functional changes of TCC in the serum of AMD patients. TCC might reduce the viability of RPE cells with subsequent loss of photoreceptor cells and loss of vision as membrane attack complex. Therefore, we compared the TCC levels in AMD patients with aged-matched controls and found in general in AMD patients increased serum TCC levels. However, these levels did not differ among patients that carry the risk haplotypes for the complement factor CFH or ARMS2. Exposing RPE cells to patients’ sera changed the immunogenic phenotype towards a pro-inflammatory profile in gene expression and secretion instead of inducing cell death. Thus, our study implies a more general role of TCC in AMD and closes the gap between systemic changes and local inflammation.

To describe the pathogenesis and the general immune mechanisms of the most frequent causes of bacterial uveitis.Narrative review.Both extra- and intracellular bacteria can induce uveitis, whereas intracellular bacteria are generally transported into the inner eye via cells of the innate immune system, mainly macrophages. Systemic adaptive immunity is usually induced before the bacteria are localized to the inner eye, and once T and B cells have detected the pathogens behind the blood-eye barriers they elicit an acute and/or chronic inflammatory response deteriorating visual acuity that can severely affect the non-regenerating, intraocular tissues.An understanding of pathogenic mechanisms, and its correlation with clinical and imaging features, can facilitate early recognition of microbial factors and institution of appropriate therapy.

PURPOSE: The long-term effect of low and moderate doses of ionizing radiation on the lens is still a matter of debate and needs to be evaluated in more detail. MATERIAL AND METHODS: We conducted a detailed histological analysis of eyes from B6C3F1 mice cohorts after acute gamma irradiation (60Co source; 0.063 Gy/min) at young adult age of 10 weeks with doses of 0.063, 0.125 and 0.5 Gy. Sham irradiated (0 Gy) mice were used as controls. To test for genetic susceptibility heterozygous Ercc2 mutant mice were used and compared to wild type mice of the same strain background. Mice of both sexes were included in all cohorts. Eyes were collected 4 hours, 12, 18 and 24 months after irradiation. For a better understanding of the underlying mechanisms, metabolomics analyses were performed in lenses and plasma samples of the same mouse cohorts at 4 and 12 hours as well as 12, 18 and 24 months after irradiation. For this purpose, a targeted analysis was chosen. RESULTS: This analysis revealed histological changes particularly in the posterior part of the lens that rarely can be observed by using Scheimpflug imaging, as we reported previously. We detected a significant increase of posterior subcapsular cataracts 18 and 24 months after irradiation with 0.5 Gy (odds ratio 9.3; 95%-confidence interval 2.1 - 41.3) independent of sex and genotype. Doses below 0.5 Gy (i.e. 0.063 and 0.125 Gy) did not significantly increase the frequency of posterior subcapsular cataracts at any time point. In lenses, we observed a clear effect of sex and aging but not of irradiation or genotype. While metabolomics analyses of plasma from the same mice showed only a sex effect. CONCLUSIONS: This paper demonstrates a significant radiation-induced increase in the incidence of posterior subcapsular cataracts, which could not be identified using Scheimpflug imaging as the only diagnostic tool.

Purpose: New tumor therapies like immune checkpoint inhibitors and small molecule inhibitors of MEK and BRAF have increased the patient's survival rate but can be burdened with severe side-effects including uveitis. Here, we show the spectrum, treatment, and outcome of uveitis types induced by tumor treatment.Methods: In this retrospective study, we have included 54 patients from different centers who were developing uveitis under tumor therapy. A 16-item questionnaire was analyzed for type, treatment, and outcome of uveitis and type of tumor treatment, which we have correlated here.Results: Irrespective of the tumor treatment, most patients developed anterior uveitis. All patients received corticosteroids and some additional immunosuppressive treatments. Cessation of tumor therapy was necessary only in a minority of cases.Conclusions: Ocular autoimmunity should be differentiated from toxic effects of cancer treatment and timely recognized since it can be generally well controlled by anti-inflammatory treatment, preserving the patient's vision without cessation of the tumor treatment.

Autoimmune uveitis is a sight-threatening, rare disease, potentially leading to blindness. Uveitis is a synonym for intraocular inflammation, presenting as various clinical phenotypes with different underlying immune responses in patients, whereas different animal models usually represent one certain clinical and immunological type of uveitis due to genetic uniformity and the method of disease induction. T cells recognizing intraocular antigens initiate the disease, recruiting inflammatory cells (granulocytes, monocytes/macrophages) to the eyes, which cause the damage of the tissue. The treatment of uveitis so far aims at downregulation of inflammation to protect the ocular tissues from damage, and at immunosuppression to stop fueling T cell reactivity. Uveitis is usually prevented by specific mechanisms of the ocular immune privilege and the blood-eye-barriers, but once the disease is induced, mechanisms of the immune privilege as well as a variety of novel regulatory features including new Treg cell populations and suppressive cytokines are induced to downregulate the ocular inflammation and T cell responses and to avoid relapses and chronicity. Here we describe mechanisms of regulation observed in experimental animal models as well as detected in studies with peripheral lymphocytes from patients.

In contrast to rats, mouse models are nowadays generally used for the investigation of immune responses and immune-mediated diseases, there are many different strains and mouse-specific tools available, and it is easy to generate transgenic and constitutive or inducible knockout mice for any gene. Many immune markers and mechanisms have been detected in mice and have been introduced as gold standard in immunology, however, some turned out to be not unconditionally transferable to the human immune system. Rats have been used more frequently in former days but are mostly outstripped by mice due to the fact that fewer strains are available, they need more space than mice, are more expensive to maintain and breed, and it is extremely difficult to generate transgenic or ko-rats. Consequently, the choice of rat-specific diagnostic tools like antibodies is quite poor and most researchers have switched to mouse models for the investigation of immune mechanisms, while rats are still widely used for toxicology by the pharmaceutical industry. However, it should be taken into consideration that there are some immunological similarities between rats and humans that are not presented in mice. Some of them like MHC class II and Foxp3 expression by activated effector T cells we have detected during our research on the immune response of rat models of experimental autoimmune uveitis.

There is increasing evidence from animal and human studies that glaucoma is an autoimmune disease. Evidence for this hypothesis includes the fact that antibodies as well as T‐cell responses to heat‐shock proteins (HSPs) are detectable in some patients with glaucoma and in an animal model of the disease. As in the human disease, experimental animal models of glaucoma have been found to demonstrate neurodegenerative changes in the optic nerve associated with immunoglobulin and T‐cell infiltration. Although there is still insufficient evidence in humans to classify all cases of glaucoma as autoimmune diseases, the implications of this hypothesis have major impact on the diagnosis and treatment of glaucoma., In this paper, we discuss the concept that glaucoma is an autoimmune disease and review emerging evidence for this concept. There is increasing experimental data that some types of normal‐pressure glaucoma may involve immune mechanisms directed at self‐antigens, such as HSP, but proof of the concept that glaucoma is an autoimmune disease remains to be conclusively demonstrated.

Antigenic mimicry is the immunological similarity of different antigens (proteins) from different origins, allowing cells of the immune system (here: T cells) to crossreact with all of them. Here we show examples how T cells are confused with peptides from a virus causing gastroenteritis, milk protein and an autoantigen from the eye, which can all induce uveitis, a destructive, potentially blinding autoimmune disease.

The eye as an immune privileged organ is mostly spared from (auto)immune attacks. Intraocular inflammation like autoimmune uveitis is a rare event. Nevertheless, tumor-related destructive autoimmune responses can affect the eye, as observed in the case of cancer- associated retinopathy (CAR), an autoantibody-mediated destruction of retinal cells induced by the ectopic expression of ocular antigens by peripheral tumors. The new tumor therapies targeting immune checkpoints to enhance anti-tumor responses can also induce autoimmune responses and result in autoimmune diseases even in immune privileged organs like the eyes. Even MEK/BRAF-inhibitor therapies using small molecules to block tumor-specific signal transduction molecules have turned out to not just inhibit tumor growth and survival and render tumors more susceptible for immune recognition, but to have additional toxic effects on non-dividing retinal cells, destroying and making them potential targets of autoimmunity.

Purpose: To explore the unmet needs in the management of patients with severe inflammatory eye disease (IED), future directions for research and therapy, and to develop and facilitate access and delivery of better medical care to patients with severe IED.Methods: The unmet needs and future directions in inflammatory eye disease were identified and discussed by experts in relevant disciplines at a recent international conference.Results: A total of 14 major unmet needs were identified and discussed by experts in the areas of ophthalmology, rheumatology, infectious disease, and internal medicine, at an international conference. The major areas discussed are summarized in this review.Conclusions: Identification of unmet needs in IED is seen as a first step in implementing changes in the way we diagnose and treat patients with these sight-threatening IEDs.

The pro-inflammatory chemokine interleukin-8 (CXCL8) exerts its function by establishing a chemotactic gradient in infected or damaged tissues to guide neutrophil granulocytes to the site of inflammation via its G protein-coupled receptors (GPCRs) CXCR1 and CXCR2 located on neutrophils. Endothelial glycosaminoglycans (GAGs) have been proposed to support the chemotactic gradient formation and thus the inflammatory response by presenting the chemokine to approaching leukocytes. In this study, we show that neutrophil transmigration in vitro can be reduced by adding soluble GAGs and that this process is specific with respect to the nature of the glycan. To further investigate the GAG influence on neutrophil migration, we have used an engineered CXCL8 mutant protein (termed PA401) which exhibits a much higher affinity towards GAGs and an impaired GPCR activity. This dominant-negative mutant chemokine showed anti-inflammatory activity in various animal models of neutrophil-driven inflammation, i.e. in urinary tract infection, bleomycin-induced lung fibrosis, and experimental autoimmune uveitis. In all cases, treatment with PA401 resulted in a strong reduction of transmigrated inflammatory cells which became evident from histology sections and bronchoalveolar lavage. Since our CXCL8-based decoy targets GAGs and not GPCRs, our results show for the first time the crucial involvement of this glycan class in CXCL8/neutrophil-mediated inflammation and will thus pave the way to novel approaches of anti-inflammatory treatment.

Autoimmune diseases usually follow a relapsing-remitting or a chronic progressive course. To understand the underlying immunopathogenesis we investigated experimental Lewis rat models displaying both disease types, which were only dependent on the autoantigen peptide used for immunization. Retinal S-Antigen-peptide PDSAg induces chronic, monophasic disease, whilst interphotoreceptor retinoid-binding protein (IRBP)-peptide R14 causes a spontaneously relapsing-remitting course. R14-mediated uveitis can be re-induced by immunization; PDSAg-induced disease is even preventable by prior CFA-injection. T cells with different antigen specificities preferentially infiltrate the eyes from different sites, e.g. choroid or retinal vessels, they remain in the retina after resolution of inflammation for many weeks. The major inflammatory cell populations in the eyes during rat uveitis are CD4+ or CD8+ monocytes/macrophages. Chemokine mutants only suppress PDSAg-mediated EAU, while IFN-α-treatment ameliorated R14-, but worsened PDSAg-induced disease. Comparison of T cells revealed upregulated expression of 26 genes related to various signal transduction pathways upstream and downstream of IFN-γ only in T cells causing relapsing EAU. Intraocular injection of IFN-γ induces synchronized relapses in R14-mediated uveitis, while VEGF-expression of PDSAg-specific T cells causing chronic disease induced chorioretinal neovascularization that is suppressed by anti-CD146 antibody. Intraocular T cells from rat eyes during EAU express IL-17, IFN-γ or IL-10, with dynamic changes of the cell populations during the disease course, differing in both disease types. Immunization of animals with a mixture of both antigens suppressed relapses, indicating a dominance of the monophasic disease. Understanding the exact pathogenesis of both disease courses is key to developing novel therapies for autoimmune diseases.

Antigen-specific tolerance induction is a desired therapy for uveitis patients. Our relapsing–remitting rat model of experimental autoimmune uveitis (EAU) induced with IRBP peptide R14 enables us to test the effect of oral tolerance on the prevention of relapsing uveitis. We investigated several peptides overlapping the sequence of R14 for prevention and different doses of R14 for therapy to determine the tolerogenic epitope and the most effective therapeutic regimen for uveitis. Lewis rats were immunized with R14-CFA to induce EAU. Oral tolerance was induced prior to immunization (prevention) or after onset of EAU to prevent relapses (therapy). Therapeutic feeding was performed with high and/or low doses of oral antigen for clonal deletion of effector and induction of regulatory T cells. Uveitis was determined clinically and histologically; mesenteric lymph node (mLN) cells of tolerized rats were tested for surface markers, cytokines and Foxp3 expression. Preventive feeding of R14 and its major epitope R16, but none of the overlapping peptides significantly suppressed EAU and also prevented relapses, irrespective of their pathogenicity. Therapeutic feeding with R14 dramatically reduced relapses, while only the consecutive feeding of high and low-dose R14 had an ameliorating effect on the first course of disease. IL-10-producing T cells from mLN decreased after oral tolerization, and with R14-stimulation in vitro the TCRαβ+/Foxp3+ population increased in the low-dose fed group. No mLN population could be clearly assigned to successful oral tolerance induction during active autoimmune uveitis.

Purpose We investigated the effect of PP-001, a new small molecule inhibitor of dihydro-orotate dehydrogenase in two experimental rat experimental autoimmune uveitis (EAU) models: a spontaneously relapsing-remitting model and a monophasic/chronic disease model that results in late chorioretinal neovascularization. Both of the diseases are induced by immunization with autoantigen peptides. Methods Prevention was tested using daily oral applications of PP-001 after immunization with the retinal S-antigen peptide PDSAg (for induction of monophasic uveitis and neovascularization) or the interphotoreceptor retinoid-binding protein peptide R14 (for induction of spontaneously relapsing-remitting EAU). Treatment to inhibit relapses and neovascularization was tested using PP-001 daily after the first attack of R14-induced or after onset of PDSAg-induced EAU. Uveitis was graded clinically and histologically. The effect of PP-001 on cytokine secretion and proliferation was evaluated using rat T-cell lines. Results Preventive feeding of PP-001 abrogated both types of EAU. Starting treatment after the resolution of the first attack led to a significant reduction of the number and intensity of relapses in R14-induced EAU. PP-001-treatment initiated after onset or after peak of PDSAg-induced EAU significantly reduced neovascularization (as determined by histology). Proliferation of antigen-specific T-cell lines and secretion of IFN-γ, IL-17, IL-10, IP-10, and VEGF were efficiently suppressed by PP-001. Conclusions We investigated a new dihydroorotate dehydrogenase inhibitor as treatment for primary and recurrent disease in relapsing-remitting and chronic rat models of experimental autoimmune uveitis. The small molecule compound PP-001 suppressed proliferation and cytokine secretion of autoreactive T cells (i.e., IFN-g, IL-17, and VEGF) and chorioretinal neovascularization in chronic EAU.

IFN-α is the only treatment capable of inducing long-term remission in some patients with ocular Behçet's disease. In this review, we focus on immune mechanisms of IFN-α in animal models and patients and compare the outcome of different clinical studies.Review of literature using PubMed and Google and original data from rat models with monophasic/chronic or relapsing experimental autoimmune uveitis treated with IFN-α.The role of IFN-α and its effect on various cell types were investigated, in some cases with contradictory results. Some patients respond very well to IFN-α treatment, while others are non-responders, which was reflected in the uveitis rat models: relapsing uveitis was ameliorated, the monophasic/chronic disease even aggravated.Despite intensive investigations in patients and animal models, the immune mechanisms explaining the therapeutic effect of IFN-α in ocular Behçet's disease are not yet fully understood and need further investigation.

Aim To outline recommendations from an expert committee on the assessment and investigation of patients with severe inflammatory eye disease commencing immunosuppressive and/or biologic therapy. Method The approach to assessment is based on the clinical experience of an expert committee and a review of the literature with regard to corticosteroids, immunosuppressive drug and biologic therapy and other adjunct therapy in the management of patients with severe sight-threatening inflammatory eye disease. Conclusion We recommend a careful assessment and consultative approach by ophthalmologists or physicians experienced in the use of immunosuppressive agents for all patients commencing immunosuppressive and/or biologic therapy for sight threatening inflammatory eye disease with the aim of preventing infection, cardiovascular, metabolic and bone disease and reducing iatrogenic side effects.

Most human autoimmune diseases have a relapsing-remitting or a chronic progressive course, while animal models are usually acute and monophasic. In our experimental animal model the disease can be either monophasic or remitting, depending on the autoantigen used for induction, and it appears to lie in the effector phenotype of the elicited T helper cell response. Since both, monophasic and relapsing courses of disease are induced by immunization as well as by adoptive transfer of peptide-specific, CD4(+) T cells, we were able to directly compare the transcriptomes of pathogenic T cell lines by gene array analysis and qPCR as well as protein expression. Upregulated genes were only determined in T cells inducing relapsing uveitis and belong to certain pathways of antigen presentation, activation, inflammation, migration and survival, comprising WNT, Hedgehog, MAP-kinase and JAK/STAT-pathways. These pathways are partially interacting with each other, and the central molecule upregulated in T cells causing relapsing disease was found to be IFN-γ. Here the course of the autoimmune diseases strictly depends on the characteristics of the autoreactive T cells, which are already determined at their early stage of antigen-specific activation. Our rat models of experimental autoimmune uveitis could help elucidating the immune mechanisms behind relapsing autoimmunity in order to develop better therapeutic strategies.

Scleritis is a heterogeneous group of diseases characterized by inflammation of the sclera, which may be due to local or systemic infections or immune mediated diseases. Numerous studies over the last decade have lead to significant progress in understanding the pathogenesis and treatment of this severe and potentially blinding disease. Immunological investigations of non-infectious scleritis and associated diseases have indicated that scleritis is an autoimmune disease and studies on the nature of the local inflammatory response have revealed the prominent role of T and B cells and cytokines, such as TNF-alpha, which in turn has resulted in clinical trials showing the effectiveness of local steroid treatment, anti-TNF and anti-B cell therapy. The widespread use of imaging has led to the realization that posterior scleritis is more common than previously recognized and testing for ANCA antibodies has revealed the prominent role of immune mechanisms in a subset of patients with scleritis and associated systemic vasculitis.

Understanding the immunopathogenesis of autoimmune and inflammatory diseases is a prerequisite for specific and effective therapeutical intervention. This review focuses on animal models of two common ocular inflammatory diseases, dry eye disease (DED), affecting the ocular surface, and uveitis with inflammation of the inner eye. In both diseases autoimmunity plays an important role, in idiopathic uveitis immune reactivity to intraocular autoantigens is pivotal, while in dry eye disease autoimmunity seems to play a role in one subtype of disease, Sjogren' syndrome (SjS). Comparing the immune mechanisms underlying both eye diseases reveals similarities, and significant differences. Studies have shown genetic predispositions, T and B cell involvement, cytokine and chemokine signatures and signaling pathways as well as environmental influences in both DED and uveitis. Uveitis and DED are heterogeneous diseases and there is no single animal model, which adequately represents both diseases. However, there is evidence to suggest that certain T cell-targeting therapies can be used to treat both, dry eye disease and uveitis. Animal models are essential to autoimmunity research, from the basic understanding of immune mechanisms to the pre-clinical testing of potential new therapies.

Autoimmune diseases often show a relapsing-remitting course. Here we describe characteristics of the autoreactive T cell response in the Lewis rat model of experimental autoimmune uveitis (EAU), a model for the clinical heterogeneity seen in human uveitis. Depending on the autoantigen used, the experimental disease course can be either monophasic or relapsing/remitting. This appears to be dictated by subtle differences in the T cell effector phenotype elicited. Using transcriptomic profiling and pathway analysis, the molecular basis for the monophasic vs. relapsing/remitting effector T cell phenotype was investigated. CD4+ T cell lines specific for peptide R14 derived from interphotoreceptor retinoid-binding protein (IRBP), which mediate the relapsing disease, were compared to the monophasic disease-inducing lines responding to retinal S-antigen peptide PDSAg. Expression profiles from T cell lines representing each specificity were analyzed using Affymetrix microarrays. Differential gene expression was confirmed and extended by quantitative PCR and verified on the protein level. A set of genes was uniquely upregulated in the R14-specific T cells. Gene ontology analysis demonstrated that these genes were linked to regulatory pathways associated with antigen presentation, lymphocyte activation, regulation of apoptosis and WNT/Hedgehog signaling. R14-specific T cells were further demonstrated to have prolonged survival in vivo, and a Th1-dominated cytokine profile, while the PDSAg-specific T cells lines were more Th17-prone. Our findings suggest that the nature of specific antigens leads to subtle programming of the effector phenotype underlying recurrent inflammation.

The biology of chemokines and their receptors have been linked to the development of chronic allograft damage. Effects of CCR1 antagonist BX 471 were studied in a Fischer to Lewis renal transplantation model at days 10, 21 and 42 after transplantation. BX 471 treatment did not effectively reduce signs of acute rejection at day 10 but significantly improved allograft function and morphology at day 21 posttransplantation. When therapy was initiated on day 21 after transplantation, glomerulosclerosis and tubulointerstitial fibrosis were significantly inhibited by day 42 posttransplantation. Parallel decrease in infiltrating and proliferating mononuclear cells (ED1, CD8 and Ki67) was observed in treated allografts. Expression of acute phase reactive and proinflammatory genes (HO-1, osteopontin) and molecules associated with fibrosis (PAI-1, TGF-beta1, biglycan) was downregulated at day 21; reduced collagen deposition was observed, parallel to a significant lower number of alpha-SMA+ interstitial myofibroblasts. In situ hybridization demonstrated that biglycan expression was reduced following CCR1 blockade in interstitium of treated allografts. CCR1 antagonism was found to inhibit CCL5-induced secretion of biglycan by macrophages in vitro. CCR1 blockade significantly inhibited development and progression of chronic allograft damage. CCR1 antagonists may represent a therapeutic option for chronic inflammation and fibrosis in renal grafts.

Peptides derived from amino acid sequence 60–80 of HLA-B27 (B27PA, aa 60–72 and B2702PA, aa 60–80) mimic cytokeratin and are able to induce in vitro proliferation of human peripheral blood lymphocytes as well as arthritis in Lewis rats. Here we show that the pathogenic epitope recognized by autoaggressive rat T cells is located at the N-terminus of the sequence, between aa 60 and 72. A C-terminally elongated 25mer peptide (B2702.60–84) showed increased pathogenicity, indicating either a second arthritogenic epitope or an immunomodulatory region within this peptide. B2702.60–84 has been described to inhibit murine and human CD8 + cytotoxic T cells (CTL) and was even successfully used for the treatment of allograft rejection. In addition to pathogenicity we have investigated the immunomodulatory effect of peptide B2702.60–84 in our rat model of experimental autoimmune uveitis (EAU), induced with retinal S-Antigen peptide PDSAg. We found that disease exacerbated following coimmunization of PDSAg with B2702.60–84. In vitro, the B27-peptide enhanced the proliferation of CD4 + T cell lines specific for retinal autoantigen peptides during coincubation of B2702.60–84 with the respective antigen. Oral tolerance induction, an effective mechanism to prevent uveitis in Lewis rats, is abrogated by cofeeding peptide B2702.60–84 with the tolerogen PDSAg. In rat EAU, naturally occurring regulatory T cells and orally induced γδ TCR + suppressor cells are CD8 + , which might be impeded by peptide B2702.60–84. As a consequence of their abrogated suppressive capacity disease was exacerbated. We propose a similar role of HLA-B27 in man: disturbing the mechanisms down-regulating self-responses might lead to autoimmune diseases. This could explain the high association of HLA-B27 with a variety of autoimmune diseases targeting different organs or tissues.

Experimental autoimmune uveitis (EAU) is an inflammatory disease of the immune privileged inner eye, mediated by CD4(+) Th1 cells specific for retinal autoantigens. To elucidate the fate of the T cells in the eye we adoptively transferred green fluorescent protein-positive (GFP(+)) T cells with specificity for R14, a peptide from interphotoreceptor retinoid-binding protein (IRBP) or OVA as foreign control antigen to naive Lewis rats. We also used the model of immunogenic uveitis, an inflammatory eye disease induced by intraocular injection of soluble OVA 1 day post transfer of OVA-specific GFP(+) cells. We investigated the timing of ocular T cell infiltration and their immunological activation state by intravital fluorescence microscopy (IVFM) of the iris until onset of intraocular inflammation. Within 30 min of injection, GFP(+) cells invaded the iris tissue, irrespective of their antigen specificity, whereas intraocular inflammation was only observed 3 days later, if cells recognized their respective antigen (R14-specific cells in EAU, OVA-specific cells in immunogenic uveitis). Using FACS analysis we found that activation markers were upregulated only on cells from uveitic eyes, but not from other sources, suggesting that intraocularly presented specific antigen is a prerequisite for T cell reactivation and subsequent recruitment of inflammatory cells.

Antigenic mimicry of infectious agents and autoantigens is a proposed pathomechanism for autoimmune diseases. Here, we describe antigenic mimicry of a peptide from rotavirus, a nutritional protein from bovine milk (alphas2-casein) and a peptide thereof as well as a highly pathogenic peptide from retinal S-antigen (PDSAg), a major autoantigen in experimental autoimmune uveitis in Lewis rats. Immunization of rats with the peptides and the casein protein induced uveitis, an intraocular inflammation leading to decreased vision and even blindness. The peptides elicited cross-reactive T cell responses and uveitis in rats and were also recognized by lymphocytes and sera from uveitis patients. Oral tolerization with PDSAg, but not with rotavirus- and casein-derived peptides or casein protein, prevented PDSAg-induced uveitis in rats. Cofeeding of casein with cholera toxin induced uveitis in rats, suggesting that breaking oral tolerance to casein during gastrointestinal infections might also be able to initiate uveitis in humans.

Autoimmune uveitis is a sight threatening disease, which is conventionally treated with immunosuppressive medication. New treatment strategies include immunological approaches and aim at antigen specificity like oral tolerance. A peptide from the sequence of certain HLA-class I molecules plays a central role in the pathogenesis. When T cells recognize the HLA-peptide and are activated they are enabled to pass the blood–retina barrier. In the eye they recognize a cross-reactive organ-specific peptide and cause inflammation, which presents as uveitis. Here, we used the HLA-peptide as oral tolerogen to treat uveitis patients in an open study. All patients showed a positive therapeutic response and could reduce their long-lasting conventional immunsuppressive treatment. We did not observe any side effects. Moreover, side effects from conventional therapy could be reduced significantly.

Equine recurrent uveitis (ERU) is an inflammatory eye disease with high similarity to uveitis in man. It is the only spontaneous animal model for uveitis and the most frequent eye disease in horses affecting up to 10% of the population. To further investigate the pathophysiology of ERU we now report the establishment of an inducible uveitis model in horses. An ERU-like disease was elicited in seven out of seven horses by injection of interphotoreceptor retinoid-binding protein (IRBP) in complete Freund's adjuvant. Control horses did not develop uveitis. The disease model is characterized by a highly reproducible disease course and recurrent episodes with an identical time course elicited in all horses by repeated IRBP injections. The histology revealed the formation of lymphoid follicle-like structures in the eyes and an intraocular infiltration dominated by CD3(+) lymphocytes, morphological patterns typical for the spontaneous disease. Antigen-specific T cell proliferation of PBL was monitored prior to clinical uveitis and during disease episodes. An initial T cell response to IRBP-derived peptides was followed by epitope spreading to S-antigen-derived peptides in response to subsequent immunizations. Thus, horse experimental uveitis represents a valuable disease model for comparative studies with the spontaneous disease and the investigation of immunomodulatory therapeutic approaches after onset of the disease.

Equine recurrent uveitis (ERU) is the most serious eye disease in horses worldwide. Despite the fact that ERU is generally considered to be immune mediated, a detailed description of the histopathology of the posterior part of ERU eyes is lacking. Here, we examined sections of paraffin-embedded eyes using histological and immunhistological methods. Twenty seven eyes of 20 horses with ERU and 30 eyes of 15 healthy control horses were included in this study. We could consistently demonstrate an involvement of the retina and the choroid in all examined eyes of horses with spontaneous ERU. In eyes with minimal histopathological changes, the infiltrates consisted almost exclusively of T-cells. Histopathological changes start with the destruction of the photoreceptor outer segments, which often leads to focal retinal detachment. In more severely affected eyes, there is additional disintegration of the ganglion cell layer and the inner nuclear layer. In almost all examined eyes, lymphoid follicle formation could be demonstrated. Typical localizations of these follicles were the iris stroma and the choroid underneath the transition zone of the retina without photoreceptor cells to the region containing photoreceptor cells. These follicles consist of a T-cell rich periphery with a small center of CD3-negative lymphocytes. In cases with extreme histopathological changes, the retinal architecture is widely disintegrated with massive infiltration of the retina, the choroid, and the ciliary body by several types of inflammatory cells. Necrotic remnants of the retina are end-stage findings and there is only a minor inflammatory infiltration left. This study provides clear evidence that the retina is involved in all stages of ERU. Inflammation is mainly driven by T-cells as T-cells were demonstrated in mild stages of the disease and are also the predominating cell type in all other stages of ERU.

Ankylosing spondylitis (AS) is highly associated with HLA-B27. We have previously shown that peripheral blood lymphocytes from AS patients respond to stimulation with a peptide from the sequence of HLA-B27. Here we report on molecular mimicry of peptides from HLA-B27 and cytokeratin, the latter being specifically expressed in synovial membranes and eyes, the main targets of the autoaggressive immune response in AS patients. Immunization of rats with these peptides induced an inflammatory response in joints, spine and eyes, resembling the symptoms in AS. Furthermore, both HLA-B27- and cytokeratin-derived peptides, are effective oral tolerogens: feeding these peptides ameliorated arthritis and uveitis induced with the cytokeratin peptide. Our model might elucidate the role of peptides from the sequence of HLA-B27 as an antigen of the immune response in AS, introducing a new aspect of antigenic mimicry between HLA-B27 and tissue-specific antigens. We propose this as a mechanism directing a systemic autoimmune response to specific target organs by antigenic mimicry of T cell epitopes.

Intraokulare Entzundungen stellen in Europa und weltweit eine wesentliche Ursache schwerwiegender Sehschadigungen dar. In der Altersgruppe der 20- bis 40-jahrigen stehen sie als Erblindungsursache zusammen mit der diabetischen Retinopathie an erster Stelle (◘ Tab. 5.1). Es konnen alle Altersgruppen betroffen sein, allerdings treten die meisten Erkrankungen im Alter zwischen 20 bis 40 Jahren auf. Rezidive werden bei etwa 30 % aller akuten Entzundungen beobachtet. Etwa 50 % aller Patienten weisen eine Grunderkrankung oder assoziierte Merkmale (z. B. HLA-B27 Antigen) auf. Hinweise auf die Pathogenese und das differentialdiagnostische Vorgehen gehen aus ▶ Abschn. 5.1.2, 5.1.4 bzw. 5.1.8 hervor.

Endogenous uveitis is a T cell mediated autoimmune disease leading to impairment of visual acuity. The association of different uveitis entities with HLA-class I antigens and the discovery of antigenic mimicry between a peptide of uveitis-associated HLA-class I antigens and a peptide of retinal autoantigen led to a new hypothesis for the pathogenesis of uveitis. On the basis of this mechanism an open trial of oral tolerance induction with the HLA-peptide B27PD was initiated for nine patients with long lasting, therapy-refractive uveitis. Within 6 weeks of oral peptide treatment all patients responded with a marked decrease of intraocular inflammation, which allowed a reduction of systemic corticosteroids in seven patients. One patient, who suffered from an acute relapse, responded within 2 weeks, followed by an increase of visual acuity. In addition, two patients discontinued azathioprine immediately prior to oral tolerance induction without the occurrence of relapses. Visual acuity remained unchanged or increased in 14 of 16 eyes. One patient did not finish oral peptide treatment. None of these patients experienced any adverse events. It was concluded that the oral application of highly tolerogenic peptides might be a potent approach for the treatment of autoimmune diseases.

Objective.To study whether peptides derived from the HLA-B27 molecule sequence can stimulate peripheral blood T lymphocytes (PBL) from patients with HLA-B27-associated spondylarthropathies. Methods.PBL from 55 HLA-B27+ patients with ankylosing spondylitis (AS), 28 HLA-B27+ patients with other spondylarthropathies, 7 rheumatoid arthritis patients, and 30 HLA-B27+ and 22 HLA-B27- healthy controls were tested in lymphocyte proliferation assays with 4 synthetic peptides derived from the HLA-B*2705 molecule. Results. A 13-mer peptide (B27PA) induced significant proliferative responses in 17 of the 55 AS patients (stimulation index [SI] 2.5–17.5), as well as in 3 of the HLA-B27+ healthy controls (SI 2.5–9.8). Another 13-mer peptide (B27PC) induced PBL proliferation (SI 2.7–5.5) in 10 AS patients and in some donors of the control groups. In B27PA-specific T cell lines, an expansion of cells positive for the γ/δ T cell receptor could be demonstrated. Conclusion. These results indicate that HLA-B27-derived peptides can be recognized as autoantigens by PBL of HLA-B27+ AS patients and B27+ healthy controls. Recent infections preceding the manifestation of AS may be involved in this process of anti-self major histocompatibility complex reactivity.

Scleritis is an uncommon disease characterized by inflammation of the sclera and adjacent ocular structures. Recent studies have led to significant progress in understanding the epidemiology, immunopathogenesis, severity assessment, treatment, and prognosis of this potentially sight threatening disease. Despite these advances, significant challenges remain regarding our understanding of the mechanisms of scleral destruction and inflammation, and the rational approach to treatment. Information from studies in associated systemic diseases and vasculitis and a small number of studies of ocular tissue has revealed the prominent role of T and B cells, autoantibodies, immune complexes, and cytokines, such as TNF-alpha. These studies have prompted clinical trials that have demonstrated the effectiveness of anti-TNF, anti-B cell therapy, systemic immunosuppression, and more recently the use of local sub-conjunctival steroid treatment.

We investigated the role of gamma/delta TCR+ T cells in induction and suppression of the T cell-mediated disease experimental autoimmune uveitis. Disease induction was studied in Lewis rats perinatally depleted of alpha/beta or gamma/delta TCR+ subpopulations. Depletion of alpha/beta TCR+ cells completely abrogated disease, whereas treatment with anti-gamma/delta antibodies had no influence on onset or intensity of uveitis. However, adoptively transferred gamma/delta+ cells from orally tolerized rats could mediate suppression of uveitis in an antigen-specific fashion. Uveitis induced by a peptide derived from the uveitogenic retinal soluble antigen (S-Ag) was suppressed by gamma/delta+ cells from rats orally tolerized with the same peptide as well as HLA peptide B27PD. This disease ameliorating effect could also be observed when rats were fed with the HLA peptide before immunization with S-Ag peptide. Transfer of alpha/beta+ T cells from the same donors as well as gamma/delta+ or alpha/beta+ cells from animals fed with control peptide had no ameliorating effect.

Vernal keratoconjunctivitis (VKC) is a bilateral, usually seasonally recurrent, allergic inflammation of the conjunctiva, characterised by limbal gelatinous hypertrophy and/or upper tarsal giant conjunctival papillae. Although rare in temperate regions, it represents an important cause of hospital referral in many parts of Africa and Asia. Clinical and immunohistochemical studies suggest that IgE-dependent (type I allergic) and IgE-independent (type IV allergic) mechanisms are involved in the immunopathogenesis of VKC, in which various inflammatory cells, including different T cell subpopulations play an active role via a cascade of chemical mediators. Endocrine, genetic, neurogenic, environmental and socioeconomic risk factors have been identified. However, its aetiology and pathophysiology remain unclear. The clinical course of this disease is usually benign and self-limiting, but a minority of patients will face very debilitating and sight threatening complications. Topical corticosteroids are often used during flare-ups in combination with mast cell stabilizers as maintenance treatment for VKC. However this management is unsatisfactory in controlling severe cases and avoiding recurrences. Non-steroidal immune modulators such as ciclosporin A and tacrolimus are promising alternatives, but tolerance to these agents needs to be improved and production costs reduced. The purpose of this review is to give an update on its epidemiology, immunopathogenesis and management.