Review of Systemic Immunosuppression for Autoimmune Uveitis.
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ABSTRACT:
SUBMITTER: Castiblanco C
PROVIDER: S-EPMC4254861 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:To investigate the anti-inflammatory effect of an adenosine monophosphate (AMP) analog, aminoimidazole carboxamide ribonucleotide (AICAR), in experimental autoimmune uveoretinitis (EAU).C57BL/6 mice were injected daily with AICAR (200 mg/kg, intraperitoneally [IP]) from day 0, the day of interphotoreceptor retinoid-binding protein (IRBP) immunization, until day 21. The severity of uveitis was assessed clinically and histopathologically. T-cell proliferation and cytokine production of IFN-?, IL-17, and IL-10 in response to IRBP stimulation were determined. In addition, regulatory T-cell (Treg) populations were measured. Co-stimulatory molecule expression (CD40, 80, 86, and I-Ab) on dendritic cells (DCs) in EAU and on bone marrow-derived dendritic cells (BMDCs) treated with AICAR was measured.AICAR treatment significantly reduced clinical and histologic severity of EAU as well as ocular cytokine production. An anti-inflammatory effect associated with the inhibition of T-cell proliferation and Th1 and Th17 cytokine production was observed. Increases in the Th2 response and Treg population were not observed with AICAR treatment. AICAR did significantly inhibit BMDC maturation by reducing co-stimulatory molecule expression.AICAR attenuates EAU by preventing generation of Ag-specific Th1 and Th17 cells. Impaired DC maturation may be an underlying mechanism for this anti-inflammatory effect observed with AICAR.
| S-EPMC3392008 | biostudies-other
Project description:Rapamycin, a potent immune modulator, is used to treat transplant rejection and some autoimmune diseases. Uveitis is a potentially severe inflammatory eye disease, and 2 clinical trials of treating uveitis with rapamycin are under way. Unexpectedly, recent research has demonstrated that low dose rapamycin enhances the memory T cell population and function. However, it is unclear how low dose rapamycin influences the immune response in the setting of uveitis.B10.RIII mice were immunized to induce experimental autoimmune uveitis (EAU). Ocular inflammation of control and rapamycin-treated mice was compared based on histological change. ELISPOT and T cell proliferation assays were performed to assess splenocyte response to ocular antigen. In addition, we examined the effect of rapamycin on activation-induced cell death (AICD) using the MitoCapture assay and Annexin V staining.Administration of low dose rapamycin exacerbated EAU, whereas treating mice with high dose rapamycin attenuated ocular inflammation. The progression of EAU by low dose rapamycin coincided with the increased frequency of antigen-reactive lymphocytes. Lastly, fewer rapamycin-treated T cells underwent AICD, which might contribute to exaggerated ocular inflammation and the uveitogenic immune response.These data reveal a paradoxical role for rapamycin in uveitis in a dose-dependent manner. This study has a potentially important clinical implication as rapamycin might cause unwanted consequences dependent on dosing and pharmacokinetics. Thus, more research is needed to further define the mechanism by which low dose rapamycin augments the immune response.
| S-EPMC3344911 | biostudies-literature
Project description:Purpose: Previous studies have shown that parental abnormal physiological conditions such as inflammation, stress, and obesity can be transferred to offspring. The purpose of this study was to investigate the impact of parental uveitis on the development and susceptibility to experimental autoimmune uveitis (EAU) in offspring. Methods: Parental male and female B10RIII mice were immunized with interphotoreceptor retinoid binding protein (IRBP) 161-180 in complete Freund's adjuvant and were immediately allowed to mate. Gross examination of the offspring gestated with EAU was performed to determine the influence of parental uveitis on offspring development after birth. Gene expression profiles were analyzed in the affected eyes of offspring under EAU to identify differentially expressed genes (DEGs). Adult offspring were given 5, 25, and 50 μg IRBP161-180 to compare their susceptibility to EAU. Immunized mice were clinically and pathologically evaluated for the development of EAU. Ag-specific T-cell proliferation and IL-17 production from spleens and lymph nodes were evaluated on day 14 or 35 after immunization. Results: Hair loss, delay of eye opening, and swollen spleens in the offspring from parents with uveitis were observed from day 14 to 39 after birth. DEGs were involved in the immune system process, muscle system process, and cell development. The altered antigen processing and presentation, cell adhesion molecules, and phagosome in the eyes of the offspring from uveitis-affected parents were enriched. Offspring gestated with EAU showed a susceptibility to EAU and an earlier onset and higher severity of EAU compared to the control group mice. IRBP-specific lymphocyte proliferation and IL-17 production were observed in the EAU offspring with exposure to parental uveitis. Conclusions: The results suggest that mouse parents with uveitis can increase their offspring's susceptibility to EAU, probably through altering cell adhesion molecules and antigen processing and presentation related to the T-cell proliferation and Th17 response.
| S-EPMC7308830 | biostudies-literature
Project description:miRNA expression profiling of CD4+ T cells comparing naïve mice and experimental autoimmune uveitis (EAU) mice. EAU was induced by immunization of retinal antigen (IRBP1-20) in complete Freund’s adjuvant (CFA). CD4+ T cells were isolated and purified from the spleen and draining lymph nodes 13 days after immunization.
2022-09-10 | GSE213034 | GEO
Project description:Noninfectious uveitis is a predominantly T cell-mediated autoimmune, intraocular inflammatory disease. To characterize the gene expression profile from patients with noninfectious uveitis, PBMCs were isolated from 50 patients with clinically characterized noninfectious uveitis syndrome. A pathway-specific cDNA microarray was used for gene expression profiling and real-time PCR array for further confirmation. Sixty-seven inflammation- and autoimmune-associated genes were found differentially expressed in uveitis patients, with 28 of those genes being validated by real-time PCR. Several genes previously unknown for autoimmune uveitis, including IL-22, IL-19, IL-20, and IL-25/IL-17E, were found to be highly expressed among uveitis patients compared with the normal subjects with IL-22 expression highly variable among the patients. Furthermore, we show that IL-22 can affect primary human retinal pigment epithelial cells by decreasing total tissue resistance and inducing apoptosis possibly by decreasing phospho-Bad level. In addition, the microarray data identified a possible uveitis-associated gene expression pattern, showed distinct gene expression profiles in patients during periods of clinical activity and quiescence, and demonstrated similar expression patterns in related patients with similar clinical phenotypes. Our data provide the first evidence that a subset of IL-10 family genes are implicated in noninfectious uveitis and that IL-22 can affect human retinal pigment epithelial cells. The results may facilitate further understanding of the molecular mechanisms of autoimmune uveitis and other autoimmune originated inflammatory diseases.
| S-EPMC2631441 | biostudies-literature
Project description:Development of novel strategies to treat noninfectious posterior uveitis is an ongoing challenge, in part because of limited availability of animal models that mimic the naturally occurring disease in humans. Mice deficient in the autoimmune regulatory gene Aire develop a spontaneous T-cell and macrophage-mediated autoimmune uveitis that closely recapitulates human endogenous uveitis and thus provide a useful model for mechanistic and therapeutic investigations. Lymphocytic and mononuclear infiltration of the retina in Aire knockout (KO) mice triggers the onset of uveitis from initial retinal inflammation to eventual destruction of the neuroretina with loss of photoreceptors. The C-C chemokine receptor type 2 protein (CCR2) functions in directing monocyte and macrophage migration to inflamed tissues via interaction with monocyte chemotactic proteins. Using the Aire KO mouse model, we demonstrated an essential role for CCR2 in the pathogenesis of autoimmune-mediated uveitis. Loss of functional CCR2 effectively reduced immune cell infiltration and rescued the retina from destruction. CCR2-dependent migration of bone marrow-derived cells provided the driving force for retinal inflammation, with CCR2-expressing mononuclear cells contributing to retinal damage via recruitment of CD4(+) T cells. These studies identify the CCR2 pathway as a promising therapeutic target that may prove an effective approach to treat uveitis associated with autoimmunity.
| S-EPMC4044718 | biostudies-literature
Project description:Whether ambient temperature influences immune responses leading to uveitis is unknown. We thus tested whether ambient temperature affects the symptoms of experimental autoimmune uveitis (EAU) in mice and investigated possible mechanisms. C57BL/6 mice were kept at a normal (22°C) or high temperature (30°C) housing conditions for 2 weeks and were then immunized with human interphotoreceptor retinoid-binding protein (IRBP651-670) peptide to induce EAU. Histological changes were monitored to evaluate the severity of uveitis. Frequency of Th1 cells and Th17 cells was measured by flow cytometry (FCM). The expression of IFN-γ and IL-17A mRNA was measured by real-time qPCR. The generation of neutrophil extracellular traps (NETs) was quantified by enzyme-linked immunosorbent assay (ELISA). Differential metabolites in the plasma of the mice kept in the aforementioned two ambient temperatures were measured via ultra-high-performance liquid chromatography triple quadrupole mass spectrometry quadrupole time of flight mass spectrometry (UHPLC-QQQ/MS). The differential metabolites identified were used to evaluate their effects on differentiation of Th1 and Th17 cells and generation of NETs in vitro. The results showed that EAU mice kept at high temperature experienced a more severe histopathological manifestation of uveitis than mice kept at a normal temperature. A significantly increased frequency of Th1 and Th17 cells in association with an upregulated expression of IFN-γ and IL-17A mRNA was observed in the splenic lymphocytes and retinas of EAU mice in high temperature. The expression of NETs as evidenced by myeloperoxidase (MPO) and neutrophil elastase (NE), was significantly elevated in serum and supernatants of neutrophils from EAU mice kept at high temperature compared to the normal temperature group. The metabolites in the plasma from EAU mice, fumaric acid and succinic acid, were markedly increased in the high temperature group and could induce the generation of NETs via the NADPH oxidase-dependent pathway, but did not influence the frequency of Th1 and Th17 cells. Our findings suggest that an increased ambient temperature is a risk factor for the development of uveitis. This is associated with the induction of Th1 and Th17 cells as well as the generation of NETs which could be mediated by the NADPH oxidase-dependent pathway.
| S-EPMC8027130 | biostudies-literature
Project description:Uveitis is an intraocular inflammatory disease which can lead to serious visual impairment. Genetic factors have been shown to be involved in its development. However, few databases have focused on the information of associations between single nucleotide polymorphisms (SNPs) and uveitis. To discover the exact genetic background of uveitis, we developed an SNP database specific for uveitis, "UVEOGENE," which includes 370 genes and 918 SNPs covering 14 uveitis entities and 40 populations from 286 PubMed English-language papers. Stratification analyses by gender, HLA status, and different clinical features were also extracted from the publications. As a result, 371 associations were judged as "statistically significant." These associations were also shared with Global Variome shared Leiden Open Variation Database (LOVD) (https://databases.lovd.nl/shared/genes). Based on these associations, we investigated the genetic relationship among three widely studied uveitis entities including Behcet's disease (BD), Vogt-Koyanagi-Harada (VKH) disease, and acute anterior uveitis (AAU). Furthermore, "UVEOGENE" can be used as a reliable and informative resource to identify similarities as well as differences in the genetic susceptibility among uveitis and other autoimmune diseases. UVEOGENE is freely accessible at http://www.uvogene.com.
| S-EPMC6590147 | biostudies-literature
Project description:OBJECTIVE:CD6 is emerging as a new target for treating many pathological conditions in which T cells are integrally involved, but even the latest data from studies of CD6 gene engineered mice were still contradictory. To address this issue, we studied experimental autoimmune uveitis (EAU), a model of autoimmune uveitis, in wild-type (WT) and CD6 knockout (KO) mice. METHODS:After EAU induction in WT and CD6 KO mice, we evaluated ocular inflammation and compared retinal antigen-specific T-cell responses using scanning laser ophthalmoscopy, spectral-domain optical coherence tomography, histopathology, and T cell recall assays. Uveitogenic T cells from WT and CD6 KO mice were adoptively transferred into WT naïve mice to confirm the impact of CD6 on T cells. In addition, we immunized CD6 KO mice with recombinant CD6 protein to develop mouse anti-mouse CD6 monoclonal antibodies (mAbs) in which functional antibodies exhibiting cross-reactivity with human CD6 were screened and identified for treatment studies. RESULTS:In CD6 KO mice with EAU, we found significantly decreased retinal inflammation and reduced autoreactive T-cell responses, and confirmed the impaired uveitogenic capacity of T cells from these mice in an adoptive transfer experiment. Notably, one of these cross-reactive mAbs significantly ameliorated retinal inflammation in EAU induced by the adoptive transfer of uveitogenic T cells. CONCLUSIONS:Together, these data strongly suggest that CD6 plays a previously unknown, but pivotal role in autoimmune uveitis, and may be a promising new treatment target for this blinding disease. In addition, the newly developed mouse anti-mouse/human CD6 mAbs could be valuable tools for testing CD6-targeted therapies in other mouse models of human diseases.
| S-EPMC5949263 | biostudies-literature
Project description:Interleukin-33 (IL-33) is associated with several important immune-mediated disorders. However, its role in uveitis, an important eye inflammatory disease, is unknown. Here, we investigated the function of IL-33 in the development of experimental autoimmune uveitis (EAU). IL-33 and IL-33 receptor (ST2) were expressed in murine retinal pigment epithelial (RPE) cells in culture, and IL-33 increased the expression of Il33 and Mcp1 mRNA in RPE cells. In situ, IL-33 was highly expressed in the inner nuclear cells of the retina of naïve mice, and its expression was elevated in EAU mice. ST2-deficient mice developed exacerbated EAU compared with WT mice, and administration of IL-33 to WT mice significantly reduced EAU severity. The attenuated EAU in IL-33-treated mice was accompanied by decreased frequency of IFN-?+ and IL-17(+) CD4+ T cells and reduced IFN-? and IL-17 production but with increased frequency of IL-5(+) and IL-4(+) CD4 T cells and IL-5 production in the draining lymph node and spleen. Macrophages from the IL-33-treated mice show a significantly higher polarization toward an alternatively activated macrophage phenotype. Our results therefore demonstrate that the endogenous IL-33/ST2 pathway plays an important role in EAU, and suggest that IL-33 represents a potential option for treatment of uveitis.
| S-EPMC4449115 | biostudies-literature