Ocular sarcoidosis in adults and children: update on clinical manifestation and diagnosis.

Sarcoidosis-associated uveitis, is the predominant ocular sarcoidosis presentation, which affects both adults and children. For adults, international ocular sarcoidosis criteria (IWOS) and sarcoidosis-associated uveitis criteria (SUN) are defined. However, for children they are not yet established internationally. Due to the specificity of pediatric manifestations of sarcoidosis, this task is even more challenging. In children, sarcoidosis is subdivided into Blau syndrome and early-onset sarcoidosis (BS/EOS) affecting younger children (< 5 years) and the one affecting older children with clinical presentation resembling adults. Differential diagnosis, clinical work-up as well as diagnostic criteria should be adapted to each age group. In this article, we review the clinical manifestation of sarcoidosis-associated uveitis in adults and children and the sensitivity and specificity of various ocular sarcoidosis diagnostic modalities, including chest X-ray and CT, FDG PET-CT, gallium-67 scintigraphy, bronchoalveolar lavage fluid, genetic testing for NOD2 mutations and serum biomarkers, such as ACE, lysozyme and IL2R.

Effect of SOCS1 overexpression on RPE cell activation by proinflammatory cytokines.

The purpose of this study was to investigate the in vitro effect of Suppressor Of Cytokine Signaling 1 (SOCS1) overexpression in retinal pigment epithelium (RPE) cells on their activation by pro-inflammatory cytokines IFNγ, TNFα and IL-17. Retinal pigment epithelium cells (ARPE-19) were stably transfected with the control plasmid pIRES2-AcGFP1 or the plasmid pSOCS1-IRES2-AcGFP1. They were stimulated by IFNγ (150ng/ml), TNFα (30ng/ml) or IL-17 (100ng/ml). The levels of SOCS1 mRNA were measured by real-time PCR. Signal Transducer and Activator of Transcription 1 (STAT1) phosphorylation and IκBα expression were analysed by western Blot (WB). IL-8 secretion was analysed by ELISA and expression of MHCII molecules and ICAM-1/CD54 by flow cytometry. Our data show that SOCS1 mRNA overexpression in RPE cells prevents IFNγ-induced SOCS1 mRNA increase and IFNγ-mediated STAT1 phosphorylation. Moreover, SOCS1 overexpression in RPE cells inhibits IFNγ-induced decrease of IL-8 secretion and prevents IFNγ-induced MHC II and ICAM1/CD54 upregulation. However, SOCS1 overexpression does not affect TNFα-induced IκBα degradation nor block TNFα-induced or IL-17-induced IL-8 secretion. On the contrary, IL-17-induced secretion is increased by SOCS1 overexpression. In conclusion, SOCS1 overexpression in RPE cells inhibits some IFNγ-mediated responses that lead to uveitis development. This notion raises the possibility that SOCS1 overexpression could be a novel target for treating non-infectious uveitis. However, some proinflammatory effects of TNFα and IL-17 stimulation on RPE are not blocked by SOCS1 overexpression.

TNFα suppresses IFNγ-induced MHC class II expression on retinal pigmented epithelial cells cultures.

PURPOSE: One major consequence of retinal pigment epithelium (RPE) cell activation during autoimmune uveitis is the induction of MHC II molecules expression at their surface. IFNγ is regarded as the main cytokine involved in this induction. As TNFα plays a central role in autoimmune uveitis, we investigated its effects on IFNγ-mediated MHC II induction on RPE cells. METHODS: Retinal pigment epithelium cells (ARPE-19) were stimulated with IFNγ, TNFα and the anti-TNFα antibody infliximab. The expression of MHCII and ICAM-1 was analysed by flow cytometry. The activation and expression of IRF-1 and STAT-1, two proteins involved in IFNγ-signalling pathway, were analysed by WB. Class II transactivator (CIITA) expression was monitored by qRT-PCR and immunoprecipitation. RESULTS: TNFα inhibits IFNγ-induced MHC II expression on ARPE cells in a dose-dependent manner. Infliximab completely reverses the inhibitory effect of TNFα. We did not observe an inhibitory effect of TNFα on the expression of ICAM-1 induced by IFNγ. Similarly, IFNγ-induced STAT1 phosphorylation and IRF1 expression were not affected by TNFα. On the contrary, we found that TNFα suppresses IFNγ-induced CIITA mRNA accumulation and protein expression. CONCLUSION: TNFα inhibits IFNγ-induced MHC II expression in RPE cells. This inhibitory effect was reversed by infliximab and was not because of a global inhibition of IFNγ -mediated RPE cell activation but rather to a specific down-regulation of CIITA expression. Those findings are consistent with the role of TNFα in the resolution of inflammation and might help to elucidate the complex development of autoimmune uveitis.