Dataset Information

Pathogenesis of Non-Infectious Uveitis Elucidated by Recent Genetic Findings.

ABSTRACT: Uveitis is a generic term for inflammation of the uvea, which includes the iris, ciliary body, and choroid. Prevalence of underlying non-infectious uveitis varies by race and region and is a major cause of legal blindness in developed countries. Although the etiology remains unclear, the involvement of both genetic and environmental factors is considered important for the onset of many forms of non-infectious uveitis. Major histocompatibility complex (MHC) genes, which play a major role in human immune response, have been reported to be strongly associated as genetic risk factors in several forms of non-infectious uveitis. Behçet's disease, acute anterior uveitis (AAU), and chorioretinopathy are strongly correlated with MHC class I-specific alleles. Moreover, sarcoidosis and Vogt-Koyanagi-Harada (VKH) disease are associated with MHC class II-specific alleles. These correlations can help immunogenetically classify the immune pathway involved in each form of non-infectious uveitis. Genetic studies, including recent genome-wide association studies, have identified several susceptibility genes apart from those in the MHC region. These genetic findings help define the common or specific pathogenesis of ocular inflammatory diseases by comparing the susceptibility genes of each form of non-infectious uveitis. Interestingly, genome-wide association of the interleukin (IL)23R region has been identified in many of the major forms of non-infectious uveitis, such as Behçet's disease, ocular sarcoidosis, VKH disease, and AAU. The interleukin-23 (IL-23) receptor, encoded by IL23R, is expressed on the cell surface of Th17 cells. IL-23 is involved in the homeostasis of Th17 cells and the production of IL-17, which is an inflammatory cytokine, indicating that a Th17 immune response is a common key in the pathogenesis of non-infectious uveitis. Based on the findings from the immunogenetics of non-infectious uveitis, a personalized treatment approach based on the patient's genetic make-up is expected.

SUBMITTER: Takeuchi M

PROVIDER: S-EPMC8072111 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:PurposeNon-infectious uveitis is a complex disease characterized by intraocular inflammation of the uveal area and the leading cause of vision impairment and blindness in young people globally. However, what triggers inflammation and contributes to its recurrence remains unclear. The complement system has been linked to various immunological and inflammatory conditions. In the present study, we have systematically evaluated the role of the alternative complement pathway in the pathogenesis of non-infectious uveitis.MethodologyQuantitative PCR was done in the peripheral leukocytes to study the expression of genes and regulatory miRNA in both anterior and posterior uveitis (n=28 in each category). Multiplex ELISA was performed to measure alternative pathway complement components, such as C3b, factor B, and CFH, and aqueous humor of infectious and non-infectious uveitis patients and non-inflammatory controls (n=10 each). Western blotting was done to validate the ELISA findings in a subset of patients and controls.ResultsDownregulation of C3 and CFH mRNA in the peripheral blood was shown by quantitative PCR in the group of anterior uveiits (AU), while the opposite result was found in the group of posterior uveitis (PU). ELISA levels of C3b and CFH proteins were significantly higher in aqueous humor of infectious and non-infectious uveitis (*p = 0.03 and **p = 0.0007 respectively) as compared to the control group. Western blotting further validated (VitH) the activation of the complement cascade in the aqueous (AH) and vitreous humor of patients with non-infectious uveitis, with an increased level of C3b (n=6) and CFH (n=4) in aqueous humor. C3b level was significantly increased while CFH was reduced relative to controls in the vitreous humor (VitH) of posterior uveitis patients compared to controls (n=27 in each category). A C3b to CFH ratio was computed to assess the regulation of complement activation and this index was several folds higher in both anterior and posterior uveitis (n=10 each). The expression of miRNA-hsa-miR-146a and miRNA-hsa-miR-155-5p that regulates CFH was downregulated and nicely correlated with the increased complement proteins in both anterior and posterior uveitis (n=10 each).ConclusionOur results demonstrate a clear role of CFH and the activation of the alternative complement pathway in the pathogenesis of non-infectious uveitis; however, its therapeutic potential warrants further investigations.

Project description:PurposeTo evaluate the role of vitreomacular adhesion (VMA) in visual and anatomic outcomes in patients with non-infectious uveitis.DesignPhase 2 clinical trial PARTICIPANTS: Data from the Safety, Tolerability, and Efficacy of Tocilizumab in Patients with Non-infectious Uveitis (STOP-Uveitis) study was analyzed.MethodsIn the STOP-Uveitis study, patients with non-infectious uveitis (NIU) received monthly intravenous infusions of either 4 or 8 mg/kg tocilizumab until month 6 (M6). Spectral domain optical coherence tomography (SD-OCT) images of patients that completed M6 of the study were analyzed at baseline to stratify the patients by the presence (VMA+) or absence (VMA-) of VMA. Patients with vitreomacular traction (VMT) or epiretinal membrane causing structural abnormalities within center 1 mm were excluded. All images were graded by two independent graders.Main outcome measuresMean change in best-corrected visual acuity (BCVA), central retinal thickness (CRT), and vitreous haze (VH) at M6.ResultsOut of 37 patients randomized in the STOP-Uveitis study, 48 eyes (27 patients) were eligible based on the study criteria. At baseline, 19 eyes were classified as VMA+, and 32 eyes were classified as VMA-. The distribution of two doses of TCZ (4 mg/kg and 8 mg/kg) were similar between the two groups. At M6, the mean improvement in BCVA was 2.00 ± 5.3 and 6.50 ± 7.98 letters in the VMA+ and VMA- groups, respectively (p = 0.02). The mean improvement in CRT was 34.85 ± 72.36 and 80.37 ± 157.21 μm in the VMA+ and VMA- groups, respectively (p = 0.18). Similarly, the mean change in VH was - 0.65 ± 0.47 and - 0.76 ± 0.71 in the VMA+ and VMA- groups, respectively (p = 0.32). Out of 16 eyes with VMA at baseline, 3 eyes developed posterior vitreous detachment (PVD) at M6. The mean change in BCVA was significantly higher (p = 0.02), while CRT and VH score were similar (p > 0.05) in eyes with PVD compared to eyes with persistent VMA.ConclusionsThe absence of VMA or development of PVD in eyes with VMA seems to have a beneficial effect on the vision of subjects receiving treatment for uveitis. Therefore, patients with uveitis should be assessed using SD-OCT for the presence of vitreomacular interface abnormalities.

Dataset Information

Pathogenesis of Non-Infectious Uveitis Elucidated by Recent Genetic Findings.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets