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New insights into key genes and pathways involved in the pathogenesis of HLA-B27-associated acute anterior uveitis

ABSTRACT: HLA-B27-associated inflammatory diseases remains one of the strongest HLA-disease known to date. HLA-B27-associated acute anterior uveitis has wide-ranging medical significance due to its ocular, systemic, immunologic, and genetic features. To investigate the genes and signalling pathways located upstream of the inflammatory processes in HLA-B27-associated acute anterior uveitis will help to know the mechanism of this disease. HLA-B27-positive and -negative monocytes isolated from human peripheral blood were stimulated with Vibrio cholera lipopolysaccharide (LPS). Gene expression microarrays were used to identify the differentially expressed genes, and they were analysed by a series of bioinformatics-based techniques. Gene expression microarray analysis revealed marked differences between B27-positive monocytes in the genes that are upregulated in response to LPS stimulation. Gene Ontology enrichment (GO) and pathway analysis indicated that genes participating in protein transport and folding were essential to the inflammatory process. The LPS receptor, TLR4, induced the Toll-like receptor signalling pathway and pathways related to Vibrio cholerae infection, which are located upstream of the network and contribute to the overall response. Among the DE genes, PIK3CA, PIK3CB, AKT3, and MAPK1 may play critical roles in inflammation.Equivalent LPS stimulation induces a different response in HLA-B27-positive monocytes compared to monocytes lacking this HLA protein, suggesting that the TLR pathway is involved in the pathogenesis of HLA-B27-associated AAU. Blocking this pathway and other pathways by siRNA interference of candidate genes may contribute to the development of a treatment for this type of AAU.

ORGANISM(S): Homo sapiens

PROVIDER: GSE37588 | GEO | 2012/06/01

SECONDARY ACCESSION(S): PRJNA167199

REPOSITORIES: GEO

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Project description:Background The striking association of HLA-B27 with spondyloarthritis (SpA) has been known for 50 years. However, its pathophysiological significance remains incompletely understood. In the HLA-B27/human-β2 microglobulin (hβ2m) transgenic rat (B27 rat) that spontaneously develops inflammatory phenotype characteristic of SpA, myeloid cells expressing the HLA-B27/h2m transgene are critical for disease induction and functionally impaired. Recently, we produced HLA-B27/hβ2m transgenic Drosophila to study non-canonical effects of HLA-B27. We showed that HLA-B27/h2m expressed in Drosophila wing imaginal disc deregulated BMP pathway by interacting physically with the type I bone morphogenetic protein (BMP) receptor (BMPR1) Saxophone (Sax), leading to a loss of crossveins. Methods Genetic interaction was studied between the activin/TGF pathway and HLA-B27/hβ2m in transgenic Drosophila wings. The HLA-B27-bound peptidome was characterized in wing imaginal discs from transgenic Drosophila by high-performance liquid chromatography and mass spectrometry of the peptide fraction eluted from affinity purified HLA-B27. In mesenteric lymph node (mLN) T cells from B27 rats, physical interaction between HLA-B27 and activin receptor-like kinase-2 (ALK2), ALK3 and ALK5 BMPR1s was assessed by proximity ligation assay and phosphorylation of SMADs and proteins of the non-canonical BMP/TGF pathway induced by its ligands was assessed by flow cytometry. Transcript level of several target genes of the TGF pathway was evaluated by real-time quantitative polymerase chain reaction in mLN subsets of T cells from B27 and control nontransgenic rats, with and without treatment by TGF. Results We showed that, in addition to the BMP pathway, inappropriate signaling through the activin/transforming growth factor β (TGFβ) pathway, involving Baboon (Babo) BMPR1, also contributed to the crossveinless wing phenotype. We identified a set of peptides bound to HLA-B27 with canonical binding motif in HLA-B27/hβ2m transgenic Drosophila wing imaginal disc, despite the lack of peptide loading complex. We then demonstrated specific physical interaction, between HLA-B27/h2m and both mammalian orthologues of Sax and Babo, i.e. ALK2 and ALK5 (i.e. TGF receptor I), in the mLN cells from B27 rat. The magnitude of phosphorylation of SMAD2/3 in response to TGFβ1 was increased in T cells from adult and premorbid B27 rats, showing evidence for deregulated TGF pathway. Accordingly, expression of several target genes of the pathway was increased in T cells from B27 rats, in basal conditions and/or after TGFexposure, including Foxp3, Rorc, Runx1 and Maf. Interestingly. Tgfb1 expression was reduced in naïve T cells from B27 rats, even premorbid, an observation consistent with a pro-inflammatory pattern. Conclusions This study highlights a complex interplay between HLA-B27 and the BMP/TGFβ pathways in both Drosophila and B27 rat. Given the importance of the TGF pathway in CD4+ T cells differenciation and regulation, the disturbance caused by HLA-B27 could contribute to the abnormal expansion of pro-inflammatory T helper 17 cells and the altered regulatory T cell phenotype observed in B27 rat.

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New insights into key genes and pathways involved in the pathogenesis of HLA-B27-associated acute anterior uveitis

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