Degradation of misfolded HLA B*2704 (associated with disease) involves UPR, autophagy and aggresomes whereas degradation of HLA B*2709 (non-associated with disease) involves the endosomal-lysosomal pathway
Ontology highlight
ABSTRACT:
INSTRUMENT(S): Orbitrap Fusion
ORGANISM(S): Homo Sapiens (human)
TISSUE(S): Epithelial Cell, Cell Culture
DISEASE(S): Ankylosing Spondylitis
SUBMITTER: 
AMIT THAKUR
LAB HEAD: Manni Luthra-Guptasarma
PROVIDER: PXD027999 | Pride | 2021-12-23
REPOSITORIES: Pride
Dataset's files
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| B2704a.raw | Raw | |||
| B2704b.raw | Raw | |||
| B2704c.raw | Raw | |||
| B2704d.raw | Raw | |||
| B2704e.raw | Raw |
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Project description:Uveitis describes a heterogeneous group of inflammatory eye diseases characterized by infiltration of leukocytes into the uveal tissues. uveitis associated with the HLA haplotype B27 (HLA-B27) is a common subtype of uveitis and a prototypical ocular immune-mediated disease. Local immune mechanisms driving human uveitis are poorly characterized mainly due to the limited available biomaterial and subsequent technical limitations. Here, we provide the first high-resolution characterization of intraocular leukocytes in HLA-B27 positive (n=3) and negative (n=2) anterior uveitis and an infectious endophthalmitis control (n=1) by combining single cell RNA-sequencing with flow cytometry and protein analysis. Ocular cell infiltrates consisted primarily of lymphocytes in both subtypes of uveitis and of myeloid cells in infectious endophthalmitis. HLA-B27 positive uveitis exclusively featured a plasmacytoid and classical dendritic cells (cDC) infiltrate. Moreover, cDCs were central in predicted local cell-cell communication. This suggests a unique pattern of ocular leukocyte infiltration in HLA-B27 positive uveitis with relevance of dendritic cells.
2021-06-25 | GSE178833 | GEO
Project description:Background and Aims: We have shown in several controlled rat and human infection studies that dietary calcium improves intestinal resistance and strengthens the mucosal barrier. Reinforcement of gut barrier function is also relevant for inflammatory bowel disease (IBD). Therefore, we investigated the effect of supplemental calcium on spontaneous colitis development in HLA-B27 transgenic rats, an experimental animal model of IBD. Methods: HLA-B27 transgenic rats were fed a purified high-fat diet containing either a low or high calcium content (30 and 120 mmol CaHPO4/kg diet, respectively) for almost 7 weeks. Inert chromium ethylenediamine-tetraacetic acid (CrEDTA) was added to the diets to quantify intestinal permeability by measuring urinary CrEDTA excretion. Relative fecal dry-weight was determined to quantify diarrhea. Colonic inflammation was determined histologically, and by measuring mucosal interleukin-1β. In addition, colonic mucosal gene expression of individual rats was analyzed, using whole genome microarrays. Interesting results were verified by Q-PCR. Results: The high-calcium diet significantly prevented the increase in intestinal permeability and diarrhea with time in HLA-B27 rats developing colitis as compared to the low-calcium group. The histological colitis score and mucosal interleukin-1β levels were lower in high-calcium fed rats. Supplemental calcium prevented the colitis-induced increase in the expression of extracellular matrix remodeling genes (e.g. matrix metalloproteinases, procollagens and fibronectin), which was confirmed by Q-PCR. Conclusions: Dietary calcium inhibits colitis development in HLA-B27 transgenic rats. Calcium prevents the colitis-related increase in intestinal permeability, diminishes diarrhea, and lowers the inflammatory response in the mucosa, resulting in less extracellular matrix breakdown. Keywords: nutritional intervention
2009-07-17 | GSE11022 | GEO
Project description: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.
2012-06-01 | GSE37588 | GEO
Project description: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. HLA-B27-positive monocytes isolated from human peripheral blood were stimulated with Vibrio cholera lipopolysaccharide (LPS) for 12 hours.
2012-05-31 | E-GEOD-37588 | biostudies-arrayexpress
Project description:HLA-B27 is a class I major histocompatibility (MHC-I) allele that confers susceptibility to the rheumatic disease ankylosing spondylitis (AS) by an unknown mechanism. ERAP1 is an aminopeptidase that trims peptides in the endoplasmic reticulum for binding to MHC-I molecules. ERAP1 shows genetic epistasis with HLA-B27 in conferring susceptibility to AS. Male HLA-B27 transgenic rats develop arthritis and serve as an animal model of AS, whereas female B27 transgenic rats remain healthy. We used large-scale quantitative mass-spectrometry to identify over 15,000 unique HLA-B27 peptide ligands, isolated after immunoaffinity purification of the B27 molecules from the spleens of HLA-B27 transgenic rats. Heterozygous deletion of ERAP1, which reduced ERAP1 level to less than half, had no qualitative or quantitative effects on the B27 peptidome. Homozygous deletion of ERAP1 affected approximately one third of the B27 peptidome, but left most of the B27 peptidome unchanged, suggesting the possibility that some of the HLA-B27 immunopeptidome is not processed in the presence of ERAP1. Deletion on ERAP1 was permissive for the AS-like phenotype. Deletion of ERAP1 increased mean peptide length, and increased the frequency of C-terminal hydrophobic residues and of N-terminal Ala, Ser or Lys. The presence of ERAP1 increased the frequency of C-terminal Lys and Arg, of Glu and Asp at intermediate residues, and of N-terminal Gly. Several peptides of potential interest in AS pathogenesis, previously identified in human cell lines, were isolated. However, rats susceptible to arthritis had B27 peptidomes similar to those of non-susceptible rats, and no peptides were found to be uniquely associated with arthritis. Whether specific B27-bound peptides are required for AS pathogenesis remains to be determined.
2017-02-13 | PXD005502 | Pride
Project description:Background and Aims: We have shown in several controlled rat and human infection studies that dietary calcium improves intestinal resistance and strengthens the mucosal barrier. Reinforcement of gut barrier function is also relevant for inflammatory bowel disease (IBD). Therefore, we investigated the effect of supplemental calcium on spontaneous colitis development in HLA-B27 transgenic rats, an experimental animal model of IBD. Methods: HLA-B27 transgenic rats were fed a purified high-fat diet containing either a low or high calcium content (30 and 120 mmol CaHPO4/kg diet, respectively) for almost 7 weeks. Inert chromium ethylenediamine-tetraacetic acid (CrEDTA) was added to the diets to quantify intestinal permeability by measuring urinary CrEDTA excretion. Relative fecal dry-weight was determined to quantify diarrhea. Colonic inflammation was determined histologically, and by measuring mucosal interleukin-1M-NM-2. In addition, colonic mucosal gene expression of individual rats was analyzed, using whole genome microarrays. Interesting results were verified by Q-PCR. Results: The high-calcium diet significantly prevented the increase in intestinal permeability and diarrhea with time in HLA-B27 rats developing colitis as compared to the low-calcium group. The histological colitis score and mucosal interleukin-1M-NM-2 levels were lower in high-calcium fed rats. Supplemental calcium prevented the colitis-induced increase in the expression of extracellular matrix remodeling genes (e.g. matrix metalloproteinases, procollagens and fibronectin), which was confirmed by Q-PCR. Conclusions: Dietary calcium inhibits colitis development in HLA-B27 transgenic rats. Calcium prevents the colitis-related increase in intestinal permeability, diminishes diarrhea, and lowers the inflammatory response in the mucosa, resulting in less extracellular matrix breakdown. Keywords: nutritional intervention Female HLA-B27/M-NM-22-microglobulin transgenic rats on an inbred Fisher 344 background (n=8 in experimental group and n=9 in control group) (Taconic Farms, Inc, Germantown, NY), 8-10 weeks old and with a mean body weight of 128 g at the start of the experiment, were housed individually in metabolic cages. Animals were kept in a temperature- and humidity-controlled environment and in a 12-h light-dark cycle. Rats were fed a purified M-bM-^@M-^XhumanizedM-bM-^@M-^Y Western diet which contained in the control situation (per kg): 200 g acid casein, 326 g corn starch, 174 g glucose, 160 g palm oil, 40 g corn oil, 50 g cellulose and 5.16 g CaHPO4.2H2O (corresponding to 30 mmol calcium/kg diet; Sigma-Aldrich, St Louis, MO). Vitamins and minerals (other than calcium) were added to all diets according to the recommendations of the American Institute of Nutrition 1993.17 The experimental diet contained more calcium (120 mmol calcium/kg diet) at the expense of glucose. All samples were individually labelled and hybridized (Cy5). Equal amounts of Cy3 cRNA of all animals were pooled to serve as standard reference pool.
2009-07-16 | E-GEOD-11022 | biostudies-arrayexpress
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.
2024-10-17 | PXD047119 | Pride
Project description:In HLA-B27/human beta-2m transgenic rat (B27-rats), the spontaneous development of a chronic inflammatory disorder closely resembling spondyloarthritis (SpA) is strongly correlated with high levels of HLA-B27/human beta-2m transgene expression and with aberrant function of dendritic cells (DCs). To dissect the mechanisms that could be involved in DCs dysfunction, we investigated the genes expression by transcriptomic analysis in DCs from B27 versus controls rats
2014-01-17 | E-MEXP-3808 | biostudies-arrayexpress
Project description:Associations of the Intestinal Microbiome and HLA-B27-associated anterior uveitis
| PRJEB55787 | ENA
Project description:Objectives How HLA-B27 contributes towards arthritis susceptibility is still unclear, but effects on the response to bacteria unrelated to the classical antigen presenting role of B27 have been suggested. This study investigated whether HLA-B27 modulates the innate response to LPS, a component shared between all Gram –ve bacteria that can trigger reactive arthritis. Methods Pools of U937 transfectants expressing either HLA-B27, HLA-A2, or the expression plasmid alone were differentiated with PMA and stimulated with LPS. Supernatants were analysed for TNF-alpha secretion and the gene expression profiles of unstimulated and LPS stimulated cells were determined by microarray analysis. Changes in gene expression that are indicative of an unfolded protein response were also analysed by quantitative PCR. Results TNF-alpha secretion, a biological marker of the inflammatory response to LPS, was not significantly different between U937-B27 and U937-control. No differences in gene expression between unstimulated U937- B27 and U937-control lines were detected. Both U937-control and U937-B27 exhibited a stereotypic response to LPS. Only 1 gene, OAS2, was differentially expressed by these cell lines, and this was confirmed by quantitative PCR. Analysis of XBP-1 splicing suggested that a small increase in the unfolded protein response is induced following LPS stimulation, but this increase was seen in all transfectants. Conclusions The expression of B27 does not profoundly alter gene expression following LPS stimulation. Therefore, additional signals, such as those provided by cytokines or intracellular infection, may be required to reveal any influence of B27 expression on the inflammatory response. Keywords: antigen response
2006-04-10 | GSE4579 | GEO