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Marcus Schmittegenolf - One of the best experts on this subject based on the ideXlab platform.
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familial juvenile onset psoriasis is associated with the human leukocyte antigen hla class i side of the extended haplotype cw6 b57 drb1 0701 dqa1 0201 dqb1 0303 a population and family based study
Journal of Investigative Dermatology, 1996Co-Authors: Marcus Schmittegenolf, Thomas Eiermann, Wolfhenning Boehncke, Markward Stander, Wolfram SterryAbstract:To further evaluate the nature of the HLA association with psoriasis, HLA haplotypes of 60 patients with type 1 (early onset, positive family history) and 30 patients with type II (late onset, no family history) psoriasis were investigated by polymerase chain reaction sequence-specific oligonucleotide hybridization (HLA class II) and serology (HLA class I). Ethnically matched blood donors (146) served as controls. In type I, but not type II psoriasis, the Caucasian HLA extended haplotype (EH) Cw6-B57-DRB1*0701-DQA1*0201-DQB1*0303 named according to the B allele EH-57.1 was highly significantly overrepresented (p cor= 0.00021). This particular EH was present in 35% of type I psoriatics but only 2% of controls. EH-57.1+ individuals therefore carry a 26 times higher risk of developing type I psoriasis than individuals who are EH-57.1-negative Further analysis of individual HLA alleles revealed that within EH-57.1, HLA class I antigens (Cw6-B57) were associated to a much higher extent with type I psoriasis than the HLA class II alleles (DRB1*0701-DQA1*0201-DQB1* 0303). Pedigree analysis of three multiply affected families over three generations revealed a cosegregation of disease with EH-57.1. These results strongly suggest that a gene for familial psoriasis is associated with the class I side of the extended haplotype Cw6-B57-DRB1*0701-DQA1*0201-DQB1*0303.
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familial juvenile onset psoriasis is associated with the human leukocyte antigen hla class i side of the extended haplotype cw6 b57 drb1 0701 dqa1 0201 dqb1 0303 a population and family based study
Journal of Investigative Dermatology, 1996Co-Authors: Marcus Schmittegenolf, Thomas Eiermann, Wolfhenning Boehncke, Markward Stander, Wolfram SterryAbstract:To further evaluate the nature of the HLA association with psoriasis, HLA haplotypes of 60 patients with type 1 (early onset, positive family history) and 30 patients with type II (late onset, no family history) psoriasis were investigated by polymerase chain reaction sequence-specific oligonucleotide hybridization (HLA class II) and serology (HLA class I). Ethnically matched blood donors (146) served as controls. In type I, but not type II psoriasis, the Caucasian HLA extended haplotype (EH) Cw6-B57-DRB1*0701-DQA1*0201-DQB1*0303 named according to the B allele EH-57.1 was highly significantly overrepresented (p cor= 0.00021). This particular EH was present in 35% of type I psoriatics but only 2% of controls. EH-57.1+ individuals therefore carry a 26 times higher risk of developing type I psoriasis than individuals who are EH-57.1-negative Further analysis of individual HLA alleles revealed that within EH-57.1, HLA class I antigens (Cw6-B57) were associated to a much higher extent with type I psoriasis than the HLA class II alleles (DRB1*0701-DQA1*0201-DQB1* 0303). Pedigree analysis of three multiply affected families over three generations revealed a cosegregation of disease with EH-57.1. These results strongly suggest that a gene for familial psoriasis is associated with the class I side of the extended haplotype Cw6-B57-DRB1*0701-DQA1*0201-DQB1*0303.
Wolfram Sterry - One of the best experts on this subject based on the ideXlab platform.
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familial juvenile onset psoriasis is associated with the human leukocyte antigen hla class i side of the extended haplotype cw6 b57 drb1 0701 dqa1 0201 dqb1 0303 a population and family based study
Journal of Investigative Dermatology, 1996Co-Authors: Marcus Schmittegenolf, Thomas Eiermann, Wolfhenning Boehncke, Markward Stander, Wolfram SterryAbstract:To further evaluate the nature of the HLA association with psoriasis, HLA haplotypes of 60 patients with type 1 (early onset, positive family history) and 30 patients with type II (late onset, no family history) psoriasis were investigated by polymerase chain reaction sequence-specific oligonucleotide hybridization (HLA class II) and serology (HLA class I). Ethnically matched blood donors (146) served as controls. In type I, but not type II psoriasis, the Caucasian HLA extended haplotype (EH) Cw6-B57-DRB1*0701-DQA1*0201-DQB1*0303 named according to the B allele EH-57.1 was highly significantly overrepresented (p cor= 0.00021). This particular EH was present in 35% of type I psoriatics but only 2% of controls. EH-57.1+ individuals therefore carry a 26 times higher risk of developing type I psoriasis than individuals who are EH-57.1-negative Further analysis of individual HLA alleles revealed that within EH-57.1, HLA class I antigens (Cw6-B57) were associated to a much higher extent with type I psoriasis than the HLA class II alleles (DRB1*0701-DQA1*0201-DQB1* 0303). Pedigree analysis of three multiply affected families over three generations revealed a cosegregation of disease with EH-57.1. These results strongly suggest that a gene for familial psoriasis is associated with the class I side of the extended haplotype Cw6-B57-DRB1*0701-DQA1*0201-DQB1*0303.
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familial juvenile onset psoriasis is associated with the human leukocyte antigen hla class i side of the extended haplotype cw6 b57 drb1 0701 dqa1 0201 dqb1 0303 a population and family based study
Journal of Investigative Dermatology, 1996Co-Authors: Marcus Schmittegenolf, Thomas Eiermann, Wolfhenning Boehncke, Markward Stander, Wolfram SterryAbstract:To further evaluate the nature of the HLA association with psoriasis, HLA haplotypes of 60 patients with type 1 (early onset, positive family history) and 30 patients with type II (late onset, no family history) psoriasis were investigated by polymerase chain reaction sequence-specific oligonucleotide hybridization (HLA class II) and serology (HLA class I). Ethnically matched blood donors (146) served as controls. In type I, but not type II psoriasis, the Caucasian HLA extended haplotype (EH) Cw6-B57-DRB1*0701-DQA1*0201-DQB1*0303 named according to the B allele EH-57.1 was highly significantly overrepresented (p cor= 0.00021). This particular EH was present in 35% of type I psoriatics but only 2% of controls. EH-57.1+ individuals therefore carry a 26 times higher risk of developing type I psoriasis than individuals who are EH-57.1-negative Further analysis of individual HLA alleles revealed that within EH-57.1, HLA class I antigens (Cw6-B57) were associated to a much higher extent with type I psoriasis than the HLA class II alleles (DRB1*0701-DQA1*0201-DQB1* 0303). Pedigree analysis of three multiply affected families over three generations revealed a cosegregation of disease with EH-57.1. These results strongly suggest that a gene for familial psoriasis is associated with the class I side of the extended haplotype Cw6-B57-DRB1*0701-DQA1*0201-DQB1*0303.
P Bowness - One of the best experts on this subject based on the ideXlab platform.
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interaction of hla b27 homodimers with kir3dl1 and kir3dl2 unlike hla b27 heterotrimers is independent of the sequence of bound peptide
European Journal of Immunology, 2007Co-Authors: S Kollnberger, Antoni Chan, Meiyi Sun, L Chen, Cynthia Wright, Kati Di Gleria, Andrew J Mcmichael, P BownessAbstract:HLA-B27 can form beta-2 microglobulin (β2m)-associated heterotrimers (HLA-B27) and β2m-free homodimers (B272). Here, we study the role of complexed peptide in the interaction of these forms of B27 with the killer cell immunoglobulin (Ig)-like receptors KIR3DL1 and KIR3DL2 and with Ig-like transcripts LILRB1 and LILRB2. HLA-B27 tetramers complexed with three of five different naturally processed self peptides and three of seven pathogen-derived epitopes bound to KIR3DL1-expressing transfectants and NK cells. Heterotrimeric complexes containing peptides with charged amino acids at position 8 did not bind to KIR3DL1; however, studies with analogue peptides demonstrated that these are not the only peptide residues involved in binding. KIR3DL1 ligation by HLA-B27 inhibited NK cell IFN-γ production in a peptide-dependent fashion. B27 but not HLA-A2, B7 or B57 heavy chains formed homodimers in the presence of peptide epitopes. B272 bound to KIR3DL1, KIR3DL2 and LILRB2 but not LILRB1. KIR3DL2 ligation by B272 inhibited NK and T cell IFN-γ production. By contrast with HLA heterotrimers, B272 binding to KIR did not depend on the sequence of the bound peptide. Differences in KIR binding to classical HLA and B272 could be involved in the pathogenesis of spondyloarthritis.
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Use of HLA-B27 tetramers to identify low-frequency antigen-specific T cells in Chlamydia-triggered reactive arthritis
Arthritis Res Ther, 2004Co-Authors: Heiner Appel, S Kollnberger, P Bowness, Wolfgang Kuon, Maren Kuhne, Stefanie Kuhlmann, Andreas Thiel, Joachim SieperAbstract:Reports of the use of HLA-B27/peptide tetrameric complexes to study peptide-specific CD8^+ T cells in HLA-B27^+-related diseases are rare. To establish HLA-B27 tetramers we first compared the function of HLA-B27 tetramers with HLA-A2 tetramers by using viral epitopes. HLA-B27 and HLA-A2 tetramers loaded with immunodominant peptides from Epstein–Barr virus were generated with comparable yields and both molecules detected antigen-specific CD8^+ T cells. The application of HLA-B27 tetramers in HLA-B27-related diseases was performed with nine recently described Chlamydia -derived peptides in synovial fluid and peripheral blood, to examine the CD8^+ T cell response against Chlamydia trachomatis antigens in nine patients with Chlamydia -triggered reactive arthritis (Ct-ReA). Four of six HLA-B27^+ Ct-ReA patients had specific synovial T cell binding to at least one HLA-B27/ Chlamydia peptide tetramer. The HLA-B27/ Chlamydia peptide 195 tetramer bound to synovial T cells from three of six patients and HLA-B27/ Chlamydia peptide 133 tetramer to synovial T cells from two patients. However, the frequency of these cells was low (0.02–0.09%). Moreover, we demonstrate two methods to generate HLA-B27-restricted T cell lines. First, HLA-B27 tetramers and magnetic beads were used to sort antigen-specific CD8^+ T cells. Second, Chlamydia -infected dendritic cells were used to stimulate CD8^+ T cells ex vivo . Highly pure CD8 T cell lines could be generated ex vivo by magnetic sorting by using HLA-B27 tetramers loaded with an EBV peptide. The frequency of Chlamydia -specific, HLA-B27 tetramer-binding CD8^+ T cells could be increased by stimulating CD8^+ T cells ex vivo with Chlamydia -infected dendritic cells. We conclude that HLA-B27 tetramers are a useful tool for the detection and expansion of HLA-B27-restricted CD8^+ T cells. T cells specific for one or more of three Chlamydia -derived peptides were found at low frequency in synovial fluid from HLA-B27^+ patients with Ct-ReA. These cells can be expanded ex vivo , suggesting that they are immunologically functional.
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lymphoblastoid cells express hla b27 homodimers both intracellularly and at the cell surface following endosomal recycling
European Journal of Immunology, 2003Co-Authors: Lucy A Bird, S Kollnberger, Andrew J Mcmichael, Chen Au Peh, Tim Elliott, P BownessAbstract:The MHC class I allele HLA-B27 is very strongly associated with development of autoimmune spondyloarthritis, although the disease mechanism remains unknown. Class I molecules classically associate in the endoplasmic reticulum (ER) with beta2-microglobulin (beta(2)m) and antigenic peptides for cell surface expression and presentation to T cells. We have previously shown that HLA-B27 is capable of forming beta(2)m-free disulfide-bonded homodimers in vitro. Here we show that HLA-B27 forms disulfide-bonded homodimers in vivo by two distinct pathways. HLA-B27 homodimers form in the ER but appear unable to egress to the cell surface in human cells. Cell surface HLA-B27 homodimers are abundantly expressed in a variety of lymphoid cell lines. Experiments with inhibitors indicate that HLA-B27 homodimers can arise from cell-surface heterodimers via an endosome-dependent recycling pathway. HLA-B27 homodimer expression on the cell surface of 721.220 is dependent on the unpaired cysteine(67) and is inhibited by restoration of tapasin function or by incubation with peptides that bind strongly to HLA-B27 heterodimers. Cell surface expressed HLA-B27 homodimers are likely to be immunologically reactive ligands for NK family immunoreceptors and, hence, could play a pathogenic role in spondyloarthritis.
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cell surface expression and immune receptor recognition of hla b27 homodimers
Arthritis & Rheumatism, 2002Co-Authors: S Kollnberger, Meiyi Sun, Andrew J Mcmichael, Lucy A Bird, Christelle Retiere, Veronique M Braud, P BownessAbstract:Objective. HLA–B27 is capable of forming in vitro a heavy-chain homodimer structure lacking 2microglobulin. We undertook this study to ascertain if patients with spondylarthritis express 2-microglobulin– free HLA–B27 heavy chains in the form of homodimers and receptors for HLA–B27 homodimers. Methods. Expression of HLA–B27 heavy chains by mononuclear cells was analyzed by fluorescenceactivated cell sorter staining, Western blotting with the monoclonal antibody HC-10, and 2-dimensional isoelectric focusing. Fluorescence-labeled tetrameric complexes of HLA–B27 heavy-chain homodimers were constructed in which each dimer comprised one His-tagged heavy chain and one biotinylated heavy chain, and were used to stain patient and control mononuclear cells and transfected cell lines. Results. Patients with spondylarthritis expressed cell-surface HLA–B27 homodimers. Populations of synovial and peripheral blood monocytes, and B and T lymphocytes from patients with spondylarthritis, and controls carried receptors for HLA–B27 homodimers. Experiments with transfected cell lines demonstrated that KIR3DL1 and KIR3DL2, and immunoglobulin-like transcript 4 (ILT4), but not ILT2, are receptors for HLA–B27 homodimers. Conclusion. Patients with spondylarthritis express both HLA–B27 heavy-chain homodimers and receptors for HLA–B27 homodimers. This may be of significance with regard to disease pathogenesis.
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cutting edge hla b27 can form a novel beta 2 microglobulin free heavy chain homodimer structure
Journal of Immunology, 1999Co-Authors: Rachel L Allen, Andrew J Mcmichael, Christopher A Ocallaghan, P BownessAbstract:HLA-B27 has a striking association with inflammatory arthritis. We show that free HLA-B27 heavy chains can form a disulfide-bonded homodimer, dependent on residue Cys67 in their extracellular alpha 1 domain. Despite the absence of beta 2-microglobulin, HLA-B27 heavy chain homodimers (termed HC-B27) were stabilized by a known peptide epitope. HC-B27 complexes were recognized by the conformation-specific Ab W6/32, but not the ME1 Ab. Surface labeling and immunoprecipitation demonstrated the presence of similar W6/32-reactive free heavy chains at the surface of HLA-B27-transfected T2 cells. HC-B27 homodimer formation might explain the ability of HLA-B27 to induce spondyloarthropathy in beta 2-microglobulin-deficient mice.
Robert A. Colbert - One of the best experts on this subject based on the ideXlab platform.
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the human leukocyte antigen hla b27 peptidome in vivo in spondyloarthritis susceptible hla b27 transgenic rats and the effect of erap1 deletion
Molecular & Cellular Proteomics, 2017Co-Authors: Eilon Barnea, Tri M Tran, Nimman Satumtira, Martha L Dorris, Robert A. Colbert, Robert E Hammer, Dganit Melamed Kadosh, Yael Haimovich, Mylinh T Nguyen, Joel D. TaurogAbstract: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 the 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 of Erap1 was permissive for the AS-like phenotype, 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. Data are available via ProteomeXchange with identifier PXD005502.
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hla b27 up regulation causes accumulation of misfolded heavy chains and correlates with the magnitude of the unfolded protein response in transgenic rats implications for the pathogenesis of spondylarthritis like disease
Arthritis & Rheumatism, 2007Co-Authors: Matthew J Turner, Shuzhen Bai, Monica L Delay, Erin I Klenk, Robert A. ColbertAbstract:Objective HLA–B27 is implicated in the pathogenesis of spondylarthritis (SpA), yet the molecular mechanisms are incompletely defined. HLA–B27 misfolding has been associated with endoplasmic reticulum stress and activation of the unfolded protein response (UPR) in macrophages from HLA–B27/human β2-microglobulin–transgenic (B27-transgenic) rats. This study was performed to assess the mechanisms that drive activation of the HLA–B27–induced UPR and to determine whether splenocytes respond in a similar manner. Methods Splenocytes were isolated and bone marrow macrophages were derived from B27-transgenic and wild-type rats. Cells were treated for up to 24 hours with cytokines that induce class I major histocompatibility complex expression. HLA–B27 expression and misfolding were assessed by real-time reverse transcription–polymerase chain reaction, flow cytometry, and immunoblotting. Activation of the UPR was measured by quantifying UPR target gene expression and X-box binding protein 1 messenger RNA (mRNA) splicing. Results HLA–B27 mRNA up-regulation was accompanied by a dramatic increase in the accumulation of misfolded heavy chains and preceded robust activation of the UPR in macrophages. When macrophages were treated with various cytokines, the magnitude of the UPR correlated strongly with the degree of HLA–B27 up-regulation. In contrast, B27-transgenic splenocytes exhibited only low-level differences in the expression of UPR target genes after exposure to interferon-γ or concanavalin A, which resulted in minimal HLA–B27 up-regulation. Conclusion These results suggest that HLA–B27–associated activation of the UPR in macrophages is attributable to the accumulation of misfolded heavy chains, and that certain cell types may be more susceptible to the effects of HLA–B27 misfolding. Strategies that eliminate HLA–B27 up-regulation and/or the accumulation of misfolded heavy chains may be useful in evaluating the role of these events in the pathogenesis of SpA.
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hla b27 misfolding in transgenic rats is associated with activation of the unfolded protein response
Journal of Immunology, 2005Co-Authors: Matthew Turner, Joel D. Taurog, Robert A. Colbert, Dawn P Sowders, Monica L Delay, Rajashree Mohapatra, Shuzhen Bai, Judith A Smith, Jaclyn R BrandewieAbstract:The mechanism by which the MHC class I allele, HLA-B27, contributes to spondyloarthritis pathogenesis is unknown. In contrast to other alleles that have been examined, HLA-B27 has a tendency to form high m.w. disulfide-linked H chain complexes in the endoplasmic reticulum (ER), bind the ER chaperone BiP/Grp78, and undergo ER-associated degradation. These aberrant characteristics have provided biochemical evidence that HLA-B27 is prone to misfold. Recently, similar biochemical characteristics of HLA-B27 were reported in cells from HLA-B27/human β 2 -microglobulin transgenic (HLA-B27 transgenic) rats, an animal model of spondyloarthritis, and correlated with disease susceptibility. In this study, we demonstrate that the unfolded protein response (UPR) is activated in macrophages derived from the bone marrow of HLA-B27 transgenic rats with inflammatory disease. Microarray analysis of these cells also reveals an IFN response signature. In contrast, macrophages derived from premorbid rats do not exhibit a strong UPR or evidence of IFN exposure. Activation of macrophages from premorbid HLA-B27 transgenic rats with IFN-γ increases HLA-B27 expression and leads to UPR induction, while no UPR is seen in cells from nondisease-prone HLA-B7 transgenic or wild-type (nontransgenic) animals. This is the first demonstration, to our knowledge, that HLA-B27 misfolding is associated with ER stress that results in activation of the UPR. These observations link HLA-B27 expression with biological effects that are independent of immunological recognition, but nevertheless may play an important role in the pathogenesis of inflammatory diseases associated with this MHC class I allele.
Markward Stander - One of the best experts on this subject based on the ideXlab platform.
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familial juvenile onset psoriasis is associated with the human leukocyte antigen hla class i side of the extended haplotype cw6 b57 drb1 0701 dqa1 0201 dqb1 0303 a population and family based study
Journal of Investigative Dermatology, 1996Co-Authors: Marcus Schmittegenolf, Thomas Eiermann, Wolfhenning Boehncke, Markward Stander, Wolfram SterryAbstract:To further evaluate the nature of the HLA association with psoriasis, HLA haplotypes of 60 patients with type 1 (early onset, positive family history) and 30 patients with type II (late onset, no family history) psoriasis were investigated by polymerase chain reaction sequence-specific oligonucleotide hybridization (HLA class II) and serology (HLA class I). Ethnically matched blood donors (146) served as controls. In type I, but not type II psoriasis, the Caucasian HLA extended haplotype (EH) Cw6-B57-DRB1*0701-DQA1*0201-DQB1*0303 named according to the B allele EH-57.1 was highly significantly overrepresented (p cor= 0.00021). This particular EH was present in 35% of type I psoriatics but only 2% of controls. EH-57.1+ individuals therefore carry a 26 times higher risk of developing type I psoriasis than individuals who are EH-57.1-negative Further analysis of individual HLA alleles revealed that within EH-57.1, HLA class I antigens (Cw6-B57) were associated to a much higher extent with type I psoriasis than the HLA class II alleles (DRB1*0701-DQA1*0201-DQB1* 0303). Pedigree analysis of three multiply affected families over three generations revealed a cosegregation of disease with EH-57.1. These results strongly suggest that a gene for familial psoriasis is associated with the class I side of the extended haplotype Cw6-B57-DRB1*0701-DQA1*0201-DQB1*0303.
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familial juvenile onset psoriasis is associated with the human leukocyte antigen hla class i side of the extended haplotype cw6 b57 drb1 0701 dqa1 0201 dqb1 0303 a population and family based study
Journal of Investigative Dermatology, 1996Co-Authors: Marcus Schmittegenolf, Thomas Eiermann, Wolfhenning Boehncke, Markward Stander, Wolfram SterryAbstract:To further evaluate the nature of the HLA association with psoriasis, HLA haplotypes of 60 patients with type 1 (early onset, positive family history) and 30 patients with type II (late onset, no family history) psoriasis were investigated by polymerase chain reaction sequence-specific oligonucleotide hybridization (HLA class II) and serology (HLA class I). Ethnically matched blood donors (146) served as controls. In type I, but not type II psoriasis, the Caucasian HLA extended haplotype (EH) Cw6-B57-DRB1*0701-DQA1*0201-DQB1*0303 named according to the B allele EH-57.1 was highly significantly overrepresented (p cor= 0.00021). This particular EH was present in 35% of type I psoriatics but only 2% of controls. EH-57.1+ individuals therefore carry a 26 times higher risk of developing type I psoriasis than individuals who are EH-57.1-negative Further analysis of individual HLA alleles revealed that within EH-57.1, HLA class I antigens (Cw6-B57) were associated to a much higher extent with type I psoriasis than the HLA class II alleles (DRB1*0701-DQA1*0201-DQB1* 0303). Pedigree analysis of three multiply affected families over three generations revealed a cosegregation of disease with EH-57.1. These results strongly suggest that a gene for familial psoriasis is associated with the class I side of the extended haplotype Cw6-B57-DRB1*0701-DQA1*0201-DQB1*0303.