Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P01889 (ankylosing spondylitis)
 5,717 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

HLA-B27 is strongly associated with susceptibility to ankylosing spondylitis and other spondyloarthropathies. Structural analysis of this antigen has revealed the existence of multiple variants, or subtypes, in human populations. The structural microheterogeneity of these subtypes deeply affects allospecific T cell recognition and most of it occurs at an spatial cluster within the peptide binding groove of the molecule. Many polymorphic residues whose combination is unique to HLA-B27 but is conserved among subtypes are clustered in a spatially separated site of the groove from that where most subtype polymorphism occurs. Site-directed mutagenesis and DNA-mediated gene transfer has been used to show that the positions that are polymorphic among subtypes are highly relevant for modulating T cell recognition, so that immunologically silent changes do not occur. These studies have also revealed an extremely high clonotypic diversity in the alloreactive response against HLA-B27. The structural basis for this diversity has been examined by sequencing the clonotypic T cell receptors. The analysis shows a certain bias in V beta gene segment usage, as well as other recurrent structural motives, among T cell receptor beta chains from HLA-B27-specific cytotoxic T cell clones.
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PMID:Structure and immune recognition of HLA-B27 antigens: implications for disease association. 170 18

In childhood, the histocompatibility antigen HLA-B27 is associated with juvenile ankylosing spondylitis, Reiter's syndrome, and the sacroiliitis of juvenile psoriatic arthritis, and inflammatory bowel diseases. The low frequency of signs or symptoms of spine or sacroiliac joint disease at onset differentiate these disorders from their adult counterparts and make early diagnosis difficult. The presence of enthesitis and the absence of rheumatoid factor and antinuclear antibody suggests the diagnosis of one of the seronegative spondyloarthropathies. The mechanisms by which HLA-B27 positivity confers susceptibility to disease are uncertain. To date, no genetically determined differences in the HLA-B27 molecule, or in the T cell receptor which recognizes antigen in the context of HLA-B27, have been consistently shown to be associated with the presence of disease. There is no explanation for the onset of disease in childhood in some individuals.
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PMID:HLA-B27 and rheumatic diseases of childhood. 208 18

The T gamma-lymphoproliferative syndrome is characterized by a proliferation of large granular lymphocytes (LGL). It is often associated with neutropenia, and in 30% of cases with rheumatoid arthritis (RA). Phenotypic analysis has demonstrated that in most cases of RA with T gamma-proliferative disease, the LGL represent T cells with a clonal rearrangement of the alpha/beta T cell receptor (TCR2). Here, three patients with gamma/delta TCR1+ LGL proliferation suffering from long-standing arthritis and neutropenia are described. The first patient with RA showed an expansion of a heterogeneous CD2+ CD16+ CD56- LGL population, of which 30% coexpressed TCR1 with V delta 1 rearrangement. The second patient with ankylosing spondylitis and RA was suffering from proliferation of TCR1+ (V gamma 9-, V delta 1-), CD2+ CD16- CD56- LGL with low coexpression of CD8. The third patient with RA was suffering from a proliferation of TCR1+ (V delta 1+, V gamma 9-) CD4- CD8- CD16- CD56- lymphocytes. On the basis of these unusual findings, the pathogenetic role of TCR1+ T cells in RA is discussed.
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PMID:TCR1+ large granular lymphocyte proliferation in rheumatoid arthritis. 787 35

Little is known about the mechanisms triggering and controlling both the development and perpetuation of extraintestinal complications in CD. The aim of the present study was to test the hypothesis that the T cell immune response in CD patients with joint complications may be altered when compared with patients without extraintestinal manifestations. We used a semiquantitative polymerase chain reaction assay to analyse the T cell antigen receptor repertoire in peripheral blood T cells from eight CD patients suffering from peripheral arthritis and ankylosing spondylitis, 12 CD patients without extraintestinal manifestations, and from seven non-CD patients with ankylosing spondylitis showing typical changes on joint radiographs. Being concerned that different patterns may be seen in different phases of the inflammatory disease process, we have also taken care to analyse sequential samples at various time points of the disease. Expression of all 22 V beta genes was found in each healthy control and in each CD patient without extraintestinal manifestations and showed no major variation over time. Southern hybridization analysis of amplified products revealed a highly restricted V beta repertoire in all CD patients suffering from peripheral arthritis and ankylosing spondylitis. In contrast, non-CD patients with ankylosing spondylitis without signs or symptoms of gastrointestinal problems demonstrated the presence of the entire V beta repertoire. Our longitudinal studies confirmed variable V beta usage over time, as certain transcripts were found only in distinct temporal phases of disease. Our data are not directly suggestive of a common superantigen model of CD, but instead emphasize a specific decrease in signals throughout the T cell receptor V beta repertoire in CD patients suffering from joint complications.
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PMID:Crohn's disease (CD) patients suffering from peripheral arthritis or ankylosing spondylitis reveal restricted T cell receptor V beta regions in different temporal phases of disease. 870 34

For more than 30 years, human leukocyte antigen B27 (HLA-B27) has been known to be closely related to the autoimmune disease ankylosing spondylitis, yet little is known about the molecular mechanisms of pathogenesis. Crystal structures of two closely related, but differently disease-associated, subtypes (B*2705 and B*2709) also did not resolve this situation as they revealed the bound nonapeptide in essentially identical conformations. As the peptide is part of putative binding epitopes for the T cell receptor, we performed molecular dynamics simulations to gain deeper insight into the dynamic behaviour of HLA-B27 molecules. We find increased flexibility of the peptide in the binding groove of subtype B*2709 due to weaker interactions in the F pocket. Possible implications of this flexibility for T cell recognition and signalling are discussed.
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PMID:A single residue exchange between two HLA-B27 alleles triggers increased peptide flexibility. 1501 9

To investigate the pathogenesis of abnormal ossification of the hip ligament in patients with ankylosing spondylitis (AS) by comparing gene expression profiles of the hip ligament in patients with AS to those in normal persons using DNA microarray technology, we studied 18 patients with AS (case group) who underwent total hip arthroplasty in our department from March 1, 2009 to January 31, 2010 and compared them with 6 patients with femoral neck fracture (control group) who underwent total hip replacement. We screened the first five patients in each group with the HumanWG-6 v3.0 Expression BeadChip. Compared to the control group, 519 genes in the case group showed statistically significant differences. Among these, there were 238 upregulated genes and 196 downregulated genes. Gene Ontology (GO) classification showed that differential genes in the hip joint ligaments of patients with AS were involved in immunity, cell adhesion, membrane transport, sugar metabolism, polysaccharide synthesis and metabolism, and cell motility. The Kyoto Encyclopedia of Genes and Genomes classification showed that these differential genes were involved in B cell receptor signaling pathways, adherens junction, protein export, fructose and mannose metabolism, T cell receptor signaling pathways, keratin sulfate biosynthesis, N-glycan biosynthesis, and regulation of the actin cytoskeleton. We tested 2 genes from the screened differential genes in 18 case patients and 6 control cases using real-time polymerase chain reaction. The results demonstrated that the expression of the B4GALT3 gene in the case group was 15.32 times higher than that in the control group (P < 0.01), and the expression of the RBP5 gene in the case group was 4.09 times higher than that in the control group (P < 0.01). This conformed to the microarray analysis. Our preliminary data suggest that differential gene expression in patients with AS includes the immune system, intracellular or extracellular signaling pathway, and bone matrix biosynthesis pathway, which might play important roles in hip joint ligament ossification.
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PMID:Changes in gene expression profiles of the hip joint ligament of patients with ankylosing spondylitis revealed by DNA chip. 2290 99

Hypervariable T cell receptors (TCRs) play a key role in adaptive immunity, recognizing a vast diversity of pathogen-derived antigens. Our ability to extract clinically relevant information from large high-throughput sequencing of TCR repertoires (RepSeq) data is limited, because little is known about TCR-disease associations. We present Antigen-specific Lymphocyte Identification by Clustering of Expanded sequences (ALICE), a statistical approach that identifies TCR sequences actively involved in current immune responses from a single RepSeq sample and apply it to repertoires of patients with a variety of disorders - patients with autoimmune disease (ankylosing spondylitis [AS]), under cancer immunotherapy, or subject to an acute infection (live yellow fever [YF] vaccine). We validate the method with independent assays. ALICE requires no longitudinal data collection nor large cohorts, and it is directly applicable to most RepSeq datasets. Its results facilitate the identification of TCR variants associated with diseases and conditions, which can be used for diagnostics and rational vaccine design.
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PMID:Detecting T cell receptors involved in immune responses from single repertoire snapshots. 3119 32

Purpose: Anterior uveitis is the most common anatomic subset of uveitis. We developed a novel multi-parametric flow cytometry panel to identify immune dysregulation signatures in HLA B27-associated acute anterior uveitis (AAU) and axial spondyloarthritis (AxSpA).Methods: We used fluorescence activated cell sorting to characterize T cell cytokine expression in stimulated T cell subsets from patients with AAU (n = 4) compared to healthy controls (n = 14) or subjects with AxSpA (n = 6).Results: Positive findings among subjects with AAU included a statistically significant increase in stimulated granulocyte-macrophage colony stimulating factor (GM-CSF), IL-17, and IL-22 synthesized by CD8 cells, a trend for stimulated ILC (innate lymphoid cells)-3 cells to synthesize more IL-22 (p = .07), and stimulated MAIT (mucosa associated innate lymphoid cells)-like cells that express the T cell receptor V alpha 7.2 to express IL-17A, IL-17F, and IL-22 in a greater percentage of cells relative to controls. IL-17F, GM- CSF, and IL-22 represent potentially novel targets in AAU.Conclusion: Our report is arguably the first to implicate IL-17F or ILC-3 and MAIT cells in the pathogenesis of AAU.Abbreviations AAU: acute anterior uveitis; AxSpA: axial spondyloarthritis; BASDAI: Bath ankylosing spondylitis disease activity index; CCR: chemokine receptor; DMSO: dimethylsulfoxide; EULAR:European League Against Rheumatism; FACS: fluorescence activated cell sorter; FBS: fetal bovine serum; FSC: orward light scatter; GM-CSF: granulocyte-macrophage colony stimulating factor; HC: healthy control; ILC: innate lymphoid cell; KIR: killer immunoglobulin receptor; MAIT: mucosal associated immune T cell; ND: not detected; NK: natural killer cell; OHSU-Oregon Health & Science University; PBMC: peripheral blood mononuclear cell; SSC: side light scatter; TCR: T cell receptor.
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PMID:Preliminary Report on Interleukin-22, GM-CSF, and IL-17F in the Pathogenesis of Acute Anterior Uveitis. 3176 50