Biochemical Features of HLA-B27 and Antigen Processing

Powis, Simon J.; Santos, Susana G.; Antoniou, Antony N.

doi:10.1007/978-1-4419-0298-6_15

Cited by 11 publications

(14 citation statements)

References 41 publications

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“…Intracellular dimers have also been detected in dendritic cells from B27-positive individuals after lipopolysaccharide activation (9). However, it was previously not possible to reproducibly demonstrate cell surface HLA-B27 2 expression in AS patients.…”

Section: Discussionmentioning

confidence: 99%

“…Previous studies have demonstrated that monocytes from patients with AS express more HC10-reactive HLA class I heavy chains than do monocytes from controls (22,23), and this was confirmed here. Intracellular dimers have also been detected in dendritic cells from B27-positive individuals after lipopolysaccharide activation (9). However, it was previously not possible to reproducibly demonstrate cell surface HLA-B27 2 expression in AS patients.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Inhibiting HLA–B27 homodimer–driven immune cell inflammation in spondylarthritis

Payeli¹,

Kollnberger²,

Belaunzaran³

et al. 2012

Arthritis & Rheumatism

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Objective. Spondylarthritides (SpA), including ankylosing spondylitis (AS), are common inflammatory rheumatic diseases that are strongly associated with positivity for the HLA class I allotype B27. HLA-B27 normally forms complexes with ␤ 2 -microglobulin (␤ 2 m) and peptide to form heterotrimers. However, an unusual characteristic of HLA-B27 is its ability to form ␤ 2 m-free heavy chain homodimers (HLA-B27 2 ), which, unlike classic HLA-B27, bind to killer cell immunoglobulinlike receptor 3DL2 (KIR-3DL2). Binding of HLA-B27 2 to KIR-3DL2-positive CD4؉ T and natural killer (NK) cells stimulates cell survival and modulates cytokine production. This study was undertaken to produce an antibody to HLA-B27 2 in order to confirm its expression in SpA and to inhibit its proinflammatory properties.Methods. We generated monoclonal antibodies by screening a human phage display library positively against B27 2 and negatively against B27 heterotrimers. Conclusion. These results demonstrate that antibody HD6 has potential for use in both the investigation and the treatment of AS and other B27-associated spondylarthritides.Positivity for HLA-B27 is strongly associated with ankylosing spondylitis (AS) and other spondylarthritides (SpA) (1-3). However, despite extensive investigation, understanding of the pathogenic role of HLA-B27 is limited (4). The canonical HLA-B27 heterotrimer structure comprises an HLA heavy chain that is noncovalently associated with a monomorphic ␤ 2 -microglobulin (␤ 2 m) light chain and a short peptide derived from self proteins, viruses, or bacteria. These heterotrimeric complexes form in the endoplasmic reticulum and egress to the cell surface, where they are recognized by CD8ϩ cytotoxic T cells through their T cell receptors (5). HLA-B27 can also form ␤ 2 m-free

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Inhibiting HLA–B27 homodimer–driven immune cell inflammation in spondylarthritis

Payeli¹,

Kollnberger²,

Belaunzaran³

et al. 2012

Arthritis & Rheumatism

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“…Relative increase in dimer levels with data normalized to T 0 . Samples were taken at T 0 , T 24 0·8 C5 C9 C10 C16 C17 C19 C20 C21 C26 C28 C33 C40 C43 C46 C48 C50 C61 C63 C64 C65 C66 C68 C69 C70 C71 C74 C75 C78 C79 C2 C4 C80 C87 P1 P2 P3 P5 P6 P7 P8 P9 P10 P12 P13 P14 P15 P16 P17 P18 P19 P20 P21 P22 P23 P26 P27 P28 9,10,16,17,19,20,21,26,28,33,40,44,46,48,50, 61, 63, 64, 65, 66, 68, 69, 70, 71, 74, 75, 78, 79); B27-positive healthy controls (C2, 4, 80, 87) and patient samples (P1, 2,3,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,26,27,28,29,30). Where standard deviations are included, n > 3.…”

Section: Bip Levels In Primary Monocyte-derived DC and Pblmentioning

confidence: 99%

“…Initially it was thought that disease pathogenesis was driven by auto-reactive CD8 + T cells, however, in the absence of a bona fide auto-antigen and because spondyloarthritis still occurs in the absence of CD8 + T cells in disease-prone HLA-B27 transgenic rats, 3 alternative features of the HLA-B27 molecule and its putative role in the aetiology of the disease have been proposed, including the formation of HLA-B27 heavy-chain dimers, and the induction of endoplasmic reticulum (ER) stress. 4,5 The assembly kinetics of HLA-B27 in the ER is slower than many other MHC class I molecules, primarily as a result of the specific residues forming the B-pocket of the peptide-binding groove. 6,7 This increase in the time taken for the heavy chain to fold and exit the ER appears to contribute to the accumulation of misfolded ER-resident molecules, which leads to ER stress and the initiation of the unfolded protein response (UPR).…”

Section: Introductionmentioning

confidence: 99%

Expression of MHC class I dimers and ERAP1 in an ankylosing spondylitis patient cohort

et al. 2011

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Summary The human leucocyte antigen HLA‐B27 is strongly associated with ankylosing spondylitis, a form of seronegative inflammatory arthritis. In this study aspects related to several hypothesized mechanisms of disease pathogenesis have been investigated. Blood monocyte‐derived dendritic cells (DC) from a small patient cohort of 29 patients with ankylosing spondylitis and one with reactive arthritis, were compared with DC from 34 healthy control subjects, of whom four were found to be HLA‐B27 positive. The ability of HLA‐B27 to form heavy‐chain dimers reactive with monoclonal antibody HC10 was tested, along with the induction of endoplasmic reticulum (ER) stress, assessed by splicing xbp1 mRNA and immunoblotting of Immunoglobulin Binding Protein (BiP). Additionally, the protein expression levels of the ER resident aminopeptidase gene ERAP1 in patients with ankylosing spondylitis was also determined, following its recent identification as a novel disease‐associated gene. No significant difference was noted in the global levels of HC10‐reactive MHC class I dimers formed in either the patient or control DC populations. Stress on the ER, as determined by xbp1 mRNA splicing, was not detected but lower levels of BiP were observed in the DC from patients. Of further potential interest, in this patient cohort the expression of ERAP1 appeared to be higher in a number of patient DC samples when compared with controls, suggesting over‐expression of ERAP1 as a mechanism promoting ankylosing spondylitic pathogenesis.

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“…In brief, there are two important characteristic structures which are different from others: the presence of B pocket and the free thiol group of Cys67 (Madden, 1995;Powis et al, 2009). …”

Section: Structure Subtypes and Epidemiology Of Hla-b27mentioning

confidence: 99%

HLA-B27 and Ankylosing Spondylitis

Tsai¹

2012

Clinical and Molecular Advances in Ankylosing Spondylitis

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Biochemical Features of HLA-B27 and Antigen Processing

Cited by 11 publications

References 41 publications

Inhibiting HLA–B27 homodimer–driven immune cell inflammation in spondylarthritis

Inhibiting HLA–B27 homodimer–driven immune cell inflammation in spondylarthritis

Expression of MHC class I dimers and ERAP1 in an ankylosing spondylitis patient cohort

HLA-B27 and Ankylosing Spondylitis

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