The Recognition of HLA-B27 by Human CD4+ T Lymphocytes

Boyle, Louise H.; Goodall, Jane C.; Opat, Stephen; Gaston, J. S. H.

doi:10.4049/jimmunol.167.5.2619

Cited by 105 publications

(59 citation statements)

References 34 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The relative merits of these and other ideas remain to be determined. It is of interest that Boyle et al (32) have isolated CD4 T cells from patients with ankylosing spondylitis that appear to recognize forms of HLA-B27 preferentially expressed on T2.B27 and .220.B27 cells, although present perhaps at lower levels on C1R.B27 (32). These responses could be blocked with W6/32 and ME.1, but not HC10, leading to the suggestion that the T cells might be recognizing dimers.…”

Section: Discussionmentioning

confidence: 99%

“…Along these lines, effects of HLA-B27 expression in monocytes and epithelial cells that cannot be explained by its function as an antigen presenting molecule have been described (28 -30). Other ideas focusing on T cell recognition of dimers as aberrant structures have also been proposed (31,32). These observations raise several questions, in particular whether HLA-B27 dimerization occurs in cells with an intact antigen presentation pathway and is related to events occurring in the ER.…”

mentioning

confidence: 99%

See 1 more Smart Citation

HLA-B27 Misfolding Is Associated with Aberrant Intermolecular Disulfide Bond Formation (Dimerization) in the Endoplasmic Reticulum

Dangoria¹,

DeLay²,

Kingsbury³

et al. 2002

Journal of Biological Chemistry

225

252

View full text Add to dashboard Cite

The class I protein HLA-B27 confers susceptibility to inflammatory arthritis in humans and when overexpressed in rodents for reasons that remain unclear. We demonstrated previously that HLA-B27 heavy chains (HC) undergo endoplasmic reticulum (ER)-associated degradation. We report here that HLA-B27 HC also forms two types of aberrant disulfide-linked complexes (dimers) during the folding and assembly process that can be distinguished by conformation-sensitive antibodies W6/32 and HC10. HC10-reactive dimers form immediately after HC synthesis in the ER and constitute at least 25% of the HC pool, whereas W6/32-reactive dimers appear several hours later and represent less than 10% of the folded HC. HC10-reactive dimers accumulate in the absence of tapasin or ␤ 2 -microglobulin, whereas W6/ 32-reactive dimers are not detected. Efficient formation of W6/32-reactive dimers appears to depend on the transporter associated with antigen processing, tapasin, and ␤ 2 -microglobulin. The unpaired Cys 67 and residues at the base of the B pocket that dramatically impair HLA-B27 HC folding are critical for the formation of HC10-reactive ER dimers. Although certain other alleles also form dimers late in the assembly pathway, ER dimerization of HLA-B27 may be unique. These results demonstrate that residues comprising the HLA-B27 B pocket result in aberrant HC folding and disulfide bond formation, and thus confer unusual properties on this molecule that are unrelated to peptide selection per se, yet may be important in disease pathogenesis.

show abstract

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

HLA-B27 Misfolding Is Associated with Aberrant Intermolecular Disulfide Bond Formation (Dimerization) in the Endoplasmic Reticulum

Dangoria¹,

DeLay²,

Kingsbury³

et al. 2002

Journal of Biological Chemistry

225

252

View full text Add to dashboard Cite

show abstract

“…Reports that CD4 T-cells can recognize normal and abnormal forms of HLA-B27 have emerged, 81 raising the question of whether this might explain the importance of these cells for SpA-like disease in B27/ hβ 2 m transgenic rats and also be involved in human disease. For human studies, CD4 T-cells were raised by stimulation with T2 cells transfected with HLA-B27.…”

Section: Hla-b27 Misfoldingmentioning

confidence: 99%

“…For human studies, CD4 T-cells were raised by stimulation with T2 cells transfected with HLA-B27. 81 T2 cells are missing a large region of the major histocompatibility complex (MHC) including TAP1 and TAP2 genes and thus are unable to transport peptides into the ER from the cytosol. They have been reported to express HLA-B27 homodimers, 24 although this was not observed in other studies.…”

Section: Hla-b27 Misfoldingmentioning

confidence: 99%

HLA-B27 Misfolding and Spondyloarthropathies

Colbert

DeLay

Layh‐Schmitt

et al. 2009

Advances in Experimental Medicine and Biology

View full text Add to dashboard Cite

HLA-B27 plays a central role in the pathogenesis of many spondyloarthropathies and in particular ankylosing spondylitis. The observation that the HLA-B27 heavy chain has a tendency to misfold has raised the possibility that associated diseases may belong in a rapidly expanding category of protein misfolding disorders. The synthesis of the HLA-B27 heavy chain, assembly with β 2 m and the loading of peptide cargo, occurs in the endoplasmic reticulum (ER) before transport to the cell surface. The evidence indicates that misfolding occurs in the ER prior to β 2 m association and peptide optimization and is manifested in the formation of aberrant inter-and intra-chain disulfide bonds and accumulation of heavy chain bound to the chaperone BiP. Enhanced accumulation of misfolded heavy chains during the induction of class I expression by cytokines, can cause ER stress resulting in activation of the unfolded protein response (UPR).Effects of UPR activation on cytokine production are beginning to emerge and may provide important missing links between HLA-B27 misfolding and spondyloarthritis. In this chapter we will review what has been learned about HLA-B27 misfolding in human cells and in the transgenic rat model of spondyloarthritis-like disease, considering it in the context of other protein misfolding disorders. These studies provide a framework to support much needed translational work assessing HLA-B27 misfolding and UPR activation in patient-derived material, its consequences for disease pathogenesis and ultimately how and where to focus intervention strategies.

show abstract

“…They developed diseases such as ankylosing enthesopathy, and rats with a high copy number of HLA-B*2705 developed axial and peripheral arthritis, gut inflammation, and lesions on the skin. Rats and mice that were kept in sterile environments did not develop joint disease or gut inflammation [2,3]. Development of the disease was dependent on the presence of gut bacteria and a high copy number of HLA-B27 in cells of bone-marrow lineage.…”

Section: Introductionmentioning

confidence: 99%

Usage of Conventional PCR Technology for the Detection of HLA-B27 Allele: A Significant Molecular Marker of Ankylosing Spondylitis

Sharma

Masood

et al. 2012

Ind J Clin Biochem

View full text Add to dashboard Cite

Ankylosing spondylitis is a chronic inflammatory disease that has been linked to the human leukocyte antigen class I allele HLA-B27. More than 90 % of patients with ankylosing spondylitis possess the HLA-B27 allele, but only 1 % of people with HLA-B27 develop the disease. Ankylosing spondylitis predominately affects young males. The present study was planned to find out the involvement of HLA-B27 specific allele in relation to age and sex in symptomatic suspected patients of ankylosing spondylitis using conventional PCR technology. Forty symptomatic patients of ankylosing spondylitis were included in the present study. SSP-PCR technique was used to detect the HLA-B27 specific allele. This study showed (out of 40 symptomatic suspected cases of ankylosing spondylitis only 12 patients were detected positive with HLA-B27 allele, while remaining 28 were negative) that the positivity rate for ankylosing spondylitis with HLA-B27 allele is low. Furthermore, it was observed that the males above 50 years are more prone to develop AS with HLA-B27 specific allele. It could be concluded that the conventional PCR technology is a rapid, sensitive, and confirmatory method for the diagnosis of ankylosing spondylitis.

show abstract

The Recognition of HLA-B27 by Human CD4+ T Lymphocytes

Cited by 105 publications

References 34 publications

HLA-B27 Misfolding Is Associated with Aberrant Intermolecular Disulfide Bond Formation (Dimerization) in the Endoplasmic Reticulum

HLA-B27 Misfolding Is Associated with Aberrant Intermolecular Disulfide Bond Formation (Dimerization) in the Endoplasmic Reticulum

HLA-B27 Misfolding and Spondyloarthropathies

Usage of Conventional PCR Technology for the Detection of HLA-B27 Allele: A Significant Molecular Marker of Ankylosing Spondylitis

Contact Info

Product

Resources

About