HLA‐B27 and the pathogenesis of spondyloarthritis

Ramos, Manuel; Castro, José A. Łópez de

doi:10.1034/j.1399-0039.2002.600301.x

Cited by 98 publications

(104 citation statements)

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“…HLA-B27 subtypes bind distinct but overlapping peptide repertoires, a feature that correlates with differential association of the subtypes with AS (16,26,27). However, since the identification of putative arthritogenic peptides remains elusive and the role of CD8 T cells in B27-associated disease in transgenic rats has been questioned (42), other alternatives must be considered.…”

Section: Discussionmentioning

confidence: 99%

“…One way to test some of these hypotheses is to take advantage of the differential association between AS and natural B27 subtypes, which differ from each other by one or few amino acid residues as well as peptide specificity (16). HLA-B*2705, B*2702, and B*2704 are strongly associated with AS, but B*2706 and B*2709 are either not associated or are only weakly associated.…”

mentioning

confidence: 99%

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Similar cell surface expression of β₂‐microglobulin–free heavy chains by HLA–B27 subtypes differentially associated with ankylosing spondylitis

Vázquez

Castro

2005

Arthritis & Rheumatism

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Objective. To determine whether the cell surface features of HLA-B27 subtypes reported to be differentially associated with ankylosing spondylitis (AS) differ in a way that correlates with disease susceptibility.Methods. Human cell transfectants expressing or lacking the transporter associated with antigen processing were used to determine the cell surface expression of B27 subtypes by flow cytometry with antibodies recognizing the B27 heterodimer or ␤ 2 -microglobulin (␤ 2 m)-free heavy chains.Results. In lymphoid cells with an intact peptideloading complex, all B27 subtypes, irrespective of their association with disease, showed similar ratios of free heavy chain to heterodimer, suggesting similar surface stability. A substantial decrease in dissociated heavy chains, which never reached 100%, was observed upon addition of a B27 ligand, with no significant differences among subtypes. This is compatible with similar surface expression of irreversible ␤ 2 m-free heavy chain forms among subtypes differentially associated with disease. In cells lacking the transporter associated with antigen processing, both disease-associated and non-diseaseassociated subtypes expressed a population of heterodimers at 26°C that was less stable than the population expressed at 37°C. In the presence of exogenous peptide, the expression of heterodimers increased, without a concomitant decrease in ␤ 2 m-free heavy chains. This suggests that in these cells, and for all subtypes tested, most of the dissociated heavy chains at the cell surface are in irreversible forms. At 37°C, the expression of ␤ 2 m-free B27 heavy chains was very low on T2 transfectant cells. Conclusion. HLA-B27 subtypes showing differential associations with AS are similar in their extent of ␤ 2 m dissociation and surface expression of free heavy chains.Class I major histocompatibility complex (MHC) proteins are heterodimers consisting of a polymorphic heavy chain that is noncovalently bound to ␤ 2 -microglobulin (␤ 2 m), a nonpolymorphic polypeptide. Assembly of MHC molecules takes place in the endoplasmic reticulum (ER), where they constitutively bind peptides. These arise mainly from proteasomal degradation in the cytosol, are transported into the lumen of the ER by means of the transporter associated with antigen processing (TAP), and bind, sometimes after trimming, to the class I molecule in a process involving several proteins collectively known as the peptide-loading complex (1). Peptides bound with sufficient affinity stabilize the native conformation of the nascent class I molecule. When this happens, the peptide-MHC complex is released from the ER and traffics to the cell surface. In cells lacking TAP, the peptide supply into the ER and the expression of class I MHC are drastically reduced. However, at 26°C, MHC molecules that are presumably devoid of peptide can be sufficiently stable to leave the ER and reach the cell surface (2).The ␤ 2 m-free class I MHC polypeptides are found at the cell surface. This can be revealed, for example, by cell surface stain...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Similar cell surface expression of β₂‐microglobulin–free heavy chains by HLA–B27 subtypes differentially associated with ankylosing spondylitis

Vázquez

Castro

2005

Arthritis & Rheumatism

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“…Importantly, Cys 67 is a feature that is shared by a relatively small cohort of class I alleles, including subtypes of HLA-B14, -B15, -B38, -B39, and -B73 (49). It is unknown whether these subtypes also form HCdimeric structures, although it is interesting to note that HLA-B39 is also reportedly linked to SpA (50,51). In this report, we have demonstrated that HC-dimer formation can be prevented by replacement of the structural Cys 164 residue.…”

Section: Effect Of Reduced Temperature and Cysmentioning

confidence: 99%

Formation of HLA-B27 Homodimers and Their Relationship to Assembly Kinetics

Antoniou

Ford

Taurog

et al. 2004

Journal of Biological Chemistry

143

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The human HLA-B27 class I molecule exhibits a strong association with the inflammatory arthritic disorder ankylosing spondylitis and other related arthropathies. Major histocompatibility complex class I heavy chains normally associate with ␤ 2 -microglobulin and peptide in the endoplasmic reticulum before transit to the cell surface. However, an unusual characteristic of HLA-B27 is its ability to form heavy chain homodimers through an unpaired cysteine at position 67 in the peptide groove. Homodimers have previously been detected within the ER and at the cell surface, but their mechanism of formation and role in disease remain undefined. Here we demonstrate, in the rat C58 thymoma cell line and in human HeLa cells transfected with HLA-B27, that homodimer formation involves not only cysteine at position 67 but also the conserved structural cysteine at position 164. We also show that homodimer formation can be induced in the non-disease-associated HLA class I allele HLA-A2 by slowing its assembly rate by incubation of cells at 26°C, suggesting that homodimer formation in the endoplasmic reticulum may occur as a result of the slower folding kinetics of HLA-B27. Finally, we report an association between unfolded HLA-B27 molecules and immunoglobulin-binding protein at the cell surface.

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“…Although the etiology of AS is unknown, several studies suggest T-cell autoreactivity, genetic and molecular associations, and infections contribute to its progression (14). Defects in coinhibitory molecules may cause autoimmune disorders.…”

Section: Discussionmentioning

confidence: 99%

Serum sCTLA-4 levels and clinical manifestations in ankylosing spondylitis patients

et al. 2018

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HLA‐B27 and the pathogenesis of spondyloarthritis

Cited by 98 publications

References 76 publications

Similar cell surface expression of β₂‐microglobulin–free heavy chains by HLA–B27 subtypes differentially associated with ankylosing spondylitis

Similar cell surface expression of β₂‐microglobulin–free heavy chains by HLA–B27 subtypes differentially associated with ankylosing spondylitis

Formation of HLA-B27 Homodimers and Their Relationship to Assembly Kinetics

Serum sCTLA-4 levels and clinical manifestations in ankylosing spondylitis patients

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HLA‐B27 and the pathogenesis of spondyloarthritis

Cited by 98 publications

References 76 publications

Similar cell surface expression of β2‐microglobulin–free heavy chains by HLA–B27 subtypes differentially associated with ankylosing spondylitis

Similar cell surface expression of β2‐microglobulin–free heavy chains by HLA–B27 subtypes differentially associated with ankylosing spondylitis

Formation of HLA-B27 Homodimers and Their Relationship to Assembly Kinetics

Serum sCTLA-4 levels and clinical manifestations in ankylosing spondylitis patients

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Product

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Similar cell surface expression of β₂‐microglobulin–free heavy chains by HLA–B27 subtypes differentially associated with ankylosing spondylitis

Similar cell surface expression of β₂‐microglobulin–free heavy chains by HLA–B27 subtypes differentially associated with ankylosing spondylitis