The arthritis-associated HLA-B*27:05 allele forms more cell surface B27 dimer and free heavy chain ligands for KIR3DL2 than HLA-B*27:09

Cauli, Alberto; Shaw, Jacqueline; Giles, Joanna; Hatano, Hiroko; Ryśnik, Oliwia; Payeli, Sravan; McHugh, Kirsty; Dessole, G.; Porru, Giovanni; Desogus, Elisabetta; Fiedler, Sarah E.; Hölper, Soraya; Carette, Amanda; Blanco-Gelaz, Miguel Ángel; Vacca, Alessandra; Piga, Matteo; Ibba, V.; Garau, Pietro; Nasa, Giorgio La; López‐Larrea, Carlos; Mathieu, Alessandro; Renner, Christoph; Bowness, Paul; Kollnberger, Simon

doi:10.1093/rheumatology/ket219

Cited by 52 publications

(39 citation statements)

References 38 publications

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“…When ERAP is absent, such peptide presentation to newly synthesized B27 molecules is impaired. This result may contribute to two of the proposed mechanisms whereby HLA-B27 contributes to disease pathogenesis, namely, misfolding of the HC of B27 within the ER, resulting in an unfolded protein response (28) phenomenon; and homodimerization of the B27 HC, leading to altered interaction with NK cells (29,30). These two phenomena associated with B27 may lead to slower transport of a diminished number of mature B27 molecules to the cell surface.…”

Section: Discussionmentioning

confidence: 99%

HLA-B27, but Not HLA-B7, Immunodominance to Influenza Is ERAP Dependent

Akram

Lin

Gracey

et al. 2014

The Journal of Immunology

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Endoplasmic reticulum–associated aminopeptidase-1 (ERAP1) plays a critical role in the processing of peptides prior to binding to MHC class I molecules. In this article, we show for the first time, to our knowledge, that the HLA-B27 immunodominant influenza nucleoprotein (NP) 383–391 epitope is made as an N-terminally extended 14-mer before it is trimmed by ERAP. In the absence of ERAP, there is a significant reduction in the CTL response to the B27/NP383–391 epitope in influenza A (flu)–infected B27/ERAP−/− mice. With the use of tetramer staining, the number of naive CD8+ T cells expressing TCR Vβ8.1 in B27/ERAP−/− transgenic mice is significantly lower than that seen in B27/ERAP+/+ mice. HLA-B27 surface expression in naive and flu-infected B27/ERAP−/− mice is also lower than the expression seen for the same allele in naive and flu-infected B27/ERAP+/+ mice. In contrast, surface expression of HLA-B7 was unaffected by the absence of ERAP in B7/ERAP−/− transgenic mice. The B7-restricted NP418–426 CTL response in flu-infected B7/ERAP−/− and B7/ERAP+/+ mice was also similar. These results provide, to our knowledge, the first in vivo demonstration of ERAP functionally influencing host immune response in an HLA allele-specific manner. This principle has relevance to diseases such as ankylosing spondylitis, in which HLA-B27 and ERAP jointly contribute to disease predisposition.

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Section: Discussionmentioning

confidence: 99%

HLA-B27, but Not HLA-B7, Immunodominance to Influenza Is ERAP Dependent

Akram

Lin

Gracey

et al. 2014

The Journal of Immunology

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“…Moreover, one report highlighted that B*2706, unlike B*2709, expressed the highest surface level of FHC, probably reflecting the poor tapasin dependence during the assembly process which produces more dissociation-prone heterotrimeric complexes [39]. More recently, Cauli and co-workers, using transfected cells, have shown that a higher cell surface FHC expression of B*2705 versus B*2709 could contribute to the differential diseaseassociation [40].…”

Section: Introductionmentioning

confidence: 99%

The interplay between HLA-B27 and ERAP1/ERAP2 aminopeptidases: from anti-viral protection to spondyloarthritis

Vitulano

Tedeschi

Paladini

et al. 2017

Clinical and Experimental Immunology

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1These authors contributed equally to this study. SummaryThe human leukocyte antigen class I gene HLA-B27 is the strongest risk factor for ankylosing spondylitis (AS), a chronic inflammatory arthritic disorder. More recently, the Endoplasmic Reticulum Aminopeptidase (ERAP) 1 and 2 genes have been identified by genome wide association studies (GWAS) as additional susceptibility factors. In the ER, these aminopeptidases trim the peptides to a length suitable to fit into the groove of the major histocompatibility complex (MHC) class I molecules. It is noteworthy that an epistatic interaction between HLA-B27 and ERAP1, but not between HLA-B27 and ERAP2, has been highlighted. However, these observations suggest a paramount centrality for the HLA-B27 peptide repertoire that determines the natural B27 immunological function, i.e. the T cell antigen presentation and, as a by-product, elicits HLA-B27 aberrant behaviours: (i) the misfolding leading to ER stress responses and autophagy and (ii) the surface expression of homodimers acting as ligands for innate immune receptors. In this context, it has been observed that the HLA-B27 carriers, besides being prone to autoimmunity, display a far better surveillance to some viral infections. This review focuses on the ambivalent role of HLA-B27 in autoimmunity and viral protection correlating its functions to the quantitative and qualitative effects of ERAP1 and ERAP2 polymorphisms on their enzymatic activity.

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“…HeLa and C1R cells expressing HLA-B*27 and six mutants at P97 (N97T, N97S, N97V, N97R, N97W and N97D) were generated using lentiviral constructs described previously 17. HeLa and C1R cells expressing HLA-B*7 and its P97 mutants (S97N, S97T and S97D), HeLa and 221 cells expressing HLA-B*51 and its P97 mutants (T97N and T97D) were also generated using lentiviruses.…”

Section: Methodsmentioning

confidence: 99%