Pathogenicity of Misfolded and Dimeric HLA-B27 Molecules

Antoniou, Antony N.; Lenart, Izabela; Guiliano, David B.

doi:10.1155/2011/486856

Cited by 14 publications

(17 citation statements)

References 74 publications

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“…First, the HLA-B27 displays an altered folding rate during the assembly into the ER [9,21,22]. This misfolding is a consequence of the particularly slow HLA-B27 maturation rate that triggers the endoplasmic reticulum (ER)-associated degradation (ERAD) of the heavy chains [22].…”

Section: Introductionmentioning

confidence: 99%

“…Another peculiarity of the HLA-B27 is related to its expression on the cell surface as a non-canonical form made by b2m-free homodimers [9,21,28]. The formation of homodimers arises from endosomal recycling compartments and is caused by the impaired and highly reactive cysteine 67 (Cys67) located into the B pocket of the peptide groove [29].…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Introductionmentioning

confidence: 99%

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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“…Generally, peptide presentation, formed from intracellular antigens, to CD8+ cytotoxic T cells and acting as a ligand for Natural Killer cells are crucial functions of MHC class I molecules. MHC class I molecules, which are glycoproteins which can fold within the lumen of the endoplasmic environment, in ER, are comprised a heavy chain noncovalently associated with the light chain beta-2-microglobulin (β2m) and loaded with a 8-13 amino acid long peptide [21,22].…”

Section: Hla-b27 Er Stress and Spondyloarthropathiesmentioning

confidence: 99%

“…Generally, SpAs are classified as autoinflammatory disease rather than autoimmune disease and proinflammatory cytokine production related with HLA-B27 misfolding and ER stress is an interesting fact for HLA-B27 misfolding and SpAsassociation [22]. Autoinflammatory disorders are manifested with inflammation without autoantibodies and antigen specific T cells, which are two important conditions that SpAs surprisingly have [42].…”

Section: Hla-b27 Misfolding Hypothesis and Upr Activationmentioning

confidence: 99%

The relation between ER stress and HLA-B27 misfolding

Yazar¹

2017

Med Res Innov

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Nowadays, understanding complex association among HLA-B27, ER stress pathways and Spondyloarthropathies (SpAs) has been considered to be important situation. Hitherto, many theories have been claimed by researchers in order to explain this association, but HLA-B27 misfolding theory can be the key theory among all theories. HLA-B27 misfolding is related to UPR (Unfolded Protein Response) and EOR (ER Overload Mechanism), since UPR mechanism protect ER homeostasis against misfolded protein and EOR system provide normal ER function to work on accumulating protein. On the other hand, ER associated degradation (ERAD) degrades unfolded or misfolded proteins which are re-translocated to cytosol for degradation. Present work aims to summarize the main pathways of UPR and ERAD, and then to reveal the relation between the tendency of HLA-B27 to misfold, ER stress and SpAs, especially Ankylosing Spondylitis (AS).

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“…16 ER stress, buffered by the activation of the UPR, is a homeostatic signalling network that orchestrates the restoration of ER function. 17 UPR activation leads to upregulation of expression of pro-inflammatory cytokines, such as TNF, IL17 and IL23, which are also known to be pathogenic in AS. Studies in the HLA-B27-transgenic rat model have implicated the association of HLA-B27 misfolding and ER-stress-dependent activation of UPR in spondyloarthritis.…”

Section: Introductionmentioning

confidence: 99%