HLA–B27 Subtype Oligomerization and Intracellular Accumulation Patterns Correlate With Predisposition to Spondyloarthritis

  title={HLA–B27 Subtype Oligomerization and Intracellular Accumulation Patterns Correlate With Predisposition to Spondyloarthritis},
  author={C Jeanty and Ad{\`e}le Sourisce and Aur{\'e}lie Noteuil and Nad{\`e}ge Jah and Aurore Wielgosik and Ingrid Fert and Maxime Breban and Claudine Andr{\'e}},
  journal={Arthritis \& Rheumatology},
Mechanisms underlying the striking association of spondyloarthritis (SpA) with the class I major histocompatibility complex molecule HLA–B27 remain poorly understood. SpA‐like disease develops spontaneously in B*2705‐transgenic rats, in conjunction with high HLA–B27 expression levels. This study was undertaken to examine the effects of increased expression of HLA–B27 alleles that are differentially associated with SpA on oligomerization and intracellular redistribution. 

HLA–B27 Subtypes Predisposing to Ankylosing Spondylitis Accumulate in an Endoplasmic Reticulum–Derived Compartment Apart From the Peptide‐Loading Complex

This study was undertaken to characterize the nature and content of HLA–B–containing vesicles and to further examine their relevance to SpA predisposition.

Differences in Cellular Clearing Mechanisms of Aggregates of Two Subtypes of HLA-B27

A clear difference was observed in protein clearance mechanisms: whereas unfolded protein response, autophagy, and aggresomes were involved in the degradation of B*2704, the endosome–lysosome machinery was primarily involved in B* 2709 degradation.

Revisiting MHC Genes in Spondyloarthritis

Candidate-gene approaches and genome-wide studies have recently allowed identification of several new loci residing outside of the MHC region that are involved in the predisposition to SpA, and some of those new genes code for aminopeptidases that were involved in MHC class I presentation and were shown to interact with HLA-B27.

Ankylosing Spondylitis: A Multi-Factorial Autoimmune Disease. MHC Class I, Antigen Presentation and others to Blame

This review highlights the different HLA -B27 hypotheses, as well as the roles of some of the other factors in determining AS susceptibility, and concludes that, individually, none of these factors can take complete credit for causing AS since it is a multi-factorial autoimmune disease.

Editorial: HLA–B27: The Story Continues to Unfold

Aberrant folding and unfolding of HLA–B27 have been linked to the IL-23–IL-17 axis through UPR-mediated increases in IL- 23 production, and triggering of CD41 Th17 T cells that express KIR3DL2, respectively.

Polymorphisms in the F Pocket of HLA–B27 Subtypes Strongly Affect Assembly, Chaperone Interactions, and Heavy‐Chain Misfolding

The purpose of this study was to investigate the factors that influence differences in dimerization between disease‐associated and non–disease‐associated HLA–B27 alleles.

The enigmatic role of HLA-B*27 in spondyloarthritis pathogenesis

High-throughput TCR (T cell receptor) sequencing has provided evidence for reduced clonal expansion and increased TCR diversity in ankylosing spondylitis and two common CD8+ TCR sequences identified in one study, similar CD8 and CD4 TCR motifs were found in another study.

The role of the unfolded protein response in axial spondyloarthritis

A major outcome of ER stress, the unfolded protein response (UPR), as well as consequences of the UPR for inflammation and autophagy are described, particularly intriguing given the centrality of cytokines in spondyloarthritis.

HLA-B27 alters BMP/TGFβ signalling in Drosophila, revealing putative pathogenic mechanism for spondyloarthritis

Antagonistic interaction of HLA-B27 with ALK2, which exerts inhibitory functions on the TGFβ/BMP signalling pathway at the cross-road between inflammation and ossification, could adequately explain SpA development.



HLA-B27 and the pathogenesis of spondyloarthritis.

A critical assessment of current pathogenetic hypotheses from evidence concerning the epidemiology of HLA-B27 association with disease, its peptide-binding specificity, and other aspects of the molecular biology and immunology of this molecule are attempted.

Peptides: the cornerstone of HLA-B27 biology and pathogenetic role in spondyloarthritis.

In this review, the pathogenetic role of HLA-B27 will be analyzed from a global perspective of its biology, emphasizing the interdependency of multiple molecular features and the likely influence of disease-modifying gene products.

The Role of HLA-B27 in Spondyloarthritis

  • J. Taurog
  • Biology
    The Journal of Rheumatology
  • 2010
Proposed directions for future research include expanded efforts to define similarities and differences among the B27 subtypes; further development of animal models; identifying the interactions of B27 with the products of other genes associated with AS; and continued investigation into the pathogenesis of spondyloarthritis.

From HLA‐B27 to spondyloarthritis: a journey through the ER

In transgenic rats, HLA‐B27 misfolding generates ER stress and leads to activation of the unfolded protein response, which dramatically enhances the production of interleukin‐23 (IL‐23) in response to pattern recognition receptor agonists.

Old and new HLA associations with ankylosing spondylitis.

This review summarizes the current findings concerning the MHC genetics of the disease, focusing in particular on the associations of HLA with AS found in different ethnic populations throughout the world, and the possible mechanisms underlying them.

Distribution of HLA-B*27 subtypes in Tunisians and their association with ankylosing spondylitis.

HLA-B27 subtypes positively and negatively associated with spondyloarthropathy.

HLA-B*2704 is positively associated with SpA, while *2706 is negatively associated with this disease (RR < 0.007), which confirms the findings of Lopez-Larrea, et al in Thailand.

The genetic basis of spondyloarthritis

  • J. Reveille
  • Biology, Medicine
    Annals of the rheumatic diseases
  • 2011
Given that more than half of patients with AS have evidence on colonoscopy of at least occult inflammatory bowel disease (IBD), it is not surprising that shared genetic influences are operative and genes important in the innate immune response, autophagy and regulation of the IL-23 pathway (IL-23R) play a role in disease susceptibility.

Two HLA-B27 alleles differently associated with spondylarthritis, B*2709 and B*2705, display similar intracellular trafficking and oligomer formation.

The results suggest that the difference in disease susceptibility conferred by HLA-B*2705 and HLA*2709 cannot be explained by their different propensity to form dimers or misfolded proteins, thus presumably implicating other, still unknown factors.

HLA-B27 subtypes in Asian patients with ankylosing spondylitis. Evidence for new associations.

The polymerase chain reaction (PCR) in combination with the sequence-specific oligonucleotide probes (SSOs) was used to analyse the polymorphism in exon 2 and 3 of HLA-B27 in two Asian groups with different genetic HLA structures: Indian and Thai populations.