Elsevier

Immunology Letters

Volume 108, Issue 1, 15 January 2007, Pages 27-33
Immunology Letters

Current views
HLA-B27 and the pathogenesis of spondyloarthropathies

https://doi.org/10.1016/j.imlet.2006.10.004Get rights and content

Abstract

The association of HLA-B27 with ankylosing spondylitis, a chronic inflammatory disease of the axial skeleton, and other spondyloarthropathies, is among the strongest of an MHC antigen and any disease. Yet, the basis for this association remains unknown. In this review the main current hypotheses concerning the pathogenetic role of HLA-B27 will be discussed. They focus on three molecular properties of the molecule: (1) its peptide-presenting specificity, (2) its slow folding and tendency to misfold, and (3) its capacity to form covalent heavy chain homodimers amenable to recognition by leukocyte receptors. On the basis of the peptide specificity spondyloarthropathies would be triggered through T-cell autoimmunity against a self-ligand of HLA-B27 elicited by a cross-reactive foreign antigen. HLA-B27 misfolding would trigger disease through activation of inflammatory pathways following induction of endoplasmic reticulum stress, thus independently of antigen presentation. Recognition of heavy chain homodimers by leukocyte receptors might be involved in disease through immunomodulation of both innate and adaptive responses to arthritogenic pathogens. None of these hypotheses can yet satisfactorily account for the pathogenesis of spondyloarthritides. It is proposed that the pathogenetic role of HLA-B27 will eventually be explained through a global understanding of its biology, in which the various features of this molecule are envisaged as inter-dependent in their contribution to disease.

Introduction

The spondyloarthropathies are a group of inflammatory rheumatic diseases, typically affecting the axial skeleton, which include ankylosing spondylitis (AS), the prototype of these disorders, and reactive arthritis (ReA), a disease that is triggered by several Gram-negative bacteria, including species of Chlamydia, Salmonella, Yersinia, Shigella, and Campylobacter. A common feature of these bacteria is that they are obligate or facultative intracellular parasites. Since the discovery of the association of HLA-B27 with these diseases, more than 30 years ago [1], [2], [3] the molecular basis of this linkage, which is among the strongest between any MHC molecule and a disease, has remained unknown and elusive.

An impressive amount of knowledge coming from different areas, including the molecular and cellular biology of MHC class I molecules and HLA-B27 itself, the genetics of spondyloarthropathies and the development and study of animal models, have converged to provide a new and more comprehensive awareness of the possible ways in which HLA-B27 might trigger spondyloarthritis. In this review I will discuss the main body of experimental evidence that has contributed to build up, or to challenge, our main current ideas on the pathogenetic role of HLA-B27.

Section snippets

The arthritogenic peptide hypothesis: hopes and caveats

MHC class I proteins are peptide-presenting molecules that constitutively bind large peptide repertoires, mostly arising from degradation of endogenous proteins, and present them at the cell surface for recognition by CD8+ T-lymphocytes. Thus, it was only logical to assume that the pathogenetic role of HLA-B27 should be related to its antigen-presenting features and to T-cell recognition. Unresponsiveness to self-peptides presented by MHC-class I molecules is ensured by tolerance, which is

Novel views on the molecular biology of HLA-B27: misfolding and homodimers

In 1999 two independent reports revealed features of HLA-B27 unrelated to antigen presentation, whose putative pathogenetic relevance became readily apparent. In one of these reports [40] it was shown that B*2705 folding was relatively inefficient and misfolded heavy chain accumulated in the ER. This phenotype could be corrected by mutating residues in the B pocket of the molecule. Since accumulation of misfolded proteins can trigger ER stress responses that, in turn, may lead to activation of

HLA-B27 misfolding and the pathogenesis of spondyloarthropathies

Misfolded HLA-B27 heavy chains that accumulate in the ER tend to form disulfide-linked homodimers and multimers even in the presence of an intact MHC class I assembly pathway [43]. Covalent dimerization seems to be a consequence rather than a cause of misfolding, since a B pocket mutant of HLA-B27 with improved folding features but still retaining the Cys67 residue did not dimerized or accumulated in the ER [43]. Furthermore, homodimer formation can be induced in HLA-A2 by slowing down its

Are HLA-B27 heavy chain homodimers involved in disease pathogenesis?

HLA-B27 heavy chain homodimers and multimers are independently produced in the ER and at the cell surface. Those produced in the ER have been discussed above. They are linked to the misfolding and accumulation processes that lead to activation of the UPR. However, as quality control mechanisms ensure that only the correctly folded MHC class I/peptide complexes are exported to the cell surface, these homodimers do not leave the ER. An exception to this might be a particular population of

Other issues

I will briefly discuss in this paragraph two unusual features of HLA-B27 whose pathogenetic relevance is unclear, but which contributes to draw a more complete picture of the complex biology of this molecule: its tapasin dependency and its capacity to modulate intracellular survival of arthritogenic Salmonella species.

Tapasin (Tpn) is a specialized chaperone of the ER involved in the quality control of peptide loading into class I molecules [62], [63]. HLA-B27 is less dependent than other class

Concluding remarks: towards a global understanding of HLA-B27 biology

The last few years have seen a shift in our thoughts about the pathogenesis of AS and a considerable increase in our knowledge of the molecular biology and immunology of HLA-B27. Without being the only ones, two issues might be singled out as being largely responsible for this shift. First, the convincing demonstration that CD8 T cells play little role in the pathogenesis of B27-associated arthritis in transgenic rats. Although this has yet to be confirmed in human spondyloarthropathies, this

Acknowledgments

The work of the author is funded by grant SAF2005-03188 from the Spanish Ministry of Science and Technology and an institutional grant of the Fundacion Ramon Areces to the Centro de Biologia Molecular Severo Ochoa.

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