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HLA-B27 misfolding: a solution to the spondyloarthropathy conundrum?

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Abstract

Compelling evidence indicates that HLA-B27 is directly involved in the etiopathogenesis of the spondyloarthropathies (SpAs). Several hypotheses based on its native antigenic structure, the peptides it presents and mimicry with bacterial epitopes, have been proposed. However, these potential mechanisms remain largely unsupported by human studies and transgenic animal models. Recent work demonstrating that HLA-B27 misfolds offers a novel alternative hypothesis. Here, we review this new information on the folding and assembly of HLA-B27, and discuss consequences of misfolding that could be relevant to the pathogenesis of SpAs.

Section snippets

Function and polymorphism of MHC class I molecules

MHC class I molecules consist of trimolecular complexes of HC, β2-microglobulin (β2m) and peptide (generally, 8–11 amino acids), which are expressed on the surface of most nucleated cells. Their biological function is to present peptides derived from cellular proteins to T-cell receptors on CTLs. When a cell is invaded by a pathogen, foreign pathogen-derived peptides are also displayed, and the cell is targeted for destruction. Class I molecules are also recognized by natural killer (NK) cells,

HLA-B27 subtypes

HLA-B27 actually encompasses a group of at least 15 alleles or subtypes more closely related to one another than to other class I molecules (reviewed in 14, 15). Thirteen of these subtypes (B*2701–B*2713) are known to have nearly identical B pockets, but differ from the most common subtype (B*2705) by 1–7 amino acids located predominantly within the peptide-binding groove. The sequences of B*2714 and B*2715 are not published. The conserved B pocket is responsible for the selection of peptides

The B pocket and spondyloarthropathies

Epidemiological data suggest that the HLA-B27-like B pocket is important for arthritogenicity. For example, several HLA-B27 subtypes with this pocket are associated with SpAs (Ref. 14). One study suggests that HLA-B39, which has a similar but not identical B pocket, might also be associated with AS in HLA-B27-negative individuals23, although this requires confirmation in other populations. Given the importance of the B pocket for peptide binding specificity, its link to arthritogenicity is

MHC class I heavy chain folding, assembly and misfolding

MHC class I molecules assemble in the endoplasmic reticulum (ER), and traffic through the Golgi to the cell surface (reviewed in Ref. 29). Detailed dissection of this pathway has revealed a series of interactions between newly synthesized HCs and resident ER proteins known as molecular chaperones. These proteins retain unassembled components along the way, until stable HC–β2m–peptide complexes form that are then released to traffic to the cell surface (Fig. 1). When components of this pathway

HLA-B27 misfolding and the B pocket

We have recently shown that newly synthesized HLA-B27 (B*2705) is slow to fold and associate with β2m relative to many other MHC class I molecules11. Deglycosylated HCs are found in the cytosol, indicating that they have been dislocated from the ER as a consequence of misfolding. Surprisingly, HLA-B27 misfolding occurs in the presence of an intact antigen processing and assembly pathway, and thus differs from MHC class I HC misfolding reported previously, which requires β2m or peptide deficiency

ER stress response

Protein misfolding is important in a number of genetic diseases (reviewed in Ref. 34). Misfolding frequently results in a defective (for example, clotting-factor deficiencies), or even potentially functional (for example, α1-antitrypsin deficiency), gene product being degraded. Sometimes accumulation of misfolded protein is pathogenic (for example, Alzheimer’s disease). Protein misfolding or accumulation in the ER can signal a stress response through two pathways (reviewed in Ref. 35). In the

The HLA-B27 misfolding hypothesis

The tendency of HLA-B27 to misfold even under optimal antigen processing and loading conditions might distinguish it from other MHC class I molecules, and could have consequences critical to the pathogenesis of SpAs. Misfolding could be the basis for the effects of HLA-B27 on intracellular signaling pathways involved in the innate immune response, or the tendency of HLA-B27 to form potentially immunogenic structures such as dimers. It could also explain why ubiquitous cell-surface expression of

Concluding remarks

Current treatments for AS are inadequate to prevent significant morbidity. Understanding the mechanism by which HLA-B27 contributes to the pathogenesis might guide investigators in the design and development of novel treatment and prevention strategies. One goal of this article is to stimulate new thinking about HLA-B27, expanding the focus from its antigenic structure to the dynamic process by which it folds, assembles and becomes an antigen. Perhaps the evolutionary drive that has created

The outstanding questions

  • Is HLA-B27 misfolding involved in the pathogenesis of SpAs in humans, and spontaneous inflammatory arthritic disease in rodents?

  • Can HLA-B27 misfolding stimulate an ER stress response and/or augment NF-κB activation initiated by Gram negative bacteria or bacterial products such as lipopolysaccharide? Is the cellular response to misfolding responsible for the differences in intracellular signaling that have been observed?

  • Are HLA-B27 HC dimers recognized by CD4+ T cells in humans and HLA-B27 tg

Acknowledgements

I thank several members of my laboratory including D.J. Kingsbury, J.P. Mear, N.S. Dangoria and T.A. Griffin for their valuable input. I also thank D.N. Glass for critical evaluation of the manuscript. Financial support from The Children’s Hospital Research Foundation, the Schmidlapp Foundation, the National Institutes of Health (P60 AR44059) and a Pfizer Scholar Award is appreciated.

Glossary

CD8+ T cells
T cells with receptors that recognize MHC class I molecules with bound peptides. These cells express CD8, a co- receptor that binds to a conserved portion of the class I molecule.
Endoplasmic reticulum (ER)
A subcellular compartment where membrane and secreted proteins are synthesized and assembled.
Enthesitis
Inflammation at the insertion of tendons or ligaments on bones.
ER stress response
Cellular response to protein misfolding and/or accumulation in the ER. Two signaling pathways have

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