OpinionHLA-B27 misfolding: a solution to the spondyloarthropathy conundrum?
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
References (46)
Genes in the spondyloarthropathies
Rheum. Dis. Clin. North Am.
(1998)Ankylosing spondylitis and HL-A 27
Lancet
(1973)The role of HLA-B27 polymorphism and molecular mimicry in spondyloarthropathy
Mol. Med. Today
(1998)HLA class I polymorphism: Structure and function and still questions
Hum. Immunol.
(1997)Differences in peptide presentation between B27 subtypes: the importance of the P1 side chain in maintaining high affinity peptide binding to B*2703
Immunity
(1994)Animal models of human leukocyte antigen B27-linked arthritides
Rheum. Dis. Clin. North Am.
(1998)A point mutation in HLA-A*0201 results in failure to bind the TAP complex and to present virus-derived peptides to CTL
Immunity
(1996)HLA-B27 as a relative risk factor in ankylosing enthesopathy in transgenic mice
Hum. Immunol.
(1995)Ankylosing spondylitis: clinical aspects
High association of an HL-A antigen, W27, with ankylosing spondylitis
New Engl. J. Med.
(1973)
HLA-B27 associated spondyloarthropathy, an autoimmune disease based on crossreactivity between bacteria and HLA-B27?
Ann. Rheum. Dis.
Presentation of HLA class I-derived peptides: potential involvement in allorecognition and HLA-B27-associated arthritis
Immunol. Rev.
Chemical reactivity of an HLA-B27 thiol group
Eur. J. Immunol.
HLA-B27 modulates intracellular survival of Salmonella enteritidis in human monocytic cells
Eur. J. Immunol.
Expression of arthritis-causing HLA-B27 on Hela cells promotes induction of c-fos in response to in vitro invasion by Salmonella typhimurium
J. Clin. Invest.
Misfolding of HLA-B27 as a result of its B pocket suggests a novel mechanism for its role in susceptibility to spondyloarthropathies
J. Immunol.
Peptides naturally presented by MHC class I molecules
Ann. Rev. Immunol.
HLA-B27 polymorphism and association with disease
J. Rheumatol.
Immunogenetics, HLA-B27 and spondyloarthropathies
Curr. Opin. Rheumatol.
Allele-specific B pocket transplant in class I major histocompatibility complex protein changes requirement for anchor residue at P2 of peptide
Proc. Natl. Acad. Sci. U. S. A.
Differences in endogenous peptides presented by HLA-B*2705 and B*2703 allelic variants
J. Clin. Invest.
Naturally occurring A pocket polymorphism in HLA-B*2703 increases the dependence on an accessory anchor residue at P1 for optimal binding of nonamer peptides
J. Immunol.
Susceptibility to ankylosing spondylitis correlates with the C-terminal residue of peptides presented by various HLA-B27 subtypes
Eur. J. Immunol.
Cited by (107)
Resistance to unfolding by acidic pH and resistance to lysosomal degradation explains disease-association of HLA-B27 subtypes
2022, International ImmunopharmacologyThe correlation between intestinal dysbiosis and the development of ankylosing spondylitis
2019, Microbial PathogenesisReactive Arthritis
2015, Textbook of Pediatric RheumatologyHLA-B27 misfolding and ankylosing spondylitis
2014, Molecular ImmunologyCitation Excerpt :These include peptide binding specificity (Jardetzky et al., 1991; Madden et al., 1993), a tendency to misfold (Dangoria et al., 2002; Mear et al., 1999), and a predilection for forming heavy chain homodimers during cell surface recycling (Allen et al., 1999; Bird et al., 2003; Kollnberger et al., 2002). Each of these properties has been hypothesized independently to play a role in the pathogenesis of spondyloarthritis (Benjamin and Parham, 1990; Colbert, 2000; Edwards et al., 2000) (summarized in Fig. 1). In the absence of definitive data to suggest otherwise, it is possible that more than one mechanism is involved.
Functional interaction of the ankylosing spondylitis-associated endoplasmic reticulum aminopeptidase 1 polymorphism and HLA-B27 in vivo
2012, Molecular and Cellular Proteomics