Table I.
Different forms of HLA-B27 and their pathogenic roles in ankylosing spondylitis.
| First author, year | HLA-B27 form | Location | Structural feature | Formation | Condition | Pathogenic role/receptor | Refs. |
|---|---|---|---|---|---|---|---|
| Chen, 2013; | Classical | ER | Expressed at the cell | Assembly of a stable | Three non-covalently | TCR, KIR3DL1, | 23 |
| Allen, 2004; | HLA-B27 | surface as heterotrimeric | HLA-B27 molecule in the ER | bound individual | LILRB1, | 35 | |
| Allen, 2001; | peptide-MHC complexes | is necessary. Following synthesis | polypeptides are all | LILRB2, | 37 | ||
| Giles, 2012; | with β2m and peptide | and glycosylation, free HCs | required: a highly | LILRA1 | 40 | ||
| Shaw, 2014 | are initially stabilized by | polymorphic HC, β2m | 57 | ||||
| chaperones (calreticulin and tapasin) | light, chain and an | ||||||
| until a conformation suitable to | oligopeptide, typically | ||||||
| bind β2m and a peptide is achieved | of 8 to 10 residues | ||||||
| Kollenberger, 2007; | Cell surface | Endosome | Formed by two covalently | Recycling of fully-folded | Acidic environment of | KIR3DL1, | 36 |
| Allen, 2001; | HLA-B27 | bonded β2m-dissociated | HLA-B27 cell surface molecules | the endosome and | KIR3DL2, | 37 | |
| Giles, 2012; | homodimers | HCs | via the endocytic pathway, the | the low affinity binding | LILRB2, | 40 | |
| Campbell, 2012; | β2m-dissociated HCs form covalent | of β2m and peptides | LILRA1 | 43 | |||
| Shaw, 2014 | homodimers by cysteine residue at | with HC | 57 | ||||
| C67 in the α1 domain, and are | |||||||
| re-express at the cell surface | |||||||
| Lenart, 2012; | ER HLA-B27 | ER | The two β2m-dissociated, | Form via C67-C67, C101-C101 or | HLA-B27 exhibited an enhanced | UPR | 17 |
| Colbert, 2009; | homodimers | partially unfolded HCs form | C164-C164 disulfide bonds. | tendency to misfold and was | 48 | ||
| Turner, 2005 | covalent homodimers, but | susceptible to aggregation | 49 | ||||
| do not transit out of the ER | |||||||
| Raposo, 2013; | Redox-induced | Exosomes/ | Fully-folded β2m- | Critically depend on C325 in the | Lower levels of glutathione inside | Intercellular | 20 |
| Lynch, 2009; | HLA-B27 | Apoptosing | associated HLA-B27 | cytoplasmic tail (or with C339 in | exosomes creating a more oxidizing | communication | 21 |
| Campbell, 2012; | dimers | cells | dimers that are detected | HLA-A alleles) | environment | 43 | |
| Shaw, 2014 | on exosomes | 57 | |||||
| Luthra-Guptasarma, | HLA-B27 | ER | Misfolded monomeric | Residues 169–181 (identical to a | β2m-free, peptide-free HCs support | UPR/recognized | 58 |
| 2004 | with peptide | HLA-B27 with the | known HLA-B27 ligand) loop | a helix-coil transition facilitating | by receptors | ||
| binding cleft | molecule's own peptide | around and occupy the molecules | rotation of backbone angles around | ||||
| occupied | binding cleft occupied | own peptide-binding cleft | amino acid 167/168 | ||||
| Dakwar, 2008; | HLA-B27 that | ER | Misfolded HLA-B27 | Misfolding occurs in the ER | B pocket in the peptide- | UPR | 26 |
| Bowness, 2011; | have not yet | monomer that folds | prior to β2m association and | binding groove conferred a | 39 | ||
| Rajagopalan, 2012 | folded properly | improperly | peptide optimization | slow folding phenotype and | 46 | ||
| a tendency to misfold |
HLA-B27, human leucocyte antigen B27; ER, endoplasmic reticulum; MHC, major histocompatibility complex; HC, heavy chain; β2m, β2-microglobulin; TCR, T-cell receptors; KIR3DL1/KIR3DL2, killer cell immunoglobulin-like receptor, three domains, long cytoplasmic tail 1/2; LILRA1, leukocyte immunoglobulin-like receptor, subfamily A (with TM domain), member 1; LILRB1/LILRB2, leukocyte immunoglobulin-like receptor, subfamily B (with TM and ITIM domains), member 1/2; UPR, unfolded protein response.