From HLA-B27 to spondyloarthritis: a journey through the ER.
Almost four decades of research into the role of human leukocyte antigen-B27 (HLA-B27) in susceptibility to spondyloarthritis has yet to yield a convincing answer. New results from an HLA-B27 transgenic rat model now demonstrate quite convincingly that CD8(+) T cells are not required for the inflammatory phenotype. Discoveries that the HLA-B27 heavy chain has a tendency to misfold during the assembly of class I complexes in the endoplasmic reticulum (ER) and to form aberrant disulfide-linked dimers after transport to the cell surface have forced the generation of new ideas about its role in disease pathogenesis. 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. These findings have led to the discovery of striking T-helper 17 cell activation and expansion in this animal model, consistent with results emerging from humans with spondyloarthritis and the discovery of IL23R as an additional susceptibility gene for ankylosing spondylitis. Together, these results suggest a novel link between HLA-B27 and the T-helper 17 axis through the consequences of protein misfolding and open new avenues of investigation as well as identifying new targets for therapeutic intervention in this group of diseases.
Colbert
Robert A
RA
National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH, Bethesda, MD 20892, USA. colbertr@mail.nih.gov
DeLay
Monica L
ML
Klenk
Erin I
EI
Layh-Schmitt
Gerlinde
G
D000818:Animals; D004195:Disease Models, Animal; D004721:Endoplasmic Reticulum / Q000276:immunology* / Q000378:metabolism; D020022:Genetic Predisposition to Disease; D015796:HLA-B27 Antigen / Q000737:chemistry / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D053759:Interleukin-23 / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic; D017510:Protein Folding; D055503:Protein Multimerization; D021381:Protein Transport; D051381:Rats; D055647:Rats, Transgenic; D018123:Receptors, Interleukin / Q000235:genetics / Q000276:immunology; D051192:Receptors, Pattern Recognition / Q000276:immunology; D012307:Risk Factors; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D025241:Spondylarthritis / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology; D056811:Unfolded Protein Response / Q000235:genetics / Q000276:immunology*
D015796:HLA-B27 Antigen; C515500:IL23R protein, human; D053759:Interleukin-23; D018123:Receptors, Interleukin; D051192:Receptors, Pattern Recognition