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HLA–B27 Subtypes Predisposing to Ankylosing Spondylitis Accumulate in an Endoplasmic Reticulum–Derived Compartment Apart From the Peptide-Loading Complex
- Source :
- Arthritis & rheumatology, Arthritis & rheumatology, 2020, 72 (9), pp.1534-1546. ⟨10.1002/art.41281⟩, Arthritis & rheumatology, Wiley, 2020, 72 (9), pp.1534-1546. ⟨10.1002/art.41281⟩
- Publication Year :
- 2020
- Publisher :
- HAL CCSD, 2020.
-
Abstract
- International audience; Objective: It was previously shown that HLA–B27 subtypes predisposing to spondyloarthritis (SpA), i.e., B*27:02, B*27:05, and B*27:07, displayed an increased propensity to form intracellular oligomers and to accumulate at a high density in cytoplasmic vesicles, as compared to the non–SpA-associated HLA–B*07:02 and HLA–B*27:06. This study was undertaken to characterize the nature and content of HLA–B–containing vesicles and to further examine their relevance to SpA predisposition. Methods: Vesicles containing HLA–B proteins were detected in transfected HeLa cells and in cells from SpA patients or HLA–B27/human β2-microglobulin (hβ2m)–transgenic rats, by microscopy. The nature and content of HLA–B–containing vesicles were characterized in colocalization experiments with appropriate markers. Results: The SpA-associated HLA–B*27:04 subtype accumulated at higher levels (P < 10−5) in cytoplasmic vesicles compared to HLA–B*27:06, from which it differs only by 2 substitutions, reinforcing the correlation between vesicle formation and SpA predisposition. Colocalization studies showed that those vesicles contained misfolded HLA–B heavy chain along with β2m and endoplasmic reticulum (ER) chaperones (calnexin, calreticulin, BiP, glucose-regulated protein 94-kd) and belonged to the ER but were distinct from the peptide-loading complex (PLC). Similar vesicles were observed in immune cells from HLA–B27+ SpA patients, in greater abundance than in healthy controls (P < 0.01), and in dendritic cells from HLA–B27/hβ2m transgenic rats, correlating with SpA susceptibility. Conclusion: Accumulation of misfolded HLA–B heavy chain along with β2m and ER chaperones into ER-derived vesicles distinct from the PLC is a characteristic feature of HLA–B27 subtypes predisposing to SpA. This phenomenon could contribute to HLA–B27 pathogenicity, via a noncanonical mechanism.
- Subjects :
- Protein Folding
Intravital Microscopy
Calnexin
[SDV.IMM.II]Life Sciences [q-bio]/Immunology/Innate immunity
0302 clinical medicine
Immunology and Allergy
chaperone
HLA-B27 Antigen
β2-microglobulin
0303 health sciences
[SDV.MHEP.RSOA] Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system
Microscopy, Confocal
biology
Chemistry
Vesicle
intracellular vesicles
Transfection
spondyloarthritis
endoplasmic reticulum
[SDV.MHEP.RSOA]Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system
[SDV.IMM.IA]Life Sciences [q-bio]/Immunology/Adaptive immunology
[SDV.IMM.IA] Life Sciences [q-bio]/Immunology/Adaptive immunology
Rats, Transgenic
musculoskeletal diseases
Immunology
Blotting, Western
Protein Disulfide-Isomerases
Major histocompatibility complex
03 medical and health sciences
Rheumatology
ankylosing spondylitis
Animals
Humans
Genetic Predisposition to Disease
HSP70 Heat-Shock Proteins
Spondylitis, Ankylosing
[SDV.IMM.II] Life Sciences [q-bio]/Immunology/Innate immunity
030304 developmental biology
HLA-B27
Endoplasmic reticulum
Cytoplasmic Vesicles
Colocalization
Membrane Proteins
Dendritic Cells
Molecular biology
Rats
Microscopy, Electron
Microscopy, Fluorescence
Chaperone (protein)
biology.protein
MHC
Calreticulin
beta 2-Microglobulin
030215 immunology
HeLa Cells
Molecular Chaperones
Subjects
Details
- Language :
- English
- ISSN :
- 23265205 and 23265191
- Database :
- OpenAIRE
- Journal :
- Arthritis & rheumatology, Arthritis & rheumatology, 2020, 72 (9), pp.1534-1546. ⟨10.1002/art.41281⟩, Arthritis & rheumatology, Wiley, 2020, 72 (9), pp.1534-1546. ⟨10.1002/art.41281⟩
- Accession number :
- edsair.doi.dedup.....5204c322cc72e57c0fba8d2fd961dfd4