<scp>HLA</scp>–B27 Subtypes Predisposing to Ankylosing Spondylitis Accumulate in an Endoplasmic Reticulum–Derived Compartment Apart From the Peptide‐Loading Complex
Nadège Jah, Aude Jobart‐Malfait, Kétia Ermoza, Aurélie Noteuil, Gilles Chiocchia, Maxime Bréban, Claudine André
Abstract
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 β 2 ‐microglobulin (hβ 2 m)–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 β 2 m 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/hβ 2 m transgenic rats, correlating with SpA susceptibility. Conclusion Accumulation of misfolded HLA –B heavy chain along with β 2 m 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.