期刊
ARTHRITIS AND RHEUMATISM
卷 58, 期 12, 页码 3693-3704出版社
WILEY
DOI: 10.1002/art.24045
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资金
- Spanish Ministry of Science and Technology [SAF2005/03L88]
- Fundacion Ramon Areces
Objective. To investigate the folding, assembly, maturation, and stability of HLA-B*1402 and B*1403, which differ by I amino acid change and are differentially associated with ankylosing spondylitis (AS), and to compare these features with those of B*2705. Methods. Stable transfectants expressing B*1402, B*1403, and B*2705 were used. Folding rates were estimated from the ratio of unfolded heavy chains to folded heavy chains that had been immunoprecipitated with specific antibodies in pulse-chase experiments. Heavy chain misfolding was measured as the half-life of endoglycosidase H (Endo H)-sensitive beta(2)-microglobulin-free heavy chains. Maturation/export rates were measured by acquisition of Endo H resistance. Association with calnexin or tapasin was analyzed by coprecipitation with chaperone-specific antibodies, and surface expression was estimated by flow cytometry. Thermostability of HLA-peptide complexes was assessed by immunoprecipitation after incubation at various temperatures. Heavy chain expression was quantified by Western blotting. Results. The folding rates of B*1402 and B*1403 were similar, and both were faster and more efficient than B*2705, but some unfolded heavy chains from both B14 subtypes remained in the endoplasmic reticulum (ER) with a long half-life. The export rates of B*1402 and B*1403 were slow, and the heterodimers partially dissociated after exiting the ER, as revealed by significant amounts of Endo H-resistant and surface-expressed free heavy chains. Both interaction with tapasin and thermostability were higher for B*2705 than for B*1402 and higher for B*1402 than for B*1403, suggesting that the repertoires of the B*1402-bound peptide and especially the B*1403-bound peptide were less optimized than that of B*2705. Conclusion. Our results indicate that the folding, maturation, and stability of B*1403 differ more from B*2705 than from B*1402. Thus, these features cannot account for the fact that only the 2 former allotypes are associated with AS.
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