HLA–B27 up-regulation causes accumulation of misfolded heavy chains and correlates with the magnitude of the unfolded protein response in transgenic rats: Implications for the pathogenesis of spondylarthritis-like disease
Article first published online: 28 DEC 2006
Copyright © 2006 by the American College of Rheumatology
Arthritis & Rheumatism
Volume 56, Issue 1, pages 215–223, January 2007
How to Cite
Turner, M. J., DeLay, M. L., Bai, S., Klenk, E. and Colbert, R. A. (2007), HLA–B27 up-regulation causes accumulation of misfolded heavy chains and correlates with the magnitude of the unfolded protein response in transgenic rats: Implications for the pathogenesis of spondylarthritis-like disease. Arthritis & Rheumatism, 56: 215–223. doi: 10.1002/art.22295
- Issue published online: 2 JAN 2007
- Article first published online: 28 DEC 2006
- Manuscript Accepted: 19 SEP 2006
- Manuscript Received: 21 MAY 2006
- NIH from the National Institute of Arthritis and Musculoskeletal and Skin Diseases. Grant Numbers: AR-046177, AR-043872
HLA–B27 is implicated in the pathogenesis of spondylarthritis (SpA), yet the molecular mechanisms are incompletely defined. HLA–B27 misfolding has been associated with endoplasmic reticulum stress and activation of the unfolded protein response (UPR) in macrophages from HLA–B27/human β2-microglobulin–transgenic (B27-transgenic) rats. This study was performed to assess the mechanisms that drive activation of the HLA–B27–induced UPR and to determine whether splenocytes respond in a similar manner.
Splenocytes were isolated and bone marrow macrophages were derived from B27-transgenic and wild-type rats. Cells were treated for up to 24 hours with cytokines that induce class I major histocompatibility complex expression. HLA–B27 expression and misfolding were assessed by real-time reverse transcription–polymerase chain reaction, flow cytometry, and immunoblotting. Activation of the UPR was measured by quantifying UPR target gene expression and X-box binding protein 1 messenger RNA (mRNA) splicing.
HLA–B27 mRNA up-regulation was accompanied by a dramatic increase in the accumulation of misfolded heavy chains and preceded robust activation of the UPR in macrophages. When macrophages were treated with various cytokines, the magnitude of the UPR correlated strongly with the degree of HLA–B27 up-regulation. In contrast, B27-transgenic splenocytes exhibited only low-level differences in the expression of UPR target genes after exposure to interferon-γ or concanavalin A, which resulted in minimal HLA–B27 up-regulation.
These results suggest that HLA–B27–associated activation of the UPR in macrophages is attributable to the accumulation of misfolded heavy chains, and that certain cell types may be more susceptible to the effects of HLA–B27 misfolding. Strategies that eliminate HLA–B27 up-regulation and/or the accumulation of misfolded heavy chains may be useful in evaluating the role of these events in the pathogenesis of SpA.