HLA-B27 misfolding in transgenic rats is associated with activation of the unfolded protein response

Matthew J. Turner, Dawn P. Sowders, Monica L. DeLay, Rajashree Mohapatra, Shuzhen Bai, Judith A. Smith, Jaclyn R. Brandewie, Joel D. Taurog, Robert A. Colbert

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Abstract

The mechanism by which the MHC class I allele, HLA-B27, contributes to spondyloarthritis pathogenesis is unknown. In contrast to other alleles that have been examined, HLA-B27 has a tendency to form high m.w. disulfide-linked H chain complexes in the endoplasmic reticulum (ER), bind the ER chaperone BiP/Grp78, and undergo ER-associated degradation. These aberrant characteristics have provided biochemical evidence that HLA-B27 is prone to misfold. Recently, similar biochemical characteristics of HLA-B27 were reported in cells from HLA-B27/human β2-microglobulin transgenic (HLA-B27 transgenic) rats, an animal model of spondyloarthritis, and correlated with disease susceptibility. In this study, we demonstrate that the unfolded protein response (UPR) is activated in macrophages derived from the bone marrow of HLA-B27 transgenic rats with inflammatory disease. Microarray analysis of these cells also reveals an IFN response signature. In contrast, macrophages derived from premorbid rats do not exhibit a strong UPR or evidence of IFN exposure. Activation of macrophages from premorbid HLA-B27 transgenic rats with IFN-γ increases HLA-B27 expression and leads to UPR induction, while no UPR is seen in cells from nondisease-prone HLA-B7 transgenic or wild-type (nontransgenic) animals. This is the first demonstration, to our knowledge, that HLA-B27 misfolding is associated with ER stress that results in activation of the UPR. These observations link HLA-B27 expression with biological effects that are independent of immunological recognition, but nevertheless may play an important role in the pathogenesis of inflammatory diseases associated with this MHC class I allele.

Original languageEnglish (US)
Pages (from-to)2438-2448
Number of pages11
JournalJournal of Immunology
Volume175
Issue number4
DOIs
StatePublished - Aug 15 2005

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ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Turner, M. J., Sowders, D. P., DeLay, M. L., Mohapatra, R., Bai, S., Smith, J. A., Brandewie, J. R., Taurog, J. D., & Colbert, R. A. (2005). HLA-B27 misfolding in transgenic rats is associated with activation of the unfolded protein response. Journal of Immunology, 175(4), 2438-2448. https://doi.org/10.4049/jimmunol.175.4.2438