Uniquely Conformed Peptide-Containing β2-Microglobulin- Free Heavy Chains of HLA-B2705 on the Cell Surface

Malik, Pratap; Klimovitsky, Polina; Deng, Lih‐Wen; Boyson, Jonathan E.; Strominger, Jack L.

doi:10.4049/jimmunol.169.8.4379

Cited by 38 publications

(29 citation statements)

References 54 publications

(42 reference statements)

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“…Instead, they appear to derive from cell surface H chain/␤ 2 m/peptide complexes that have lost ␤ 2 m (19). Consistent with this observation, relatively stable ␤ 2 m-free HLA-B27 H chains have been found on the cell surface (21). Thus, cell surface dimer formation appears to be mechanistically distinct from HLA-B27 misfolding.…”

supporting

confidence: 69%

HLA-B27 Misfolding in Transgenic Rats Is Associated with Activation of the Unfolded Protein Response

Turner

Sowders

DeLay

et al. 2005

The Journal of Immunology

218

198

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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.

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supporting

confidence: 69%

HLA-B27 Misfolding in Transgenic Rats Is Associated with Activation of the Unfolded Protein Response

Turner

Sowders

DeLay

et al. 2005

The Journal of Immunology

218

198

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“…However, these studies did not look for evidence of homodimerization. Very recently, Malik et al [35] described a population of peptide-containing g 2 m-free HLA-B27 monomers on the surface of transfected lymphoblastoid cell lines that react with the mAb MARB4. The MARB4-reactive species are distinct from the HC-10-reactive molecules and are contained within the ME-1-reactive cohort.…”

Section: Discussionmentioning

confidence: 99%

Lymphoblastoid cells express HLA‐B27 homodimers both intracellularly and at the cell surface following endosomal recycling

et al. 2003

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The MHC class I allele HLA-B27 is very strongly associated with development of autoimmune spondyloarthritis, although the disease mechanism remains unknown. Class I molecules classically associate in the endoplasmic reticulum (ER) with g 2-microglobulin ( g 2 m) and antigenic peptides for cell surface expression and presentation to T cells. We have previously shown that HLA-B27 is capable of forming g 2 m-free disulfide-bonded homodimers in vitro. Here we show that HLA-B27 forms disulfide-bonded homodimers in vivo by two distinct pathways. HLA-B27 homodimers form in the ER but appear unable to egress to the cell surface in human cells. Cell surface HLA-B27 homodimers are abundantly expressed in a variety of lymphoid cell lines. Experiments with inhibitors indicate that HLA-B27 homodimers can arise from cell-surface heterodimers via an endosome-dependent recycling pathway. HLA-B27 homodimer expression on the cell surface of 721.220 is dependent on the unpaired cysteine 67 and is inhibited by restoration of tapasin function or by incubation with peptides that bind strongly to HLA-B27 heterodimers. Cell surface expressed HLA-B27 homodimers are likely to be immunologically reactive ligands for NK family immunoreceptors and, hence, could play a pathogenic role in spondyloarthritis.

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“…Recent studies, however, have demonstrated multiple HC-dimeric structures, which may form independently in the ER during the early stages of biosynthesis or at the cell surface following unfolding of normal HLA-B27 molecules, possibly involving trafficking through an endocytic compartment. The existence of HC-dimers has been called into question (48). In our own experience, we find that some HCdimers may be formed as a result of inefficient sample alkyla- tion, especially those deriving from the cell surface.…”

Section: Effect Of Reduced Temperature and Cysmentioning

confidence: 93%

Formation of HLA-B27 Homodimers and Their Relationship to Assembly Kinetics

Antoniou

Ford

Taurog

et al. 2004

Journal of Biological Chemistry

100

143

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The human HLA-B27 class I molecule exhibits a strong association with the inflammatory arthritic disorder ankylosing spondylitis and other related arthropathies. Major histocompatibility complex class I heavy chains normally associate with ␤ 2 -microglobulin and peptide in the endoplasmic reticulum before transit to the cell surface. However, an unusual characteristic of HLA-B27 is its ability to form heavy chain homodimers through an unpaired cysteine at position 67 in the peptide groove. Homodimers have previously been detected within the ER and at the cell surface, but their mechanism of formation and role in disease remain undefined. Here we demonstrate, in the rat C58 thymoma cell line and in human HeLa cells transfected with HLA-B27, that homodimer formation involves not only cysteine at position 67 but also the conserved structural cysteine at position 164. We also show that homodimer formation can be induced in the non-disease-associated HLA class I allele HLA-A2 by slowing its assembly rate by incubation of cells at 26°C, suggesting that homodimer formation in the endoplasmic reticulum may occur as a result of the slower folding kinetics of HLA-B27. Finally, we report an association between unfolded HLA-B27 molecules and immunoglobulin-binding protein at the cell surface.

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Uniquely Conformed Peptide-Containing β2-Microglobulin- Free Heavy Chains of HLA-B2705 on the Cell Surface

Cited by 38 publications

References 54 publications

HLA-B27 Misfolding in Transgenic Rats Is Associated with Activation of the Unfolded Protein Response

HLA-B27 Misfolding in Transgenic Rats Is Associated with Activation of the Unfolded Protein Response

Lymphoblastoid cells express HLA‐B27 homodimers both intracellularly and at the cell surface following endosomal recycling

Formation of HLA-B27 Homodimers and Their Relationship to Assembly Kinetics

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