A novel pathogenic role of the ER chaperone GRP78/BiP in rheumatoid arthritis

Yoo, Sehoon; You, Sungyong; Yoon, Hyunho; Kim, Dongho; Kim, Hyun‐Sook; Lee, Kyung-Ho; Ahn, Jin Hee; Hwang, Daehee; Lee, Amy; Kim, Ki-Jo; Joo, Young Bin; Cho, Chul-Soo; Kim, Wan‐Uk

doi:10.1084/jem.20111783

Cited by 136 publications

(128 citation statements)

References 55 publications

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“…These properties are quite distinct from those displayed by intracellular, endoplasmic reticulum localized BiP, which regulates the unfolded protein response and induces cytoprotective and anti-apoptotic signals when cells are challenged by endoplasmic reticulum stress [25]. Thus, intracellular BiP may augment chronic inflammation through anti-apoptotic protection of inflammatory cells, such as the rheumatoid fibroblast-like synoviocyte [26] yet, as an extracellular protein, regulate inflammation on secretion from stressed cells [16]. A more complete dissection of the relative contributions of intracellular and extracellular BiP to the pathogenesis and resolution of chronic inflammation will require greater understanding of cells transduced by lentiviral vectors, the receptor or receptors to which BiP binds on the cell surface and the downstream signalling pathways employed.…”

Section: Discussionmentioning

confidence: 99%

Systemic gene transfer of binding immunoglobulin protein (BiP) prevents disease progression in murine collagen-induced arthritis

Shields

Klavinskis

Antoniou

et al. 2015

Clinical and Experimental Immunology

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SummaryRecombinant human binding immunoglobulin protein (BiP) has previously demonstrated anti-inflammatory properties in multiple models of inflammatory arthritis. We investigated whether these immunoregulatory properties could be exploited using gene therapy techniques. A single intraperitoneal injection of lentiviral vector containing the murine BiP (Lenti-mBiP) or green fluorescent protein (Lenti-GFP) transgene was administered in low-or high-dose studies during early arthritis. Disease activity was assessed by visual scoring, histology, serum cytokine and antibody production measured by cell enzyme-linked immunosorbent assay (ELISA) and ELISA, respectively. Lentiviral vector treatment caused significant induction of interferon (IFN)-γ responses regardless of the transgene; however, further specific effects were directly attributable to the BiP transgene. In both studies Lenti-mBiP suppressed clinical arthritis significantly. Histological examination showed that low-dose Lenti-mBiP suppressed inflammatory cell infiltration, cartilage destruction and significantly reduced pathogenic anti-type II collagen (CII) antibodies. Lenti-mBiP treatment caused significant up-regulation of soluble cytotoxic T lymphocyte antigen

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Section: Discussionmentioning

confidence: 99%

Systemic gene transfer of binding immunoglobulin protein (BiP) prevents disease progression in murine collagen-induced arthritis

Shields

Klavinskis

Antoniou

et al. 2015

Clinical and Experimental Immunology

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“…VEGF is another common factor for vascular remodeling under various physiological and pathological conditions, which can not only specifically promote vascular endothelial cell proliferation and angiogenesis, but also change the extracellular matrix. It has been shown that GRP78 can promote angiogenesis directly, or indirectly, through the VEGF pathway (Raiter et al, 2010; Yoo et al, 2012). In this study, we found that the expression levels of FVIII-RAg and VEGF in lung tissues gradually increased as the disease progressed, and the increased GRP78 were positively correlated with the elevated FVIII-Rag and VEGF, respectively.…”

Section: Discussionmentioning

confidence: 99%

Glucose-regulated protein 78 may play a crucial role in promoting the pulmonary microvascular remodeling in a rat model of hepatopulmonary syndrome

Zhang

Zhao

et al. 2014

Gene

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Objective This study is to investigate the role of glucose-regulated protein 78 (GRP78) in the pulmonary microvascular remodeling during hepatopulmonary syndrome (HPS) development. Methods The rat models with liver cirrhosis and HPS were induced by multiple pathogenic factors for 4 to 8 wk. The concentrations of alanine transferase (ALT) and endotoxin in plasma were detected in the models, followed by the detection of GRP78 expression. RT-PCR, quantitative real-time PCR and Western blotting were employed to assess the mRNA and protein expression levels of vascular endothelial growth factor (VEGF), respectively. Immunohistochemistry staining was used to examine the expression of a specific vascular marker, factor VIII-related antigen (FVIII-RAg), and several cell proliferation- and apoptosis-related proteins, including CHOP/GADD153, caspase-12, Bcl-2 and nuclear factor (NF)-κB. Results The levels of endotoxin and ALT in plasma were gradually increased as the disease progressed, so did GRP78, which were in a positive correlation. The expression levels of VEGF (both mRNA and protein) and FVIII-RAg were significantly elevated in the HPS models, indicating active angiogenesis, which was also positively correlated with GRP78 expression. Furthermore, the expression levels of the pro-apoptotic proteins of CHOP/GADD153 and caspase-12 were dramatically decreased, while the anti-apoptotic proteins of Bcl-2 and NF-κB were significantly elevated, in the HPS models. There were also close correlations between these proteins and GRP78. Conclusions Over-expression of GRP78 in lungs may be the critical pathogenic factor for HPS. Through promoting cell proliferation and survival and inhibiting apoptosis, GRP78 may promote the pulmonary microvascular remodeling in HPS pathogenesis. Our results provide a potential therapeutic target for clinical prevention and treatment for HPS and related complications.

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“…Furthermore, the endoplasmic reticulum (ER) stress‐associated protein GRP78/BiP is described as a potential autoantigen. The ER stress response is increased in RA synovial tissue and fluid and the ER chaperone, GRP78, is important for synoviocyte proliferation and angiogenesis, which are substantial indicators of RA …”

Section: The Problem Of Targeting Autoantigen(s) – Which Ones?mentioning

confidence: 99%

Targeting of tolerogenic dendritic cells towards heat‐shock proteins: a novel therapeutic strategy for autoimmune diseases?

et al. 2017

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SummaryTolerogenic dendritic cells (tolDCs) are a promising therapeutic tool to restore immune tolerance in autoimmune diseases. The rationale of using tolDCs is that they can specifically target the pathogenic T-cell response while leaving other, protective, T-cell responses intact. Several ways of generating therapeutic tolDCs have been described, but whether these tolDCs should be loaded with autoantigen(s), and if so, with which autoantigen(s), remains unclear. Autoimmune diseases, such as rheumatoid arthritis, are not commonly defined by a single, universal, autoantigen. A possible solution is to use surrogate autoantigens for loading of tolDCs. We propose that heat-shock proteins may be a relevant surrogate antigen, as they are evolutionarily conserved between species, ubiquitously expressed in inflamed tissues and have been shown to induce regulatory T cells, ameliorating disease in various arthritis mouse models. In this review, we provide an overview on how immune tolerance may be restored by tolDCs, the problem of selecting relevant autoantigens for loading of tolDCs, and why heat-shock proteins could be used as surrogate autoantigens.

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A novel pathogenic role of the ER chaperone GRP78/BiP in rheumatoid arthritis

Abstract: The ER chaperone GRP78/BiP is crucial for the development of rheumatoid arthritis.

Cited by 136 publications

References 55 publications

Systemic gene transfer of binding immunoglobulin protein (BiP) prevents disease progression in murine collagen-induced arthritis

Systemic gene transfer of binding immunoglobulin protein (BiP) prevents disease progression in murine collagen-induced arthritis

Glucose-regulated protein 78 may play a crucial role in promoting the pulmonary microvascular remodeling in a rat model of hepatopulmonary syndrome

Targeting of tolerogenic dendritic cells towards heat‐shock proteins: a novel therapeutic strategy for autoimmune diseases?

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