Immunoglobulin heavy-chain-binding protein (BiP): a stress protein that has the potential to be a novel therapy for rheumatoid arthritis

2014 ◽  
Vol 42 (6) ◽  
pp. 1752-1755 ◽  
Author(s):  
Gabriel S. Panayi ◽  
Valerie M. Corrigall

Immunoglobulin heavy-chain-binding protein (BiP) or glucose-regulated protein 78 (Grp78) is a vital ubiquitous resident of the endoplasmic reticulum (ER). As an intracellular chaperone, BiP correctly folds nascent polypeptides within the ER and regulates the unfolded protein response ensuring protection of the cell from denatured protein and reinforcing its anti-apoptotic role, when the cell is under stress. Additionally, BiP is a member of the heat-shock protein (HSP) 70 family and, as a stress protein, is up-regulated by conditions of reduced oxygen and glucose. Cell stress induces surface expression and secretion of BiP. Consequently, BiP is detectable in several bodily fluids including serum, synovial fluid (SF) and oviductal fluid. However, as an extracellular protein, BiP has additional properties that are quite distinct from the intracellular functions. Extracellular BiP is immunoregulatory and anti-inflammatory causing development of tolerogenic dendritic cells (DCs), induction of regulatory T-cells, abrogation of osteoclast development and function, induction of anti-inflammatory cytokine production, including interleukin (IL)-10, IL-1 receptor antagonist and soluble tumour necrosis factor (TNF)-receptor type II, and attenuation of TNFα and IL-6. Together, these functions help drive the resolution of inflammation. Disease models of inflammatory arthritis have helped to demonstrate the novel mode of action of BiP in which the pharmacokinetics and pharmacodynamics are dissociated. The three murine models to be discussed each show BiP induced long-term therapeutic protection and therefore has potential for long-lasting drug-free therapy in rheumatoid arthritis (RA).

Enzyme ◽  
1990 ◽  
Vol 44 (1-4) ◽  
pp. 310-319 ◽  
Author(s):  
Dennis G. Macejak ◽  
Peter Sarnow

2001 ◽  
Vol 15 (13) ◽  
pp. 2463-2470 ◽  
Author(s):  
WU-GUO DENG ◽  
KE-HE RUAN ◽  
MIN DU ◽  
MICHAEL A. SAUNDERS ◽  
KENNETH K. WU

1988 ◽  
Vol 8 (10) ◽  
pp. 4250-4256
Author(s):  
L M Hendershot ◽  
J Ting ◽  
A S Lee

The 78,000-dalton glucose-regulated protein (GRP78) and the immunoglobulin heavy-chain-binding protein (BiP) were shown to be the same protein by NH2-terminal sequence comparison. Immunoprecipitation of GRP78-BiP induced by glucose starvation and a temperature-sensitive mutation in a hamster fibroblast cell line demonstrated the association of GRP78-BiP with other cellular proteins. In both fibroblasts and lymphoid cells, GRP78-BiP was found to label with 32Pi and [3H]adenosine. Phosphoamino acid analysis demonstrated that GRP78-BiP is phosphorylated on serine and threonine residues. Conditions which induce increased production of GRP78-BiP resulted in decreased incorporation of 32Pi and [3H]adenosine into GRP78-BiP. Furthermore, we report here that the phosphorylated form of BiP resides in the endoplasmic reticulum and that BiP which is associated with heavy chains is not phosphorylated or labeled with [3H]adenosine, whereas free BiP is. This suggests that posttranslational modifications may be important in regulating the synthesis and binding of BiP.


2021 ◽  
Author(s):  
Hung-Cheng Tsai ◽  
Chik-On Choy ◽  
Tsai-Hung Wu ◽  
Chih-Wei Liu ◽  
Yu-Jen Pan ◽  
...  

Abstract Objectives Rheumatoid Arthritis (RA) is associated with polymorphism in major histocompatibility complex class II genes and dysregulations of CD4+ T cells which cause abnormalities in immune repertoire (iR) expression and intracellular signaling. We monitored nucleotide sequence changes in iR of immunoglobulin heavy chain (IGH), particularly complementarity determining region 3 (CDR3) during the course of treatments in RA patients using massively parallel sequencing technology.Methods CDR3 sequencing was carried out on clinical blood samples from RA patients for disease progress monitoring. The iR of each sample was measured using next generation sequencing (NGS) pipeline. Data analysis was done with a web-based iRweb server. Principal components analysis (PCA) was completed with commercial statistical pipeline. Results Datasets from 14 patients covered VDJ regions of IGH gene. D50 stayed low for all cases (mean D50 = 6.5). A pattern of shared CDR3 sequences was confirmed by a clustering pattern using PCA. Shared profile of 608 CDR3 sequences unique to the disease baseline was identified. D50 analyses revealed clonal diversity would remain low throughout the disease course even after treatment (mean D50 = 11.7 & 8.2 for csDMARD & bDMARD groups respectively) regardless of fluctuated disease activity. PCA has provided a correlation of change in immune diversity along the whole course of RA. Conclusion We have successfully constructed the experimental design, data acquisition, processing, and analysis pipeline of a high throughput massively parallel CDR3 sequences detection to be used to correlate RA disease activity and IGH CDR3 iR during disease progression with or without treatments.


1987 ◽  
Vol 8 (4) ◽  
pp. 111-114 ◽  
Author(s):  
Linda Hendershot ◽  
David Bole ◽  
John F. Kearney

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