Calreticulin is an abundant intracellular protein which is proposed to have numerous biological functions. However, there is increasing evidence to suggest that calreticulin plays a multifunctional role as an autoantigen present in patients with systemic lupus erythematosus. In this review we detail some of the recent evidence which indicate that calreticulin may play a supportive role in the formation of the autoantigen complex-Ro/SS-A. In addition, several proposed mechanisms of release and surface expression of calreticulin are described in relation to SLE mediated responses to the autoantigen. In particular, the generation of autoantibodies to specific regions of the protein and the ability of calreticulin to interfere with complement mediated inflammatory processes.
"Crt has also been shown to be associated with the immune response in several ways (Eggleton et al., 1997; Kishore et al., 1997). It may be a target for circulating autoantibodies, and may contribute to the autoimmune process (Eggleton et al., 1997; Michalak et al., 1992; Treves et al., 1998). "
[Show abstract][Hide abstract] ABSTRACT: Calreticulin (Crt) is a molecular chaperone ubiquitously present in the endoplasmic reticulum. In non-human primates, age-related occurrence of anti-Crt antibody has not been reported. We developed an ELISA assay for an anti-Crt antibody and determined the age-related increase in the levels of anti-Crt antibody in three groups of cynomolgus monkeys: juvenile (1.5 yr), young adults (5-10 yr) and aged adults (20-34 yr). Mean ± SD auto-antibody levels at 450 nm in juvenile, young adults and aged groups were 0.23 ± 0.18, 0.30 ± 0.28, and 0.55 ± 0.33, respectively. Statistically significant differences were noted in the autoantibody levels to Crt among the aged group and juvenile or young adults. This is the first report to demonstrate the expression of anti-Crt autoantibody in aged monkeys and indicates that cynomologous monkeys may serve as an appropriate nonhuman primate model for studies of age-related alteration of immune function in elderly humans. Though preliminary, this finding merits further investigation to determine the relationship between immunosenescence and expression of antibodies to Crt.
"Although its chaperone and calcium-binding activities in the endoplasmic reticulum have been well characterized, its functions on the cell surface and in secreted forms are less clear. Calreticulin is raised in the circulation of patients with a number of autoimmune conditions, including systemic lupus erythematosus (Eggleton et al., 1997 "
[Show abstract][Hide abstract] ABSTRACT: Pre-eclampsia is a disorder of human pregnancy that involves pregnancy-induced maternal hypertension and proteinuria. Evidence indicates that pre-eclampsia involves widespread activation of maternal endothelial cells. Calreticulin is a ubiquitously expressed, multi-functional protein that has been shown to have both pro- and anti-inflammatory effects on cultured endothelial cells in vitro and in whole animals. In order to clarify the role of this protein in normal human pregnancy and in pre-eclampsia, this study has measured expression of calreticulin in maternal blood and in placenta in patients with pre-eclampsia and in control pregnancies. There was a significant increase (approximately 5-fold) in calreticulin in plasma in term pregnant women compared with women who were not pregnant. There was no difference, however, in calreticulin in plasma from women who were sampled at first trimester, second trimester and at term. In addition, there was a significant increase (approximately 50%) in calreticulin in plasma from pre-eclamptic women compared to controls. Calreticulin mRNA and protein expression in placenta were not changed between pre-eclampsia and control pregnancies. These novel results indicate that calreticulin is increased in peripheral maternal blood early in pregnancy and remains elevated throughout normal gestation and that there is a further increase in calreticulin in pre-eclampsia.
Molecular Human Reproduction 06/2008; 14(5):309-15. DOI:10.1093/molehr/gan017 · 3.75 Impact Factor
"The sources of extracellular calreticulin have been subject to speculation, nevertheless the serum level of calreticulin in patients with systemic lupus erythematosus averages 4.44 µg/ml versus 0.42 µg/ml in control sera (Eggleton et al. 1997). "
[Show abstract][Hide abstract] ABSTRACT: Calreticulin is a Ca2+-binding protein of the ER/SR, from where it acts as a chaperone, and affectscalcium homeostasis, gene expression and cell adhesion. Cell adhesion to the extracellular matrix cangenerate transmembrane signals important for cell survival and migration. In a variety of cell types,integrin stimulation by ECM proteins, such as fibronectin, leads to changes in intracellular proteintyrosine phosphorylation. Tyrosine phosphorylation leads to the co-localization of focal adhesion kinase,vinculin and paxillin at focal contacts. Interaction between focal adhesion kinase and paxillin is criticalfor the activation of signaling cascades involved in cell survival and motility. Fibroblasts either over- orunderexpressing calreticulin show differences in their adhesive properties, which are related to thecalmodulin/CaMKII pathway. Inhibition of these pathways causes the weekly adhesive calreticulinunderexpressing cells to behave like the calreticulin overexpressers, through increased spreading andincreased levels of focal adhesion kinase, paxillin and fibronectin. We propose that calreticulin, via itsCa2+-homeostatic effects, may affect fibronectin synthesis and matrix assembly by modulating fibronectingene expression, and by influencing formation of cellular adhesions, both of which are instrumental inmatrix assembly and remodelling. Interestingly, it appears that besides the calmodulin/CaMKII pathway,differential calreticulin expression also modulates the c-src pathway.
Journal of applied biomedicine 01/2005; 4(1). · 1.30 Impact Factor
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