Functional Analysis of Recombinant Calreticulin Fragment 39–272: Implications for Immunobiological Activities of Calreticulin in Health and Disease

Cheng, Hong; Qiu, Xiang; Li, Yue; Huang, Qianrong; Zhong, Zhaoyan; Zhang, Yan; Lei, Yu; Sun, Lin; Lv, Ping; Gao, Xiao‐Ming

doi:10.4049/jimmunol.1000536

Cited by 38 publications

(93 citation statements)

References 48 publications

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“…Furthermore, our result agreed with that of Hong et al (17) who documented that the serum CRT level was significantly higher in their RA patients than the control group. Moreover, the present study revealed statistically significant correlations between the serum CRT levels and CRP (p<0.001), ESR (p=0.002), swollen joints count (p=0.01), tender joints count (p=0.001), and JA-DAS-27 (p=0.001): these results were consistent with the results of Tarr et al (18) who found that CRT levels were positively correlated with ESR, CRP, SJC, and DAS-28 in RA patients.…”

Section: Discussionsupporting

confidence: 83%

Serum calreticulin as a novel biomarker of juvenile idiopathic arthritis disease activity

et al. 2017

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Objective: This study aimed to investigate the relations between calreticulin (CRT) serum level and both disease activity and severity parameters in juvenile idiopathic arthritis (JIA). Material and Methods:In this study, 60 children with JIA and 50 age-and-sex-matched healthy subjects were enrolled. The assessment of the disease activity was done using juvenile arthritis disease activity score 27 (JADAS-27). The assessment of disease severity was done via gray-scale ultrasonography (US) and power Doppler US (PDUS). Enzyme-linked immunosorbent assay (ELISA) was used to assay the serum level of human CRT. Results:The mean serum CRT levels in JIA patients was 8.6±1.2 ng/mL and showed a highly significant increase (p=0.001) as compared to the mean serum levels in the controls (5.02±0.77 ng/mL). There were statistically significant positive correlations between the serum CRT levels and disease duration, tender joint count, swollen joint count, visual analog scale, erythrocyte sedimentation rate, JADAS-27, C-reactive protein, rheumatoid factor titer, and ultrasonographic grading for synovitis and neovascularization.Conclusion: Elevated serum CRT levels in JIA patients and its correlations with JIA disease activity and severity parameters signified that CRT might be used as a novel biomarker for disease activity and severity in JIA.

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Section: Discussionsupporting

confidence: 83%

Serum calreticulin as a novel biomarker of juvenile idiopathic arthritis disease activity

et al. 2017

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“…Therefore, there is a limitation for the detection of sCRT. Another sandwich ELISA system previously reported could only detect sCRT in sera from 23.3% RA patients and 21.9% SLE patients and could not detect sCRT in any of the 48 serum samples from healthy subjects [9]. Thus, new detecting systems for measuring sCRT sensitively need to be developed further.…”

Section: High Expression Level Of Crt In Human Lung Cancer Tissuesmentioning

confidence: 96%

“…Production of mouse mAbs to recombinant CRT/39-272 Complete Freund's adjuvant was mixed with 20 lg of rCRT/39-272 antigen [9]. Female BALB/c mice (6 weeks old) were immunized at day 0 by subcutaneous (s.c.) injection.…”

Section: Samples From Patients and Healthy Subjectsmentioning

confidence: 99%

“…It has been detected that there were higher levels of sCRT in the sera of patients with autoimmune disease such as rheumatoid arthritis and systemic lupus erythematosus [9]. In cancers, sCRT has been detected in sera of liver cancer patients [10] and in the urine of bladder cancer patients [11,12].…”

Section: Introductionmentioning

confidence: 97%

“…There have been reports on the association between CRT expression level and various diseases [9][10][11][12][13][14][15][16][17]. It has been detected that there were higher levels of sCRT in the sera of patients with autoimmune disease such as rheumatoid arthritis and systemic lupus erythematosus [9].…”

Section: Introductionmentioning

confidence: 99%

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Calreticulin as a potential diagnostic biomarker for lung cancer

Liu

Gong

Chen

et al. 2011

Cancer Immunol Immunother

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Calreticulin (CRT) is an endoplasmic reticulum luminal Ca(2+)-binding chaperone protein. By immunizing mice with recombinant fragment (rCRT/39-272), six clones of monoclonal antibodies (mAbs) were generated and characterized. Based on these mAbs, a microplate chemiluminescent enzyme immunoassay (CLEIA) system with a measured limit of detection of 0.09 ng/ml was developed. Using this CLEIA system, it was found that soluble CRT (sCRT) level in serum samples from 58 lung cancer patients was significantly higher than that from 40 healthy individuals (only 9 were detectable, P < 0.0001). Among them, serum sCRT in the small cell lung cancer was lower than that in adenocarcinoma (P = 0.0085), while both were lower than that in the squamous cell carcinoma (P = 0.013, P = 0.0012, respectively). Moreover, it was found that sCRT in sera from the patients after chemotherapy was higher than that from the patients without chemotherapy (P = 0.042). Further study by immunohistochemistry showed that CRT was also highly expressed in the cytoplasm and on the membrane of the lung cancer cells, while there was a trace amount of CRT expression in normal lung cells. Correspondingly, the expression level of CRT on lung cancer cell membrane was associated with the tumor pathological grade. This study demonstrates that sCRT concentration in sera of lung cancer patients is higher than that in sera of healthy individuals, and CRT expression level on lung cancer cell membrane is associated with tumor pathological classification and grade. These findings suggest that CRT may be used as a biomarker in lung cancer prediction and diagnosis.

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Modulation of cellular immunity by antibodies against calreticulin

et al. 2012

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Although caltreticulin (CRT) is mainly a residential ER protein, it is also expressed on the membrane surface of various types of cells exhibiting multiple functions. We report here that intraperitoneal administration of a soluble recombinant CRT fragment (rCRT/39-272) led to a substantial decrease in delayed type hypersensitivity (DTH) responses in BALB/c mice and EAE in C57BL/6 mice. In the recall response against keyhole limpet hemocyanin (KLH) in vitro, draining lymph node cells from the rCRT/39-272-treated mice produced less IFN-γ but more IL-4 as compared with the cells from the control group. The immunomodulating effect of intraperitoneally administered rCRT/39-272 was attributed to anti-CRT Abs thereby induced, because, in passive transfer experiments, the CRTspecific antiserum could suppress DTH in BALB/c mice. B-cell-deficient μMT mice were not susceptible to rCRT/39-272-mediated DTH suppression. Furthermore, CRT appears on the surface of murine T cells soon after activation and remains detectable (at relatively low level) by flow cytometry for approximately 5 days in vitro. Anti-CRT Abs were able to inhibit AKT phosphorylation, proliferation, and cytokine production by activated murine T cells. We propose that cell surface CRT could play a role in the function of effector T cells and may be considered a target for immunological manipulation.Keywords: Anti-CRT antibodies r Calreticulin r Immunoregulation Supporting Information available online IntroductionCalreticulin (CRT) is a multifunctional glycoprotein of 46 kDa, and is most abundant in the ER of the cell [1][2][3][4][5][6]. It folds into three domains: (i) a lectin-like N domain, (ii) a proline-rich P domain, and (iii) a Ca 2+ -binding C-domain. CRT has well-recognized physiological roles in intracellular Ca 2+ storage and signaling and also as a molecular chaperone [1,5,6]. It has been detected in soluble form in the sera of patients with rheumatoid arthritis (RA) and systemic lupus erythematosus [7,8]. We have shown that a recombinant CRT fragment 39-272 containing its partial NCorrespondence: Prof. Xiao-Ming Gao e-mail: xmgao@suda.edu.cn and P-domains (CRT/39-272) exhibits potent immunostimulatory activity and strong adjuvanticity [7], implying soluble CRT may be involved in immunopathological and inflammatory reactions leading to the development of RA and/or systemic lupus erythematosus. Moreover, CRT can be exposed at the membrane surface of various types of cells and exhibits multiple cellular functions as a surface molecule [6]. For example, cell-surface CRT (csCRT) mediates thrombospondin (TSP) triggered disassembly of focal contacts, exhibits antithrombotic effects, and inhibits melanoma cell spreading and angiogenesis [5,9,10]. Ligation of neuronal csCRT by complement C1q triggers increased levels of cellular * These authors contributed equally to this work. Eur. J. Immunol. 2012. 42: 2419-2430 reactive oxygen species [11]. There is also ample evidence showing that surface exposure of CRT enhances the immunogenicity of tumor cells and ...

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Functional Analysis of Recombinant Calreticulin Fragment 39–272: Implications for Immunobiological Activities of Calreticulin in Health and Disease

Cited by 38 publications

References 48 publications

Serum calreticulin as a novel biomarker of juvenile idiopathic arthritis disease activity

Serum calreticulin as a novel biomarker of juvenile idiopathic arthritis disease activity

Calreticulin as a potential diagnostic biomarker for lung cancer

Modulation of cellular immunity by antibodies against calreticulin

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