Rheumatology Advance Access originally published online on December 18, 2006
Rheumatology 2007 46(2):364-365; doi:10.1093/rheumatology/kel404
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LETTERS TO THE EDITOR |
Membrane glucocorticoid receptors (mGCR) on monocytes are up-regulated after vaccination
Department of Rheumatology and Clinical Immunology, Charité University Hospital, Campus Mitte, Berlin, Germany, 1Department of Immunology and Biotechnology, University of Pécs, Pécs, Hungary and 2German Arthritis Research Centre (DRFZ), Berlin, Germany
Correspondence to: C. M. Spies. E-mail: cornelia.spies{at}charite.de
SIR, Glucocorticoids are essential in limiting and resolving the inflammatory process in health and disease [1, 2]. The anti-inflammatory and immunosuppressive effects of glucocorticoids rely on several molecular mechanisms, which include (i) direct effects on gene expression by the binding of activated glucocorticoid receptors (GCRs) to glucocorticoid responsive elements, (ii) indirect effects on gene expression through the interactions of activated GCR with transcription factors such as nuclear factor-
B or activator protein 1, (iii) glucocorticoid signalling through membrane-associated receptors and second messengers (so-called specific non-genomic pathways) and (iv) non-specific non-genomic actions via interactions of the glucocorticoid molecules with biological membranes at very high concentrations [2, 3].
Membrane glucocorticid receptors (mGCRs) have been reported for amphibian neuronal membranes and human lymphoma cells [4, 5]. We recently detected mGCR on the surface of human monocytes and B-lymphocytes by means of high-sensitivy immunofluorescence, and presented evidence for a higher expression of mGCR on monocytes following immunostimulation with lipopolysaccharide in vitro as well as in patients with rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) [6, 7]. In RA, mGCR are up-regulated and positively correlated to disease activity [6]. In SLE, we did not find a correlation to disease activity but a down-regulation of mGCR induced by high-dosage glucocorticoid-therapy [7]. This study aimed at further investigating if also a defined immunostimulation, such as vaccination, is capable of up-regulating these receptors.
We examined peripheral blood mononuclear cells (PBMCs) obtained from 21 healthy vaccinees (11 women and 10 men, aged 18–53 yrs, mean age 32.6 ± 8.6 yrs) before vaccination, after 3 weeks of vaccination, and after 6 weeks of vaccination. Ethics Committee (Charité) approval was secured and written informed consent was obtained. Vaccination was performed as a matter of routine. Probands showing signs of infection 8 weeks before or following vaccination were excluded. Different types of vaccines were used. We included vaccinations against tetanus (n = 10), hepatitis B (n = 7) and influenza (n = 4), respectively. PBMCs were isolated by density gradient centrifugation as described previously [6, 7]. For immunofluorescence analysis, a monoclonal IgG1-antibody anti-GCR 5E4 directed against the conserved regulatory sequence of human GCR (aa150–176) conjugated to digoxigenin (Dig) (Roche) was used [8]. The mGCRs were detected by high-sensitivity flow cytometry using anti-GCR-Dig followed by anti-Dig-magnetofluorescent liposomes [9] as described previously [6, 7]. We also used anti-CD14-phycoerythrin, anti-CD19-allophycocyanin and anti-CD3-peridin-chlorophyll (Becton Dickinson) to identify the different cell types. Further details have been previously reported [6, 7]. We considered the frequency of mGCR-positive cells to be increased above the normal range, if it was higher than the highest value found in a previously examined large control group of healthy probands, i.e. >9.2% in monocytes (CD14+) and >12.3% in B-lymphocytes (CD19+); in T-lymphocytes (CD3+) a significant mGCR expression had not been detectable (n = 58) [7].
As shown in Fig. 1, 3 weeks after vaccination the frequency of mGCR-positive monocytes (CD14+) was increased above the normal range in four of the 21 vaccinees (19.0%), with values up to 19.9% mGCR-positive cells. Six weeks after vaccination two of the probands (9.5%) showed elevated frequencies. These two probands had been positive at 3 weeks, too. Interestingly, these two ‘long-reacting’ individuals were male, whereas the other two positive probands were female. Three of the four positive vaccinees had been vaccinated against tetanus and one against influenza. None of the hepatitis-B vaccinees reacted (although a follow-up measurement of the anti-HBs-titre did show a sufficient vaccination). Whilst mGCR-expression increased in a minority of individuals, there was a decrease in many others so that the median stayed the same at 3 weeks, and was numerically even somewhat lower 6 weeks after vaccination (2.5 vs 2.8 vs 2.0%). Vaccination did not have any measurable effect on the frequency of mGCR-positive B-lymphocytes (CD19+). T-lymphocytes (CD3+) were found to be mGCR-negative either before as well as after vaccination. Our previously published data on mGCR expression in rheumatic diseases showed the frequency of mGCR-positive monocytes (CD14+) to be increased in nine of the 19 examined RA-patients (47.4%) with values up to 19.6% mGCR-positive cells and in 10 of 33 SLE-patients (30.3%) with a maximum value of 35.4%, respectively [6, 7].
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We conclude mGCR to be up-regulated in patients with rheumatic diseases as well as following vaccination. This supports the hypothesis that mGCR are up-regulated by immunostimulation and not to be specifically involved in the pathogenesis of autoimmune diseases. We suggest a role of mGCR within a negative feedback loop to control glucocorticoid action [6]. However, only a small number of vaccinees had elevated levels of mGCR-positive monocytes as compared with RA- and SLE-patients. The highest frequency of mGCR-positive monocytes was found in SLE-patients whereas lower but similar frequencies occurred in RA-patients and vaccinees. This leads to the conclusion that vaccination is obviously a less strong immunostimulus as compared with rheumatic diseases, at least if induction of mGCR-expression is used as an outcome parameter.
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Acknowledgements |
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This study was supported by the Deutsche Forschungsgemeinschaft. We thank B. Hörner from the Bundeswehrkrankenhaus Berlin for the support.
The authors have declared no conflicts of interest.
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