Complement systems C4, C3 and CH50 not subject to a circadian rhythm

Thomas Lung; Katja Matozan; Martin Risch; Benjamin Sakem; Urs E. Nydegger; Lorenz Risch

doi:10.1515/dx-2018-0003

Article

Complement systems C4, C3 and CH50 not subject to a circadian rhythm

Thomas Lung , Katja Matozan , Martin Risch , Benjamin Sakem , Urs E. Nydegger and Lorenz Risch

Published/Copyright: May 29, 2018

Published by

Become an author with De Gruyter Brill

Submit Manuscript Author Information Explore this Subject

From the journal Diagnosis Volume 5 Issue 2

Abstract

Background:

The circadian fluctuations in the blood levels of selected components of the complement system are ill-defined. Some authors found nadir serum levels of C4 and C3 components, together with C3a at nighttime, while others reported insomnia when pro-inflammatory components exhibited increased serum levels. In this study, we quantitatively estimate the morning and evening daytime serum levels of CH50, C4, C3, put into context with C-reactive protein (CRP), cortisol, parathyroid hormone (PTH) and 25(OH)vitamin D at 07:00 A.M. and at 07:00 P.M.

Methods:

Seven healthy adult women and 11 men who were voluntary participants agreed to a fasting venipuncture in the morning after having normally eaten through the day and in the evening. The C4 and C3 serum levels were measured on a Cobas (Roche Diagnostics, Switzerland) modular analyzer, CH50 was estimated using the COMPL300 enzyme-linked immunosorbent assay (ELISA) of Wieslab (Malmö, Sweden). CRP, 25(OH)vitamin D, PTH and cortisol concentrations were assessed with electro-chemiluminescence immunoassay (ECLIA) on the Roche Cobas 6000 platform; IgG was measured using nephelometry (Siemens, Germany).

Results:

With the exception of higher PTH levels in the evening [3.12–5.46, 95% confidence interval (CI)] compared to the morning (2.93–4.65, 95% CI), the mean and median values of C4, C3, CH50 as well as CRP, PTH and 25(OH)vitamin D fell within the established reference intervals. Cortisol levels were measured as an internal positive control for diurnal fluctuations (morning: 294–522 nmol/L, 95% CI; evening: 106–136 nmol/L, 95% CI).

Conclusions:

The concentrations of the assessed complement components C4 and C3 as well as CH50 surrogate assay did not yield significantly different values between early morning and evening. This does not exclude their participation in the circadian metabolome; this pilot study with healthy participants suggests that patients with an autoimmune disease in remission can give their blood samples independently during daytime with or without fasting.

Keywords: chronobiology; circadian rhythm; complement system

Corresponding author: Prof. em Dr. Med. Urs E. Nydegger, Labormedizinisches Zentrum Dr. Risch, Buchs SG und Liebefeld bei Bern BE, Waldeggstr. 37, 3097 Liebefeld bei Bern, Bern, Switzerland, Phone: +4158 523 3466, Fax: +4158 523 3499

Acknowledgments

The authors acknowledge the precious secretarial help of Simone Inderbitzin. Madeleine Lehmann helped as study nurse.

Author contributions: TL and UN wrote the first draft. KM and TL introduced the TTC test in our lab. BS and LR did the statistical evaluations. LR and UN applied at Ethical Committee. MR and LR validated the study. All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.
Research funding: None declared.
Employment or leadership: None declared.
Honorarium: None declared.
Competing interests: The funding organization(s) played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.

References

1. Ricklin D, Mastellos DC, Reis ES, Lambris JD. The renaissance of complement therapeutics. Nat Rev Nephrol 2018;14:26–47.10.1038/nrneph.2017.156Search in Google Scholar PubMed PubMed Central

2. Ruseva MM, Ramaglia V, Morgan BP, Harris CL. An anticomplement agent that homes to the damaged brain and promotes recovery after traumatic brain injury in mice. Proc Natl Acad Sci USA 2015;112:14319–24.10.1073/pnas.1513698112Search in Google Scholar PubMed PubMed Central

3. Peffault de Latour R, Fremeaux-Bacchi V, Porcher R, Xhaard A, Rosain J, Castaneda DC, et al. Assessing complement blockade in patients with paroxysmal nocturnal hemoglobinuria receiving eculizumab. Blood 2015;125:775–83.10.1182/blood-2014-03-560540Search in Google Scholar PubMed

4. Berentsen S, Sundic T. Red blood cell destruction in autoimmune hemolytic anemia: role of complement and potential new targets for therapy. Biomed Res Int 2015;2015:363278.10.1155/2015/363278Search in Google Scholar PubMed PubMed Central

5. Wouters D, Zeerleder S. Complement inhibitors to treat IgM-mediated autoimmune hemolysis. Haematologica 2015;100:1388–95.10.3324/haematol.2015.128538Search in Google Scholar PubMed PubMed Central

6. Reis ES, Mastellos DC, Yancopoulou D, Risitano AM, Ricklin D, Lambris JD. Applying complement therapeutics to rare diseases. Clin Immunol 2015;161:225–40.10.1016/j.clim.2015.08.009Search in Google Scholar PubMed PubMed Central

7. Nydegger UE, Medina Escobar P, Risch L, Risch M, Stanga Z. Chronobiology and circadian rhythms establish a connection to diagnosis. Diagnosis 2014;1:295–303.10.1515/dx-2014-0036Search in Google Scholar PubMed

8. Man K, Loudon A, Chawla A. Immunity around the clock. Science 2016;354:999–1003.10.1126/science.aah4966Search in Google Scholar PubMed PubMed Central

9. Mohawk JA, Green CB, Takahashi JS. Central and peripheral circadian clocks in mammals. Annu Rev Neurosci 2012;35: 445–62.10.1146/annurev-neuro-060909-153128Search in Google Scholar PubMed PubMed Central

10. Reis ES, Lange T, Kohl G, Herrmann A, Tschulakow AV, Naujoks J, et al. Sleep and circadian rhythm regulate circulating complement factors and immunoregulatory properties of C5a. Brain Behav Immun 2011;25:1416–26.10.1016/j.bbi.2011.04.011Search in Google Scholar PubMed

11. Katz Y, Nadiv O, Rapoport MJ, Loos M. IL-17 regulates gene expression and protein synthesis of the complement system, C3 and factor B, in skin fibroblasts. Clin Exp Immunol 2000;120:22–9.10.1046/j.1365-2249.2000.01199.xSearch in Google Scholar PubMed PubMed Central

12. Katz Y, Strunk RC. IL-1 and tumor necrosis factor. Similarities and differences in stimulation of expression of alternative pathway of complement and IFN-beta 2/IL-6 genes in human fibroblasts. J Immunol 1989;142:3862–7.10.4049/jimmunol.142.11.3862Search in Google Scholar

13. Cutolo M, Seriolo B, Craviotto C, Pizzorni C, Sulli A. Circadian rhythms in RA. Ann Rheum Dis 2003;62:593–6.10.1136/ard.62.7.593Search in Google Scholar PubMed PubMed Central

14. Cao Q, Zhao X, Bai J, Gery S, Sun H, Lin DC, et al. Circadian clock cryptochrome proteins regulate autoimmunity. Proc Natl Acad Sci USA 2017;114:12548–53.10.1073/pnas.1619119114Search in Google Scholar PubMed PubMed Central

15. Ejaz Hussain M, Golam Sarwar AH, Alam MS, Noohu MM, Zannat W, Pandi-Perumal SR, et al. Polysomnographic correlates of inflammatory complement components in young healthy males. Sleep Sci 2016;9:123–7.10.1016/j.slsci.2016.04.001Search in Google Scholar PubMed PubMed Central

16. James FO, Cermakian N, Boivin DB. Circadian rhythms of melatonin, cortisol, and clock gene expression during simulated night shift work. Sleep 2007;30:1427–36.10.1093/sleep/30.11.1427Search in Google Scholar PubMed PubMed Central

17. Lincoln GA, Ebling FJ, Almeida OF. Generation of melatonin rhythms. Ciba Found Symp 1985;117:129–48.10.1002/9780470720981.ch9Search in Google Scholar PubMed

18. Cajochen C, Chellappa SL. Commentary: melanopsin regulates both sleep-promoting and arousal-promoting responses to light. Front Neural Circuits 2016;10:94.10.3389/fncir.2016.00094Search in Google Scholar PubMed PubMed Central

Received: 2018-1-26

Accepted: 2018-5-3

Published Online: 2018-5-29

Published in Print: 2018-6-27

You are currently not able to access this content.

Articles in the same Issue

https://doi.org/10.1515/dx-2018-0003

Keywords for this article

chronobiology; circadian rhythm; complement system