Complement Activation by CpG in a Human Whole Blood Loop System: Mechanisms and Immunomodulatory Effects
Open accessAbstract
Phosphorothioate oligodeoxynucleotides can activate complement, and experimental murine studies have revealed differential effects upon simultaneous TLR stimulation and complement activation compared with either event alone. We set out to investigate the immune stimulatory effects of CpG 2006 in fresh non-anticoagulated human blood with or without presence of active complement. We also sought to elucidate the mechanism behind complement activation upon stimulation with phosphorothioate CpG 2006. In a human blood loop system, both backbone and sequence-specific effects by CpG were counteracted by selective inhibition of C3. Furthermore, DNA backbone-mediated CD40 and CD83 expression on monocytes and sequence-specific IL-6 and TNF production were reduced by complement inhibition. CpG-induced complement activation occurred via either the classical or the alternative pathway and deposits of both IgM and properdin, two activators of complement, were detected on CpG after incubation with EDTA plasma. Quartz crystal microbalance with dissipation monitoring demonstrated alternative pathway convertase build-up onto CpG as a likely pathway to initiate and sustain complement activation. Specific inhibition of C3 suppressed CpG 2006 uptake into monocytes indicating that C3 fragments are involved in CpG internalization. The interplay between complement and TLR9 signaling demonstrated herein warrants further investigation.
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All of the AAV-induced cytokines and chemokines can be upregulated by activation of TLR9 in the periphery using synthetic CpG-rich oligonucleotides.
“all of the AAV-induced cytokines and chemokines can be upregulated by activation of TLR9 in the periphery using synthetic CpG-rich oligonucleotides.8,9,10,11,12,52,53,54,55,56,57,58”
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- Authors
- Mangsbo, S. M., Sanchez, J., Anger, K., Lambris, J. D., Ekdahl, K. N., Loskog, A. S., Nilsson, B., & Tötterman, T. H.
- Affiliations
- Uppsala University (SE)
- Department of Oncology, Radiology and Clinical Immunology, Division of Clinical Immunology, Uppsala University , Uppsala,
- University of Pennsylvania (US)
- Corresponding author
- Anger, Kerstin
- Nilsson, Bo
- Venue
- The Journal of Immunology
- Publisher
- Oxford University Press (OUP)
- Published
- 2009-11
- Volume
- 183
- Issue
- 10
- Pages
- 6724-6732
- ISSN
- 0022-1767 (ISSN-L)
- 1550-6606
- PMC
- PMC2857538
- OpenAlex
- W1808677409
- Cited by
- 42
- References
- 47
- Citations by year
- 2025: 3 · 2024: 2 · 2023: 1 · 2022: 4 · 2021: 2 · 2020: 1 · 2019: 2 · 2018: 1 · 2017: 3 · 2016: 4 · 2015: 5 · 2014: 2 · 2012: 3
- FWCI
- 1.73
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- The Journal of Immunology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of General Medical Sciences (GM-62134, R01GM062134)
- National Institute of Allergy and Infectious Diseases (AI 068730, P01AI068730)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Complement system in diseases
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Life Sciences › Immunology and Microbiology › Immunology › Biomarkers in Disease Mechanisms
- Keywords
- complement activation, phosphorothioate oligodeoxynucleotides, TLR9 signaling, alternative complement pathway, classical complement pathway, monocytes, CD40, CD83, interleukin-6, TNF-α, properdin, IgM, immunomodulation
- MeSH terms
- CD83 Antigen, Adjuvants, Immunologic, Complement System Proteins, Complement Activation, Complement Pathway, Alternative, Humans, Immunoglobulin M, Immunoglobulins, Membrane Glycoproteins, Monocytes, Oligodeoxyribonucleotides, Peptides, Cyclic, Properdin, Tumor Necrosis Factor-alpha, Antigens, CD, Interleukin-6, Cytokines, CD40 Antigens, Phosphorothioate Oligonucleotides
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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