The quantitative role of alternative pathway amplification in classical pathway induced terminal complement activation
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SUMMARY: Complement activation with formation of biologically potent mediators like C5a and the terminal C5b-9 complex (TCC) contributes essentially to development of inflammation and tissue damage in a number of autoimmune and inflammatory conditions. A particular role for complement in the ischaemia/reperfusion injury of the heart, skeletal muscle, central nervous system, intestine and kidney has been suggested from animal studies. Previous experiments in C3 and C4 knockout mice suggested an important role of the classical or lectin pathway in initiation of complement activation during intestinal ischaemia/reperfusion injury while later use of factor D knockout mice showed the alternative pathway to be critically involved. We hypothesized that alternative pathway amplification might play a more critical role in classical pathway-induced C5 activation than previously recognized and used pathway-selective inhibitory mAbs to further elucidate the role of the alternative pathway. Here we demonstrate that selective blockade of the alternative pathway by neutralizing factor D in human serum diluted 1 : 2 with mAb 166–32 inhibited more than 80% of C5a and TCC formation induced by solid phase IgM and solid- and fluid-phase human aggregated IgG via the classical pathway. The findings emphasize the influence of alternative pathway amplification on the effect of initial classical pathway activation and the therapeutic potential of inhibiting the alternative pathway in clinical conditions with excessive and uncontrolled complement activation.
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The alternative pathway is responsible for the majority of C5a and MAC formation, which suggests that the terminal pathway may be causative in CNV formation.
“The alternative pathway is responsible for the majority of C5a and MAC formation [164], which suggests that the terminal pathway may be causative in CNV formation.”
From Bruch’s Membrane: A Key Consideration with Complement-Based Therapies for Age-Related Macular Degeneration (2023) · cites this paper as [164]
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- Authors
- HARBOE, M., ULVUND, G., VIEN, L., FUNG, M., & MOLLNES, T. E.
- Affiliations
- Oslo University Hospital (NO)
- Tanox Inc, Houston, Texas 77025, USA
- Corresponding author
- MOLLNES, T E
- ORCID
- MOLLNES, T E
- Venue
- Clinical and Experimental Immunology
- Publisher
- Oxford University Press (OUP)
- Published
- 2004-10-28
- Volume
- 138
- Issue
- 3
- Pages
- 439-446
- ISSN
- 0009-9104 (ISSN-L)
- 1365-2249
- PMC
- PMC1809239
- OpenAlex
- W1980493655
- Cited by
- 319
- References
- 33
- Citations by year
- 2026: 14 · 2025: 20 · 2024: 20 · 2023: 23 · 2022: 32 · 2021: 23 · 2020: 22 · 2019: 13 · 2018: 14 · 2017: 11 · 2016: 23 · 2015: 14 · 2014: 8 · 2013: 7 · 2012: 16
- FWCI
- 2.88
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model (vor)
- Locations
- Clinical & Experimental Immunology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- EkstraStiftelsen Helse og Rehabilitering (Stiftelsen Dam)
- Norsk Revmatikerforbund
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Complement system in diseases
- Life Sciences › Immunology and Microbiology › Immunology › Biomarkers in Disease Mechanisms
- Health Sciences › Medicine › Genetics › Coagulation, Bradykinin, Polyphosphates, and Angioedema
- Keywords
- alternative complement pathway, classical complement pathway, terminal complement activation, C5a, membrane attack complex, factor D, ischemia-reperfusion injury, IgG aggregation, IgM, complement inhibition therapy
- MeSH terms
- Antibodies, Monoclonal, Epitopes, Complement Activation, Complement Pathway, Alternative, Complement Pathway, Classical, Complement C5, Humans, Immunoglobulin G, Immunoglobulin M, Complement Factor D, Autoimmunity, Complement C5a, Complement C5b
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