The phylogeny of the complement system and the origins of the classical pathway
Alister W Dodds1, Misao Matsushita
1MRC Immunochemistry Unit, Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, UK. alister.dodds@bioch.ox.ac.uk
Insights
The complement system originated with early multicellular life, likely resembling the lectin pathway. The C1q molecule predates antibodies, functioning as a lectin in lampreys to activate complement.
Area of Science:
- Immunology
- Evolutionary Biology
- Biochemistry
Background:
- The complement system is crucial for innate and adaptive immunity.
- Its evolutionary origins and early activation mechanisms remain incompletely understood.
- The classical pathway, initiated by C1q, is a key component in vertebrates.
Purpose of the Study:
- To investigate the evolutionary origins of the complement system.
- To determine the ancestral function of the C1q molecule.
- To elucidate the relationship between the lectin and classical complement pathways.
Main Methods:
- Comparative analysis of complement system components across species.
- Biochemical characterization of C1q function in primitive vertebrates.
- Investigation of C1q interactions with other complement proteins.
Main Results:
- Evidence suggests the earliest complement activation resembled the lectin pathway.
- C1q was found in lampreys, which lack an acquired immune system and antibodies.
- In lampreys, C1q functions as a lectin, binding MASPs and activating complement.
Conclusions:
- The C1q molecule predates the evolution of antibodies.
- The classical complement pathway evolved as a specialized arm of the lectin pathway.
- C1q's ancestral role was likely carbohydrate recognition, later adapted for immunoglobulin binding.
Abstract:
The origins of the complement system have now been traced to near to the beginnings of multi-cellular animal life. Most of the evidence points to the earliest activation mechanism having been more similar to the lectin pathway than to the alternative pathway. C1q, the immunoglobulin recognition molecule of the classical pathway of the vertebrates, has now been shown to predate the development of antibody as it has been found in the lamprey, a jawless fish that lacks an acquired immune system. In this species, C1q acts as a lectin that binds MASPs and activates the C3/C4-like thioester protein of the lamprey complement system. The classical pathway can, therefore, be regarded as a specialised arm of the lectin pathway in which the specificity of C1q for carbohydrate has been recruited to recognise the Fc region of immunoglobulin.
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