Which came first, the lectin/classical pathway or the alternative pathway of complement?

Area of Science:

• Immunology
• Evolutionary Biology
• Complement System

Background:

• The complement system comprises distinct pathways: classical, lectin, and alternative.
• Traditionally, the alternative pathway is considered evolutionarily older than the lectin/classical pathways.
• This view is supported by the presence of C3 and factor B proteins in invertebrates.

Purpose of the Study:

• To re-evaluate the evolutionary timeline of the complement system's pathways.
• To question the established view of the alternative pathway's primitive nature.
• To investigate the structural and functional evidence for invertebrate complement proteins.

Main Methods:

• Comparative analysis of protein families (C3/C4/C5, factor B/C2).
• Examination of gene duplication events within the vertebrate lineage.
• Review of the distribution of key complement components (e.g., factor D) across species.

Main Results:

• Gene duplications for C3/C4/C5 and factor B/C2 occurred specifically in vertebrates.
• Invertebrates possess lectins and MASP/C1r/C1s-like proteins.
• Factor D, crucial for the alternative pathway, is found only in bony fish and higher vertebrates.

Conclusions:

• The naming of invertebrate proteins as C3 and factor B may stem from preconceptions, not evidence.
• The lectin pathway's evolution is traceable through recognition of non-self.
• The alternative pathway's evolution is harder to conceptualize without pre-existing control proteins for self-protection.