The Complement System
The complement system is a complex functional network of proteins that aids innate and adaptive immune pathways via promoting opsonization (tagging targets for phagocytosis, attracting macrophages) and inflammatory responses. On a macro level, the complement system is a cascade of catalytic proteins that cleave and activate the next protein(s) in the pathway. There are three paths: the classical, alternative, and lectin pathways.
The classical pathway is initiated by antigen-antibody complexes. It can thus be viewed as an extension of the adaptive immune pathway. The compatible antibody types include IgG and IgM. The classical pathway is as follows: the antibody-antigen complex* activates a protein cascade (by complexing with C1) which eventually creates C3 convertase, which cleaves C3 into C3a and C3b. C3b binds C3 convertase and forms C5 convertase, which cleaves C5 into C5a and C5b. C5b, along with other complement proteins, forms the membrane attack complex (MAC) which forms holes in pathogen walls. This allows water to rush in and blow up the cell (osmotic shock).
The alternative pathway is triggered when C3b binds a pathogen. C3b is normally ubiquitous in the blood; however, it is only activated when it binds foreign particles (it’s regulated by other complement factors such that it doesn’t react to self cells). Once C3b binds the pathogen, the rest of the cascade proceeds identically to the classical pathway (C3b binds C3 convertase, etc), forming the MAC once again and lysing the pathogen.
Here’s how both pathways are connected:
The lectin pathway is initiated by special sugar-binding proteins, or lectins** (mannose-binding lectin/MBL, ficolin, or mannose-binding protein which is made by the liver), recognizing surface carbohydrates or glycoproteins characteristic of certain pathogenic species. The advantage of recognizing surface carbohydrates or glycoproteins is that this form of immune defense can attack many kinds of pathogens, from fungi like Candida (causes vaginal yeast infections), to bacteria like Salmonella (uh idk raw chicken), to viruses like HIV (ruins helper T cells, read more about how here).
The mechanism of the lectin pathway is identical to the classical pathway, in that it begins with the C2b and C4b fragments, and proceeds forward. The only difference is the initial activating force; for classical, it’s the antibody-antigen complex*, and for lectin, it’s the surface sugars.
To conclude, I just wanted to mention that many members of the complement cascade have other immune functions, like increasing vascular permeability or controlling allergic responses etc.
So yeah! That’s it. Hope it lived up to my hype lol. Leave a comment / DM me with article ideas <3 Also, if you’ve given me something and I haven’t done it yet, I haven’t forgotten about you, I’m just studying the topic still (y’all give me some crazy loaded topics lol, keep ‘em coming though).
Anyways, here are some more great resources to learn more about the complement cascade!
More details on the classical pathway: https://en.wikipedia.org/wiki/Classical_complement_pathway.
More details on the alternative pathway: https://en.wikipedia.org/wiki/Alternative_complement_pathway.
More details on the lectin pathway: https://en.wikipedia.org/wiki/Lectin_pathway.
Video from Osmosis that I haven’t watched in a while (I remember it was helpful, but I can’t rewatch it since my free trial is over and I’ve used my personal and school email accounts): https://www.osmosis.org/learn/Complement_system.
Very cool article about complement: https://www.ncbi.nlm.nih.gov/books/NBK27100/.
Vander’s immune chapter, although Wikipedia did a better job of explaining this (imo).
* The classical complement pathway can also be activated by apoptotic/necrotic cell proteins, as well as proteins that increase in concentration due to inflammation (acute phase proteins like C-reactive protein).
** Sound familiar? You might recall learning about selectins, which participate in extravasation (basically immune cells moving from the blood to infected tissue). Here’s a picture explaining the role they play:
