Research in 1890 showed that sheep antiserum to which microbe caused bacterial lysis?
Vibrio cholerae
What destroyed the bacteriolytic activity of the sheep antiserum?
Heating it to 55°C for 30 min
How was the bacteriolytic activity restored in the sheep antiserum? What did it contain?
Adding fresh serum that did NOT contain antibody to the bacteria. It contained complement proteins C1-C9, factors B, D, and P, plus regulatory proteins
How many complement proteins are there?
More than 30
Where is complement synthesized?
Liver and by macrophages, blood monocytes, and epithelial cells
Explain how interferons work
- Virus enters cell
- Interferon gene switches on
- Cell produces interferons and secretes them
- Interferons bind interferon receptors on a different host cell
- IFN binding stimulates new cell to turn on antiviral genes
- Antiviral proteins block viral reproduction in new cell
Which cells secrete IFN-gamma?
lymphocytes
Which IFN types are alpha, beta, and gamma?
Alpha and beta = Type I
Gamma = Type II
IFNs activate which cells?
Macrophages and NK cells
At which step do the classical and alternative complement activation pathways meet?
C3
How are the classical and alternative pathways activated?
Classical: antibodies
Alternative: spontaneous
List the complement protein order of the classical pathway
C1 -> C4 -> C2 -> C3 -> C5 -> C6 -> C7 -> C8 -> C9
What are the main functions of complement?
- Opsonize to enhance phagocytosis
- Anaphylactic is to induce inflammatory response
- Direct killing through membrane attack complex (MAC) causing lysis
- Immune clearance, removing complexes from circulation
List the 3 anaphylatoxins of the classical complement pathway in order of their inflammatory potency
C5a -> C3a»_space;> C4a
Which Igs can activate complement?
IgM and IgG, except IgG4
Which Ig most potently activates complement? Why?
IgM because only one alone sufficient to activate, whereas need at least 2 IgG to activate
Which pathway comes first in fighting infection? Which was discovered first?
Alternative pathway comes first, but classical pathway was discovered first and requires adaptive immune system
Describe the first 3 steps of classical complement activation
- IgG opsonizes target and C1 binds two evenly spaced apart IgGs
- C1 cleaves C4 into C4a and C4b. C4a remains in the fluid phase as an anaphylatoxin while C4b binds the cell surface/C1
- C4b binds C2, which gets cleaved by C1s esterase into C2a and C2b. C2b remains in fluid phase. C2a binds C4b and creates the complex called C4b2a (C3 convertase). This formula is specific to the classical pathway!
Describe the 4th step of complement activation
C3 convertase (C4b2a) cleaves C3 in to C3a and C3b. C3a remains in fluid phase as anaphylatoxin and C3b binds the complex to form C4b2a3b (C5 convertase).
Describe the 5th step of the classical complement pathway
Once C5 convertase is formed, it cleaves C5 into C5a (anaphylatoxin) and C5b. C5b binds the complex. C5b is the first subunit of the MAC complex
Describe the terminal steps of the classical complement pathway
Once C4b2a3b5b is formed, C6-C9 are recruited to form the MAC complex
List the overall order of the alternative complement activation pathway
C3- > B -> C3 -> C5 -> C6 -> C7 -> C8 -> C9
Which C proteins are not present in the alternative pathways?
C1, C2, and C4
Describe the steps of the alternative pathway, right before the terminal steps
- C3 gets cleaved into C3a and C3b
- Factor B gets cleaved by factor D into Ba and Bb. Ba remains in fluid phase while Bb remains bound to C3b. This forms the C3bBb (C3 convertase) complex). Factor P stabilizes this complex
- C3 convertase cleaves another C3 and C3b binds the other side of C3b, forming C3bBb3b (C5 convertase) complex
- C5 convertase cleaves C5 and C5b remains bound to the complex.
