Complement - Vanessa Flashcards
What are complements?
Heat labile proteins that act in cascade to increase inflammation, opsonize, and lyse microbials. You can use serum (which is plasma without clotting factors) to analyze the complements present.
How do complements gain access to the tissues?
cytokines cause leakiness of the endothelium and when blood and leukocytes rush into site of infection, so do complement proteins.
How do macrophages work in conjunction with opsins?
Microbe will bind to TLR of a macrophage and it will release TNFa, IL-1, IL-12 which causes inflammation/leakiness/and recruitment of leukocytes. Opsins enter into site of infection too and bind to pathogen (as C3b). Macrophages have complement receptors that recognize them and phagocytose the marked pathogen
Why is C3 and C5 cleavage important?
C3 makes C3b and C3a. C3b is the central opsin, and C3a is an anaphylatoxin for inflammation. C5a is an inflammatory factor that attracts neutrophils, and C5b binds to pathogen for completion of cascade
How does alternative pathway work?
C3 directly binds to microbe and is spontaneously hydrolyzed to be active. Factor B is cleaved by factor D = Bb+ C3b + Bb = C3 convertase, which cleaves C3’s. C3bBb3b is also a C5 convertase.
How does mannose lectin binding pathway work?
C4b and C2a bind together on MBL to form C3 convertase. C5 convertase then cleaves C5 to C5b and C5a.
What’s specific about the classical pathway?
it requires binding of antibodies (specifically IgM and IgG), or CRP which is a pentameric opsonin. This creates a docking site for C1 complex, then C4b and C2a bind to make a C3 convertase. This cleaves C3’s to C3bs which covalently bind to microbe. This also forms the C42a3b = C5 convertase.
How does the MAC complex form?
When C5 convertase is made after C3 convertase, it cleaves C5 proteins. C5b binds to microbe and and sequentially C6, C7, C8, and C9.
How do macrophages and B cells recognize C3bs on microbe?
It had a CR1 receptor that recognizes. B cells have CR2.
What happens to patients who are deficient in early complements?
encapsulated bacteria are difficult to kill and require activation of complements. So patients who don’t have early complements like C1, C2, C3, C4 they get more infections from things like Neisseria meningitidis, strep pneumoniae, and H. influenza. An example is in systemic lupus erythematosus, which is a build up of immune complexes (antibody and antigen) which are usually cleared by classical complement pathway.
What happens to patients who lack C5-C9?
Again more infections from gram negatives.
How do C3a and C5a cause and decrease inflammation?
cause smooth muscle contraction, degranulation of mast/basophils, release histamines, and increase permeability. Complement regulatory proteins activation proteins. One example, C1 INH (C1 complex inhibitor) binds and prevents C1 from being proteolytically active. The other example is DAF/CD55 which is a lipid surface protein decay factor that interferes with C3 convertase formation by blocking Bb or C2a (classical) binding.
What happens in patients who are C1INH deficient?
Patients get hereditary angioedema, which is edema of mucosal surfaces. This is caused by overuse of C1, c4, or C2 because of low C1IHN levels and low levels of C4 (because constantly broken down).
What happens with lack of DAF/CD55?
complement mediated RBC lysis and paroxysmal nocturnal hemoglobinuria
How is C3 cleavage regulated?
Factor I cleaves C3b (alternative) and C4b (lectin and classical), and it uses cofactor H (or co factor C4BP in lectin/classical) to cause dissociation of the C3 convertases.
