The Complement system

Activities of the Complement System

Lysis
Clearance of Immune Complexes
Oponization
Activation of Inflammatory response

Classical pathway

adaptive immune response
initiated by Ag-Ab complex

Lectin and alternate pathway

innate immune response
initiated by microbial surface

C5 convertase

where do the 3 pathways converge

C5B

Binds to target cell and leads to membrane attack complex (MAC) formation

MAC

forms large pores causing the microbes to die 

C1 ro C9

complement components of the classical pathway

C4b2a

C3 convertase of the classical pathway

C4b2a3b

C5 convertase of the classical pathway 

2

how many IgGs are required to activate the C1q component classical complement pathway

1

how many IgMs are required to activate the C1q component classical complement pathway

first step of the classical pathway

C1q antigen-bound antibody, and induces a conformational change in one C1r molecule, activating it. This C1r then activates the second C1r and the C1s molecules

second step in the classical pathway

C1s cleaves C4
The small C4a fragments diffuses away, but the larger C4b fragment binds to the membrane
This exposes a binding site for C2
When C2 binds C4b, it becomes susceptible to sleavage by C1s with creates C3 convertase - C4b2a

third step in the classical pathway

C3 convertase hydrolyzes many C3 molecules. Come bombine with C3 convertase to form C5 convertase

Anaphyatoxin

complement fragments act as inflammatory mediators. They degranulate mast cells and basophils, resultin in release of mediator that induce contraction of smooth muscle and increase vascular permeability

Fourth step in the classical pathway

the C3b component of C5 convertase binds C5, permitting C4b2A to cleave C5

C5b

in the classical pathway ___ fragment binds in the surface of the target cell and initiates the MAC

CRP

C1q binds to ___ complexed with exposed phosphorylcholine residues on the bacteria and C1 gets activated

Lectin Pathway

initiated by binding of serum protein (mannose-binding lectin) to mannose-containing component of microbial cell walls

MBL

acts as a classical pattern recognition receptor in the lectin pathway
belongs to collectin faily
is an APR
increases in concentration during an inflammatory response
similar is structure to C1q
binds to carbohydrate residue on the surface of pathogen

MASP-1 and MASP-2

bind to MBL
structurally similar to C1r and C1s

C3 convertase

in the lectin pathway MBL-associated serine proteases, MASP-1 and MASP-2 bind to MBL and forms an active complex that cleaves C2 and C4 and forms the _____
where the lectin pathway converges with the classical pathway

Alternative pathway trigger

continuous hydrolysis of C3 “tick over”

C3bBb

C3 convertase of the alternative pathway

C3bBbC3b

C5 convertase of the alternative pathway

1st step of the alternative pathway

initiated with C3 undergoeas spontaneous hydrolysis yielding the molecule C3(H2O)

2nd step of the alternative pathway

C3(H2O) binds factor B making it susceptible to Factor D cleavage

Factor D

what cleaves factor B after it is attached to C3(H2O)

3rd step of the alternative pathway

C3(H2O)Bb forms fluid phase C3 convertase and cleaves C3 into C3a and C3b

C3(H2O)Bb

fluid phase C3 convertase

4th step of the alternative pathway

some of the C3b formed in fliud phase binds to pathogenic membrane

5th step of the alternative pathway

membrane C3b bonds to factor B. Factor D cleaves C3b bound B into Bb and Ba, forming membrane bound C3bBb or C3 convertase

6th step of the alternative pathway

membrane bound C3bBb is stabilized by properdin (factor P). C3 convertase cleaves C into C3a and C3b

Properdin (factor P)

stabilizes C3 convertase and C5 convertase in the alternative pathway

7th step of the alternative pathway

addition of C3b to C3bBb complex forms C5 convertase which is also stabilized by properdin

8th step of the alternative pathway

C5 convertase cleaves C5 into C5a and C5b

Protein S (Vibronectin)

prevents the bystander effect of the MAC

bystander effect

the C5b67 is released and can insert into a neighboring cell membrane

anaphylatoxins

C3a, C4a, and C5a

C3b and C4b

facilitates oponization

C5a

increases the CR1 expression from 5,000 on a resting cell to 50,000 on an activated phagocytic cells

C3b and C4b

binds CR1

Neutralizes infectivity of some viruses

locks attachment of virus to susceptible host cells
antibody-complement coated virus particle gets phagocytosed
effective in lysing enveloped viruses

Clears immune complexes

RBC express the CR1 receptor to which C3b coated immune complexes bind
in the liver and spleen, immune complexes are stripped from the RBC and phagocytosed

C3b

binds to immune complexes and the CR1 of RBCs so they can be stripped in the liver and spleen

Regulators of Complement Activation (RCA)

genes that encode for regulatory proteins

C1 inhibitor (C1INH)

is a serine protease inhibitor that inhibits both C1s2r2 protease of the classical pathway and MASP-2 protease of the lectin pathway

Decay Accelerating Factor (DAF/CD55)

on the surface of host cells
degrades C3 convertase of both pathways
requires CR1 and C4BP as cofactors

Factor I

serine protease the cleases C3b and C4b into inactive fragments only when it is associated on the host membrane with necessary cofactors

S protein (vibronectin)

binds soluble C5b67 and prevents insertion into the host cell membrane

homologous restriction factor (HRF)

binds C5b678 on host cells thereby blocking C9 and formation of poly-C9 complex
also called protectin, CD59, or Membrane Inhibitor of Reactive lysis (MIRL)