The Complement System Can lead to

2. Increase
Role of C2b edema if
• Complement – to help or to make complete capillary
fragment complement is
• Part of the innate and adaptive immune response permeability
not controlled
• Heat labile series of 18 plasma proteins Attract cells and
o Enzymes or proteinases play important
C5a – most
• Complement proteins 3. Chemotaxis efficient
role in
o Named with a capital C followed by a number recruitment of
chemotaxis
o Small letter – results from the cleavage of a larger cells to an influx
precursor by a protease site
o C3a/C3b Enhances
neutralization
o Larger fragment – designated as b 4. Virus
C4 of viruses by
o Smaller fragment – designated as a neutralization
homologous
▪ Exception: C2 fragments antibodies
▪ Larger – C2a, smaller fragment – C2b C3b on particles
Complement Components such as bacteria
or an Ab-Ab
• Proteins and glycoproteins synthesized mainly by complex
liver 5. Opsonization C3b promotes the
• Most circulate in the serum functionally as inactive attachment and
forms called proenzymes/zymogens – inactive form ultimate
ingestion of
of complement proteins
particles
• Produces a cascade phenomenon where the
product of one reaction is the enzymatic catalyst of Three Pathways of Complement
the next
Alternate/
Functions of Complement Classical Alternative/ Lectin
1. Lysis of cells, bacteria, and viruses Properdin
Initiated by:
2. Opsonization – coating of cells, making it more
1. Aggregates
susceptible to phagocytosis Initiated by:
of IgA
3. triggers specific cell functions, inflammation and 1st to be studied With mannose
2. Yeast cell or
secretion of immunoregulatory molecules Initiated by Ag- and other
zymogen
4. immune clearance: removal of immune complexes Ab complex (Ab similar sugars in
3. CVF: Cobra
and deposition in the spleen and liver dependent) the cell wall
Venom
(Ab
Factor
Biological Functions independent)
4. LPS
Main
complement Three Phases
Functions Comment
component Recognition event which will
involved Initiation initiate complement cascade
They bind to Phase Classical and Alternate pathway
receptors on differ at this phase
mast cells and Activation of early components
basophils Amplification/ culminate in activation of C3, which
C3a
1. Anaphylatoxins C4a Induce Activation is the critical component
C5a degranulation Phase Classical and Alternate pathway
and release of differ at this phase
influx mediators Culminates in target cell lysis
Membrane
including Classical and Alternate pathway is
Attack Phase
histamine the same at this phase
Activation of Complement o C1q will recognize antigen-antibody complex –
C1q will now recognize the fragment crystallizable
Classic Mannose
Alternative of the antibody
Pathway Binding
o C1q will bind to the Fc portion of the antibody,
Contact with a
then will activate the C1r and C1s that will result
foreign surface Binding of the
such as the complex of to C1qrs
Bonding of polysaccharide mannose o C1qrs will now activate both C4 and C2, C4 will be
C1 complex coating of binding lectin activated first and cleave to produce C4a and C4b
(C1q, C1r, microorganism and associated o C2 will cleave and produce C2b and C2a
C1s) to Covalent bonding serine o C4b2a (C3 convertase) cleave C3 and produce C3a
antibodies of a small amount proteases and C3b
bound to an of C3b to hydroxyl (MASP1 and o C4b2a3b (C5 convertase) will activate C5 to
antigen on groups on cell MASP2) to produce C5a and C5b
the surface surface arrays of o C5b will now be the one to activate C6, C7, C8, and
of a bacterial carbohydrates and mannose C9 that will lead to cell lysis and from MAC
cell proteins groups on the
Activated by low- surface of a Alternative Pathway
grade cleavage of bacterial cell
C3 in plasma • First described by Pillemer and his associates in the
early 1950s
• Originally named Properdin (only a factor in order
Classical Pathway to stabilize the complement components)
• Needs an antigen-antibody complex in order for the • Antibody is not required
different complement proteins to recognize the • Innate immunity
fragment crystallizable of a certain antibody, either • 4 serum proteins: C3, factor B, factor D, and
an IgG or IgM properdin
• Major effector mechanisms of antibody-mediated • Initiated by cell-surface constituents that are
immunity foreign to the host (gram + and gram – bacterial cell
• Principal components: C1 – C9 walls)
• Activation: C1, 4, 2, 3, 5, 6, 7, 8 and 9 • Factors capable of activating the alternative
• C3 pathway
o Present in the plasma in the largest quantities o Inulin
o Fixation of C3 is the major quantitative reaction of o Zymosan
the complement cascade o Bacterial polysaccharides and endotoxins
• Three major stages: o Aggregated IgG2, IgA and IgE
o Recognition • Process
o Amplification of proteolytic complement cascade o C3 will now be activated, hydrolyzed by water to
o Membrane attack complex (MAC) produce C3b which binds to factor B and together
• Begins with the formation of soluble antigen- they attach to the target cells surface
antibody complexes or with binding of antibody to o Factor B is cleaved by factor D into fragments Ba
antigen on a suitable target such as a bacterial cell and Bb, Bb combines with C3b to form C3b-Bb (C3
• Activated by IgG (only a monomer, 2 IgG molecules convertase)
needed) or IgM (most efficient activating o More C3 is cleaved forming more C3b-Bb,
complement, only 1 molecule needed) stabilized by properdin and continues to cleave
o IgM, IgG1, IgG2, IgG3 only additional C3b
• Ag-Ab-IgM: conformational change in Fc: exposing a o C5 convertase contains C3b, Bb, P, and C3b
binding a binding site for C1 Mannose Binding Lectin Pathway
• Process
• Lectins: proteins that recognize and bind to specific
carbohydrate targets (specifically mannose)
• After initiation proceeds thru action of C4 and C2 to
produce C3---C5 convertase
• Activated by binding of mannose-binding lectin to
mannose residues on glycoproteins or
carbohydrates on the surface of microorganisms
such as Salmonella, Listeria, Neisseria, Cryptococcus
and Candida
• Process
o Activated MASP-2 (mannose binding lectin
associated serin protease) cleaves C4 to C4a and
C4b. some C4b binds covalently to the microbial
surface.
o Activated MASP-2 also cleaves C2 to C2a and C2b
o C2a binds to surface C4b forming the classical
C3convertase, C4b2a
o C4b2a binds C3 and cleaves it to C3a and C3b. C3b
binds covalently to the microbial surface and
activate also C5 convertase

Membrane Attack Complex

• Three pathways: active C5 convertase to cleave C5--

-C5a and C5b (initiates the final steps to form MAC)
• Forms a large channel through the membrane of
the target cell enabling ions and small molecules to
diffuse freely across the membrane destroying the
pathogen