Chapter 2
Innate Immunity
The immediate response to infection
1. Innate immunity
• immediate- ready for action at
all times
• induced- few hours - 4 days once
cells recognize presence of
lines of infection
defense 2. Adaptive immunity- more powerful,
provide long lasting immunity,
reserved for the few infections that
the innate immune system cannot
control
INTRACELLULAR VS.
EXTRACELLULAR PATHOGENS
• Intracellular pathogens- replicate
inside human cells
• not accessible to soluble
secreted molecules
• Defense strategy is to kill
human cell in which pathogen
resides
• Extracellular pathogens- live and
replicate in spaces between human
cells
• accessible to soluble secreted
molecules
Many pathogens have lifecycle
inside and outside the cell
• Soluble proteins
• made constitutively by liver
• present in the blood, lymph and extracellular
fluid
• Coat surface of bacteria and extracellular viruses
and promote phagocytosis
• Complement proteins are proteases
Complement • Inactive form of proteins are termed zymogens
• Infection triggers activation
• Complement system made up of 30+ proteins
• Component C3 most important
Individuals lacking complement proteins other than C3- no
major immunodeficiency observed
Individuals lacking C3 – susceptible to severe infections
Complement
fixation
• Complement fixation- when C3b becomes
covalently bound to pathogen
• C3b tags pathogen for destruction via
phagocytosis and formation of protein
complexes that damage membrane of
pathogen
• C3a acts as chemoattractant to recruit
effector cells from blood to the site of
infection
Unusual feature of C3
Three complement pathways
Alternate pathway- iC3Bb
1. hydrolysis of C3
2. iC3 binds inactive factor B
3. factor D cleaves factor B
4. iC3Bb complex = C3 soluble convertase protease
that cleaves C3 into C3a and C3b fragments
5. Some C3b fragments become covalently attached
to pathogen surface
Alternate pathway- C3bBb
• Positive feed back
• Progressive amplification of C3 cleavage
• Ultimate outcome: pathogen rapidly
becomes coated with C3b
C3bBb complex = alternative
C3 convertase- Surface bound
Why do we need complement
control proteins?
How do complement control
Complement proteins work?
control • Stabilize or degrade C3b at cell
surfaces
proteins • Plasma proteins that interact with
C3b attach to human or microbial
cell surface
• Membrane protein on human cells
that prevent complement fixation
at cell surface
Complement
control proteins
(plasma proteins)
Properdin (factor P)-
plasma protein
• Increases speed
and power of
complement
activation
• Binds C3
convertase C3bBb
preventing
degradation by
proteases
Complement
control proteins
(plasma proteins)
Factor H and Factor I-
plasma proteins
• Counters effect of
properdin
• Binds C3b and
facilitates cleavage to
form iC3b by plasma
serine protease factor I
• iC3b cannot assemble a
C3 convertase
• Individuals lacking
Factor I
Complement • Works to distinguish human cells from microbial cells
control • Discrimination of non-self from self
proteins
(membrane
proteins on
human cells)
• First effector cell that pathogen
encounters in tissue
• Mature form of circulating
monocytes that have left the blood
and taken up residence in tissues
• Long lived phagocytic cells
Macrophages • Innate and adaptive immunity
• Macrophage receptors increase
efficiency of phagocytosis
• Complement receptor 1 (CR1)
• Complement receptor 3 (CR3)
• Complement receptor 4 (CR4)
• Binds C3b fragment bound to pathogen
• Protects surface of cells on which it is expressed
• Disrupts C3 convertase by making C3b susceptible
to cleavage by factor I
• Made of CCP modules
• Some CR1 bind C3b on pathogen surface to help
in phagocytosis
Complement
receptor 1
(CR1)
• Members of integrin family
Complement • Structurally not related to CR1
Receptor 3 (CR3) • Bind iC3b fragment on pathogen surface
• iC3b has no convertase activity, but it
and Complement facilitates phagocytosis and pathogen
Receptor 4 (CR4) destruction by serving as ligand for CR3
and CR4
Complement C5
• C3b binds alternative C3 convertase – C3b2Bb
called alternative C5 convertase
• C5- structurally similar to C3, but no thioester
bond
• Very different function from C3
• C5a- small fragment
• C5b- large fragment
• Initiates membrane attack complex (MAC)
• Makes holes in membrane of pathogens
and eukaryotic cells
• C6 and C7 bind C5b
• hydrophobic site in C7 inserts into lipid bilayer
• hydrophobic site in C8 is exposed and inserts
into membrane
• C8 initiates polymerization C9
• C9 component forms transmembrane pore
Membrane • Up to 16 molecules C9 can be added to
polymer to create transmembrane channel
Attack
Complex
(MAC)
Complement
proteins
• Importance of C5-C9 is limited:
• Increase in susceptibility to Neisseria infections, but inherited
deficiencies are not uncommon
Regulation of Terminal Complement Proteins
S protein Prevent soluble complex C5b with
Clusterin C6 and C7 from associating with
Factor J cell membranes
Homologous restriction factor (HRF) Prevent recruitment C9 by
C5b, C6, C7 and C8 complex
CD59 (protectin)
Paroxysmal nocturnal hemoglobinuria-
Disease characterized by episodes of
complement mediated lysis of RBC that
lack cell surface DAF, HRF or CD59.
Impaired synthesis of tail of proteins is
cause.
Role of small peptides C3a and C5a
Increase inflammation at site of complement activation
Can induce anaphylactic shock so called anaphylatoxins
Anaphylatoxins
• contraction of smooth muscle
• degranulation of mast cells and basophils
• histamine release -increased capillary
permeability and increased blood flow
• Easier for plasma proteins and cells to
move out of blood into site of infection
C5a acts on neutrophils and monocytes
• increase adherence to blood vessel walls
• chemoattractant to site of complement fixation
Increases phagocytic activity of these cells
Increases expression of CR1 and CR3 on cell surface
Coagulation system
• Form blood clots- immobilize
Plasma pathogens
• Prevent entry into blood and
proteins decrease loss of blood and fluid
• Platelets release substances that
that limit are antimicrobial, inflammatory and
help in wound healing
the
Kinin system
spread of
• Plasma proteins induced by tissue
infection damage
• Induce vasodilation which helps
gets cells and soluble substances
out of blood and into tissue
• Protease Inhibitors
Plasma α2-macroglobulins- inhibit broad range proteases
proteins
that limit
the
spread of
infection
Defensins- antimicrobial peptides
• Antimicrobial peptides
• α-defensins
Secreted by Paneth cells in small intestine
• β-defensins
Produced by broad range of epithelial cells
• Skin, respiratory tract and urogenital
tract
• Penetrate and disrupt pathogen membrane
• Constitutively secreted at mucosal surface
• Neutrophils also produce defensins
• Packaged in granules and used to kill
pathogens that neutrophil has
phagocytized
Pentraxins
• Plasma proteins
• Bind pathogens and target them for destruction
• Cross-link pathogen and phagocyte
• Similar role as Ab in adaptive immune response
• Pentraxins and Abs bind same surface receptor on
phagocytes
