Section 2: Innate Immunity (Complement) Flashcards
Pathogens
-can vary greatly in their strategies to live and replicate within the human body
-also possess various strategies of harming the body
-important distinction is made by the immune system when recognizing pathogens based on where they might exists during infection
-innate and adaptive immune systems utilize different strategies to combat these pathogens depending on the physiological compart they infect
3 mechanism by which pathogens cause tissue damage
- exotoxin release (ex: vibrio cholerae, cholerae)
- endotoxin release (ex: yersinia pestis, plague)
- direct cytopathic effect-virus replicates until cell dies (Influenza virus, Influenza)
extracellular pathogen
infections and pathogens that replicate in the spaces between outside of cells
intracellular pathogens
infections and pathogens that replicate inside of cells
extracellular innate immune response in interstitial spaces, blood, lymph
organism: viruses, bacteria, protozoa, fungi, worms
defense mechanism: complement system, neutrophils, macrophages
extracellular innate immune response in epithelial surfaces
organisms: Neisseria gonorrhea, candida Albicans, worms
defense: antimicrobial peptides
intracellular innate immune response in cytoplasmic
organisms: viruses, listeria, protozoa
defense: NK cells
intracellular innate immune response in vesicular
organism: mycobacteria, trypanosomes, cryptococcus neoformans
defense: activated macrophages
complement system
-the first thing to respond in innate immune response
-is a system of plasma proteins that mark pathogens for destruction
-they circulate in fluids and tissues generally that are actively searching for pathogens
-can think of the complement proteins as proteases (proteolytic enzymes)
-complement proteins circulate in an inactive state
-more than 30 proteins make up the complement system
proteases
are enzymes that perform proteolysis, that is they break the peptide bond linking amino acids in proteins
(proteins that break other proteins)
zymogen
the inactive form of a complement protein
what is the most important protein in the complement system
complement component 3 (C3)
What happens when the complement is activated by infection?
cleavage of C3 occurs
- C3–> C3a + C3b
- a subunit is always the smallest and flushes off and does something else
- b subunit always the largest and bind to other things and lyse/cleave something
-just the presence of C3b alone can clear bacteria
complement fixation
covalent binding of the C3b subunit to the pathogen
-C3b marks the pathogens to be phagocytized
-C3a acts as the chemoattractant (chemokine) recruiting white cells to the site
alternate pathway
predominately at the start of the infection, and occurs the most often
- in the plasma circulating C3 spontaneously hydrolyzes (binds with water) and forms into a complex (convertase C3) where it can cleave itself and deposit onto the membrane at low frequency to microbial surfaces (thioester bond of C3)
-this binding initiates a cascade of effects resulting in the enhanced deposition of C3b on pathogen surfaces and release of C3a as a chemoattractant
-the complex formed is C3bBb
lectin pathway
-requires time to gain full strength
-needs mannose-binding lectin (produced by the liver)
-2nd pathway activated
classical pathway
-is part of both the innate and adaptive immunity
-requires binding of antibody (Ab) or C-reactive protein (CRP) to an antigen on the pathogen surface
-happens the least of the three pathways and the last one to occur
What occurs after C3b binds to the pathogen surface?
- recruitment of inflammatory cells
- optimization of pathogens, facilitating uptake and killing by phagocytes
- perforation of pathogen cell membranes
c3bBb (alternative C3 convertase)
is a highly active protease that results in the rapid and explosive deposition of C3b
-this forms the alternative C5 convertase (C3b2Bb) which will initiate the formation of the membrane attack complex (MAC)
complement control proteins
-two broad categories of proteins that have evolved to control this reaction
1. plasma proteins
2. membrane proteins
properdin (factor P)
increases the speed and power of complement activation
-increase C3b
-example of plasma protein
Factor H + Factor I
work together to bind and cleave C3b to iC3b (an inactive form) and lessen deposition of C3b on bacterial surfaces
-decreases C3b
-example of plasma protein
Decay Accelerating factor (DAF)
binds the C3b portion of C3bBb causing it to dissociate and become inactive
-decreases C3b
-example of membrane proteins
Membrane co-factor protein (MCP)
similar function to DAF but also makes C3b susceptible to cleavage and inactivation by factor I
-decreases C3b
-example of membrane proteins
mannose-binding lectin (MBL)
-is an acute-phase protein (producing these proteins after a signal has come to the liver takes time) complex that binds mannose-containing carbohydrates on pathogen surfaces and initiates the lectin pathway
-associated with two accessory proteins, MASP 1 and 2, which have an enzymatic activity that produce a potent C3 convertase
-can function as an opsonin that facilitates the uptake by monocytes
C4a
potent anaphylatoxin that can recruit leukocytes
- (weaker than C3a and C5a)
Lectin pathway IL-6
- bacteria induced macrophage to produce IL-6, which acts on hepatocytes to induce synthesis of acute phase proteins
- C-reactive protein binds to phosphocholine on bacterial surfaces, acting as an opsonin and a complement activator
- Mannose-binding lectin binds to carbohydrates on bacterial surfaces, acting as a opsonin and as a complement activator
Lectin pathway: mannose binding protein (MASP-1 and MASP-2)
- activated MASP-2 cleaves C4 to C4a and C4b. Some C4b binds covalently to the microbial surface
- activated MASP-2 cleaves C2 to C2a (bigger subunit) and C2b (smaller subunit)
- C2a binds to surface C4b forming the classical C3 convertase, C4b2a
- C4b2a binds C3 and cleaves it into C3a and C3b. C3b covalently binds to microbial surface
C-reactive protein (CRP)
an acute phase protein that binds to the phosphocholine component of lipopolysaccharides in bacteria and fungal cell walls
-when bound to a pathogen surface bind C1, the first component of the classical pathway
-this binding leads to a cascade which results in the formation of classical C3 convertase
- can also act as a opsonin
C1
is similar MBL in structure and function
-this binding leads to a cascade which results in the formation of classical C3 convertase
- can also act as a opsonin
macrophages
-in the immune response the first effector cells of the immune system to act
-are the mature form of circulating monocytes that take up residence in tissue
-will phagocytose pathogens in a non-specific fashion but this process is made efficient through specific binding of ligands on pathogens to receptors on macrophages
-one example is the complement receptor 1 (CR1) recognizing its ligand C3b
Kupffer cells
macrophages of the lungs and liver
opsonization
the coating of a pathogen with proteins that facilitate phagocytosis
complement and phage process
- complement activation leads to deposition of C3b on the bacterial cell surface
- CR1 on macrophages bind to C3b on bacterium
- endocytosis of the bacterium by the macrophage
- macrophage membrane fuses creating a membrane bounded vesicle, the phagosome
- lysosomes fuse with the phagosomes forming phagolysosomes
Terminal complement proteins
-the cascade of complement reactions produces these that lead to the formation of a membrane pore
1. C5
2. C6
3. C7
4. C8
5. C9
What does protein C5 do?
on activation the soluble C4b fragment initiates assembly of the membrane attack complex in solution
What does protein C6 do?
binds to and stabilizes C5b, forms a binding site for c7
What does protein C7 do?
binds to C5b,C6 and exposes a hydrophobic region that permits attachment to the cell membrane
What does protein C8 do?
binds to C5b,C6,C7 and exposes a hydrophobic region that inserts into the cell membrane
What does protein C9 do?
polymerization on the C5b, C6, C7, C8 complex to form a membrane spanning channel that disrupts the cell’s integrity and result in death
What is the classic C5 convertase
C4bC2aC3b
Membrane attack complex (MAC)
-will punch holes (form pores) in the cell membrane of pathogens and perhaps host cell
-on the cells of pathogen complement components C5-9 assemble a complex that perforates the cell membrane
What prevents the formation of pores by the MAC complex on human cells
CD59 prevents pore formation by binding to complex C5b, C6, C7 ,C8 and preventing polymerization of C9
-CD (cluster designation)
anaphylatoxins
-small active protein fragments formed during complement activation (C3a, C5a, C4a)
-called this because in some circumstances these normal byproducts of complement activation cause anaphylactic shock
Examples of anaphylatoxins and what they can cause
- contraction of smooth muscle
- degranulation of mast cells and basophils
- increase blood flow
- increase vascular permeability
- Alters adhesion of monocytes and neutrophils
- acts as chemoattractant
complement factor I
- C3b/C4b
- is a complex of C1r, C1q, and C1s
- looks like mannose-binding lectin (finger structure)
-the fingers bind to C-reactive protein and form a complex with C1 a cleavage subunit opens up (C1s)
