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Innate Immunity
Innate Immunity
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Mechanisms that do not depend on prior
exposure to the pathogen
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Have evolved over time to protect against
groups of organisms that have distinctive
molecular features
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Some elements have also been co-opted for
use in the specific acquired immune response
Elements of Innate Immunity
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External Barriers
Phagocytic cells
Complement
Humoral mechanisms
Extracellular Killing
External Barriers
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Skin
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Very effective barrier to infection – cuts, burns etc,
infection is major complication
Mucus and mucosal surfaces
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Mucus can trap and move foreign things along
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Some secretions have bacteriocidal components
Normal bacterial flora can play a protective fole
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Environment (e.g: vaginal pH)
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Colicins
Phagocytic Cells
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Polymorphonuclear
Leukocytes (a.k.a PMNs
or “Polys”
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Macrophages
(lit: “big eater” Gr.)
Phagocytic Cells
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Polymorphonuclear neutrophils: PMNs
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White cells (leukocytes), multi-lobed nuclei (look
like many nuclei in section)
Neutrophil: does not take up the major dyes
Short-lived; lots of glycogen (energy from
glycolysis even if O2 is not available)
Macrophages
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Mononuclear cells
Long lived, significant RER
Do not circulate, but hang out in lymph nodes and
other interesting places
Recognition by Phagocytic cells
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Phagocytes have evolved a system of receptors that can
recognize molecular patterns on the surface of pathogen that
are
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Conserved
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Shared by many infections agents
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Different from “self”-patterns
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Examples:
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The lipopolysaccharide of certain bactreia
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Yeast cell wall mannans
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Mycobacterial glycolipids
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But not glactose and sialic acid group that are typical the ends of
mammalian surface polysaccharides
Phagocytosis
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Engagement of receptors generates internal
signal to start phagocytosis
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An actin—myosin contractile sytsem for putting
pseudopods around the particle
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Lysosomes discharge their contents into the
phagosome
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Several biochemical pathways ensue to degrade
content
Complement
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A system of 20 or so different proteins that are “set
off” in a cascade of events.
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Cascade: one molecule, when activated, catalyzes a
change in the next, makes it active, so that it
catalyzes a change in the next etc. Such protein
cascades allow a profound response to a trigger.
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Complement proteins modify each other, and the
fragments may have other effects as well
Complement has 2 pathways:
the classical and the “alternative”
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The classical pathway was figured out first, but
may be more recent in evolution, because it
depends acquired immune response (antibodies)
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So we will talk about that later!
The “alternative” pathway is activated by
microbial polysaccharides, and is part of innate
immunity
Complement: Act I, Scene 1
Complement activation by bacterial cell walls
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C3 is routinely cleaved at slow rates to C3b
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Factor B is cleaved by a plasma enzyme, Factor D to Bb
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C3b and Bb bind together to form an enzyme, C3bBb, or C3
convertase.
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This convertase very actively cleaves C3 to C3a and C3b
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C3b is the central molecule – sets off complement-mediated killing …..
so how is this prevented from running amok in the uninfected state?
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A protein H binds to C3bBb, and then another protein I binds to the
C3bBbH complex, inhibiting it.
However ….
Complement: Act I, Scene 2
If certain bacteria are present, the cascade is not inhibited.
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Some mico-organisms can stabilize the convertase
C3bBb, so that it does not bind Factor H
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If the convertase does not bind H, it also does not bind I,
so it is not inhibited, so….
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The reaction does get amplified, and much more
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C3b is made
Complement: Act II
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The C3b can for a short time, react covalently with
local hydroxyl or amino groups at the microbial cell
surface
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C3b bound to the surface makes the cell “tasty to
macrophages” – the surface is “opsonized”
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In the presence of extra C3b, the C3bBb changes its
enzymatic specificity such that it now cleave C5 into
C5a and C5b
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C5b stays bound to C3b at the surface of the invading
cell.
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Seeing C5b bound, C6, C7, C8 and C9 bind, and form
a membrane pore (called the Membrane Attack
Complex)
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The cell lyses
Complement: Act III
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The smaller fragments C3a and C5a stimulate
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Phagocytosis
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Mast cell degranulation
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Histamine (causes vasodialation, capillary permeability,
bronchioconstriction)
Proteases and other degradative enzymes
Chemotactic factors (recruit phagocytes)
Interleukins further activation of macrophage activity ,
and other things
= basic inflammatory response
Overview --complement
alternative pathway
Humoral Mechanisms provide a second
defensive strategy
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The term “humoral” means soluble in serum of other fluids;
non involving cells
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Antibodies are humoral defenses (but specific acquired
immunity, so discussed later)
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Among the innate humoral immune defenses:
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Complement
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Clotting Factors (cascade, fibrin and fibinogen)
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Lysozyme (in many secretions, attacks bacterial cell wall)
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Acute phase proteins
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Intereferons
Complement
Clotting Cascade
Acute Phase Proteins
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Concentration increases in response to alarm
proteins, such as IL-1
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IL-1 is released by macrophages when they are activated
(by bacterial endotoxins, foreign molecular patterns,
complement etc)
Increase in C-Reactive protein, and mannan binding
proteins (as much as 1000-fold).
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These bind to bacteria, and activate the classical pathway
of complement (take the place of the C1 proteins that are
normally activated by Ab)
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C3b opsonizes the foreign cells
Extracellular Killing
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NK (Natural Killer) cells kill virallyinfected cells using perforin
Induce apoptosis
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Apoptosis = Programmed cell death
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A series of reactions, cascade of proteolytic
enzymes (capases); the end result is rapid
degradation of the nucleus, and cutting DNA in to
nucleosome size pieces