Transcript Innate Immunity

Innate Immunity
Innate Immunity

Mechanisms that do not depend on prior
exposure to the pathogen

Have evolved over time to protect against
groups of organisms that have distinctive
molecular features

Some elements have also been co-opted for
use in the specific acquired immune response
Elements of Innate Immunity





External Barriers
Phagocytic cells
Complement
Humoral mechanisms
Extracellular Killing
External Barriers

Skin



Very effective barrier to infection – cuts, burns etc,
infection is major complication
Mucus and mucosal surfaces

Mucus can trap and move foreign things along

Some secretions have bacteriocidal components
Normal bacterial flora can play a protective fole

Environment (e.g: vaginal pH)

Colicins
Phagocytic Cells

Polymorphonuclear
Leukocytes (a.k.a PMNs
or “Polys”

Macrophages
(lit: “big eater” Gr.)
Phagocytic Cells

Polymorphonuclear neutrophils: PMNs




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



Mononuclear cells
Long lived, significant RER
Do not circulate, but hang out in lymph nodes and
other interesting places
Recognition by Phagocytic cells

Phagocytes have evolved a system of receptors that can
recognize molecular patterns on the surface of pathogen that
are

Conserved

Shared by many infections agents

Different from “self”-patterns

Examples:

The lipopolysaccharide of certain bactreia

Yeast cell wall mannans

Mycobacterial glycolipids

But not glactose and sialic acid group that are typical the ends of
mammalian surface polysaccharides
Phagocytosis

Engagement of receptors generates internal
signal to start phagocytosis

An actin—myosin contractile sytsem for putting
pseudopods around the particle

Lysosomes discharge their contents into the
phagosome

Several biochemical pathways ensue to degrade
content
Complement

A system of 20 or so different proteins that are “set
off” in a cascade of events.

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.

Complement proteins modify each other, and the
fragments may have other effects as well
Complement has 2 pathways:
the classical and the “alternative”

The classical pathway was figured out first, but
may be more recent in evolution, because it
depends acquired immune response (antibodies)


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

C3 is routinely cleaved at slow rates to C3b

Factor B is cleaved by a plasma enzyme, Factor D to Bb

C3b and Bb bind together to form an enzyme, C3bBb, or C3
convertase.

This convertase very actively cleaves C3 to C3a and C3b

C3b is the central molecule – sets off complement-mediated killing …..
so how is this prevented from running amok in the uninfected state?

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.

Some mico-organisms can stabilize the convertase
C3bBb, so that it does not bind Factor H

If the convertase does not bind H, it also does not bind I,
so it is not inhibited, so….

The reaction does get amplified, and much more

C3b is made
Complement: Act II

The C3b can for a short time, react covalently with
local hydroxyl or amino groups at the microbial cell
surface

C3b bound to the surface makes the cell “tasty to
macrophages” – the surface is “opsonized”

In the presence of extra C3b, the C3bBb changes its
enzymatic specificity such that it now cleave C5 into
C5a and C5b

C5b stays bound to C3b at the surface of the invading
cell.

Seeing C5b bound, C6, C7, C8 and C9 bind, and form
a membrane pore (called the Membrane Attack
Complex)

The cell lyses
Complement: Act III

The smaller fragments C3a and C5a stimulate

Phagocytosis

Mast cell degranulation




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

The term “humoral” means soluble in serum of other fluids;
non involving cells

Antibodies are humoral defenses (but specific acquired
immunity, so discussed later)

Among the innate humoral immune defenses:

Complement

Clotting Factors (cascade, fibrin and fibinogen)

Lysozyme (in many secretions, attacks bacterial cell wall)

Acute phase proteins

Intereferons
Complement
Clotting Cascade
Acute Phase Proteins

Concentration increases in response to alarm
proteins, such as IL-1


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).

These bind to bacteria, and activate the classical pathway
of complement (take the place of the C1 proteins that are
normally activated by Ab)

C3b opsonizes the foreign cells
Extracellular Killing


NK (Natural Killer) cells kill virallyinfected cells using perforin
Induce apoptosis

Apoptosis = Programmed cell death

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