Transcript Chapter 3 Innate Immunity

Chapter 3
Innate Immunity
Macrophage interacting with Bacteria
Oct 3, 5 & 12, 2006
你需要學習的問題:
1. 有哪些分子及細胞參與先天性免疫反應 (innate
immunity)？ 它們的特性是什麼？
2. 什麼叫做「模式辨認受體」 (pattern recognition
receptor，PRR)？
3. 什麼叫做「發炎反應」 (inflammatory response)？
4. 什麼叫做 Toll-like receptors ? 有何功能？
5. 先天性免疫反應在演化上的意義。
- Innate immunity is the most ancient
defense against microbes.
- Some forms of innate immunity has
been found in all multicellular plants
and animals.
- Adaptive immunity evolved in jawed
vertebrates and is a much more recent
evolutionary invention than innate
immunity.
Anatomical Barriers
Skin and
Epithelial
Barriers to
Infection
How does the innate immune
response initiate?
- The host has “sensors” to detect the invader.
- Soluble or membrane-bound molecules of
the host can precisely discriminate between
self (host) and nonself (pathogen).
- These molecular sensors recognize broad
structural motifs (主結構) that are present in
microbes but are absent from the host.
Pattern Recognition Receptors (PRR)
- Because the molecular sensors recognize
particular patterns, such receptors of the host are
called pattern recognition receptors (PRR)
- The patterns found on pathogens are called
pathogen-associated molecular patterns (PAMP)
- PRRs : soluble: e.g., complement system
membrane-bound: Toll-like receptors (TLR)
- PAMPs : combinations of sugars, certain proteins,
particular lipid-bearing molecules, and
some nucleic acid motifs
Inflammation
Localized Inflammatory Response
described by the Romans almost 2000 years ago:
Swelling
Redness
Heat
Pain
Loss of function
(2nd century by a Greek physician,
Galen 蓋倫, 129 -200 A.D.)
Vasodilation
Edema
increase in vascular diameter
rise of blood volume in the area
→ heats the tissue and causes it to redden
increase of vascular permeability
leakage of fluid from the blood vessels
→ accumulation of fluid that swells the tissue
Extravasation
Phagocytosis
adherence of leukocytes to endothelium
→ pass through capillaries and into the tissues
leukocytes phagocytose invading pathogens
release molecular mediators
recruit and activate effector cells
Inflammation
vasoactive
chemotactic
exudate
chemotaxis
extravasation
Soluble mediators released by inflammatory cells:
1. Cytokines : hormone- or growth-factor-like proteins
that communicate via cell receptors to
induce specific cell activities, e.g.,
interleukin-1 (IL-1), IL-6 & tumor
necrosis factor α (TNF-α)
2. Chemokines : a subgroup of cytokines whose activity is
their capacity to act as chemoattractants
(agents that cause cells to move toward
higher concentrations of the agent)
A major role of the cells attracted to the inflamed site
is phagocytosis of invading organisms :
Leukocyte extravasation is essential for inflammation :
rolling → activation → arrest/adhesion → migration
Interaction between Neutrophils and Endothelium
Cellular Adhesion
Molecules (CAMs):
1.
2.
3.
4.
Mucin-like CAMs
Selectins
Integrins
Ig-superfamily CAMs
Soluble Molecules
Antimicrobial peptides are produced at the
site of infection or injury and act locally
*
* Paneth
cells provide host defense
against microbes in the small intestines.
They are functionally similar to
neutrophils (also phagocytic and
containing lysozymes). When exposed
to bacterial antigens, Paneth cells
secrete a number of antimicrobial
molecules into the lumen of the crypt,
thereby contributing to maintenance of
the gastrointestinal barrier.
Crypt 腺窩
Secretion of defensins by paneth cells within intestinal
crypts serves as a primary barrier to bacterial infection
Paneth cells
Soluble Pattern Recognition Receptors
Acute phase response (APR) proteins:
- Complement
- C-reactive protein (CRP)
- Mannose-binding lectin (MBL)
Lipopolysaccharide-binding protein (LBP)
Nucleotide-binding oligomerization domain (NOD)
Acute phase response (APR) proteins:
Complement system (Chapt 7)
C-reactive protein (CRP):
A pentameric protein, which binds phosphorylcholine,
which is present on the surface of many microbes. CRP
bound to a microbe promotes uptake by phagocytes and
activates a complement-mediated attack on the microbe.
Mannose-binding lectin (MBL):
Recognizes mannose-containing molecular patterns found
on microbes but not on vertebrate cells. MBL directs a
complement attack on the microbes to which it binds.
Lipopolysaccharide-binding protein (LBP) recognizes
lipopolysaccharide (LPS), a component of the outer
cell wall of Gram negative (G -) bacteria.
of G (−) bacteria
(LPS)
Nucleotide-binding oligomerization domain (NOD)
proteins are cytosolic proteins which recognize
degraded products of peptidoglycans of Gram
positive (G +) bacteria.
Relative structure of gram negative
(top) and gram positive (bottom)
cell walls.
The major differences lie in the
thickness of the rigid peptidoglycan
layer and in the presence of an outer
membrane. In gram negative cells,
the peptidoglycan layer is very thin,
being only a few molecules thick,
whereas in gram positive cells this
layer is very thick.
outer
membrane
peptidoglycan
gram-positive
anthrax bacilli
Gram’s stain (with crystal violet)
of cerebrospinal fluid
Effectors of Innate Immune Responses to Infection
Membrane-associated
Pattern Recognition
Receptors
Structure of a Toll-like Receptor (TLR)
(XLXXLXLXX)
highly conserved
among all
members of the
TIR family
Toll/IL-1R
(Myeloid differentiation
factor 88)
(IL-1R-associated
kinase)
(TNFR-associated factor)
(TGF-activated
kinase)
Cell Types of Innate Immunity
(ROS)
(RNS)
Interferon 
TNF
Interleukin 1 (IL-1)
Interleukin 6 (IL-6)
Tumor necrosis Factor  (TNF)
(phox)
activated by
phagocytosis
The O2 consumed by phagocytes to support ROS production by
the phox enzyme is provided by a metabolic process known as
the respiratory burst, during which O2 uptake by the cell
increases severalfold.
Generation of Nitric Oxide (NO)
in Phagocytes
L-arginine + O2 + NADPH → NO + L-citrulline + NADP
inducible nitric oxide synthetase (iNOS)
NO : accounts for much of the antimicrobial activity of
macrophages against bacteria, fungi, parasitic worms
and protozoa.
Adaptive Immunity Has to be Initiated
by Innate Immunity
Ubiquity of Innate Immunity
Well-developed system of innate immunity in nonvertebrate phyla
Sea squirt : complement-like lectins
(海鞘)
Toll-like receptors
Fruit fly : NFκB family pathway
antibacterial peptide diptericin
prophenoloxidase cascades
– deposition of melanin around invading organisms
Tomato & other plants :
- generation of oxidative bursts
- raising of internal pH
- localized death of infected regions
- induction of chitinase – digest fungal wall
- induction of α-1,3 glucanase – digest bacterial walls
- antimicrobial peptides
- nonpeptide organic molecules, such as phytoalexins,
that have antibiotic activity
- isolate cells in the infected area by strengthening the
walls of surrounding cells
Questions:
1. What are the differences between innate
immunity and adaptive immunity?
2. Describe an inflammatory response.
3. Examples of pattern recognition and the receptors
for pattern recognition.
4. How does a phagocyte kill pathogens?
5. How does a dendritic cell bridge innate immunity
to adaptive immunity?