Transcript Document

Dr. Geahlen
HANS 431A
Email: [email protected]
Peter Parham
The Immune System
Second Edition
Chapter 8
The Body’s Defenses
Against Infection
Copyright © 2005 by Garland Science Publishing
The body’s defenses against infection-Chpt. 8
To combat infections, the body uses both the innate and adaptive immune
systems.
•
the innate immune system contains the initial infection while the adaptive
immune system clears the infection.
•
It is probable that the
innate immune system
eliminates the vast majority of
infections before any symptoms
begin.
Figure 8.1
The type of immune response required to combat the infection depends on where
the pathogens live and replicate in the host.
1. Extracellular
pathogens - accessible to
antibodies and complement,
phagocytosis
2. Intracellular replicate in cytosol - killed by
CD8 and NK cells
3. Intracellular replicate in macrophage
vesicles - killed by TH1 and
NK cell-mediated macrophage
activation.
Figure 8.4
Innate immunity
•
Surface epithelia (e.g., skin and mucosal epithelial linings) forms a barrier to
keep pathogens out.
•
Also contain a variety of chemical agents to fight infections
•
lysozyme in tears and saliva
•
acid and hydrolytic enzymes in stomach
•
epithelial cells and neutrophils secrete defensins –
antimicrobial peptides (a- and b-defensins).
•
nonpathogenic commensal microorganisms compete with pathogenic
microorganisms. e.g., antibiotic-associated diarrhea and C. difficile.
Defensins function by disrupting the
membranes of bacteria, fungi and enveloped
viruses by forming ion channels.
Ganz, T. (2002) Science, 298, 977-979.
Figure 8-7
•The first cells to respond to extracellular pathogens are
macrophages already resident within the infected tissue.
•Macrophages have two major roles in the innate immune response:
•phagocytosis of invading pathogens
•release of cytokines.
•Macrophages recognize infectious organisms by a couple of
important mechanisms:
•complement receptors - recognize C3B or iC3B bound
to infectious organism
•pattern recognition receptors - recognize common
components of infectious organisms (e.g., polysaccharides,
etc.)
•Complement system - complement activation occurs mainly via the
alternative pathway. This is the non-antibody mediated pathway.
•initial recognition of the pathogen involves component C3b binding
covalently to any one of several polysaccharides on the surfaces of
pathogens.
•The deposition of C3b on the pathogen cell surface serves three major
functions:
C3b
Phagocytosis by complement receptors CR1,
CR3, CR4
Lysis by membrane-attack complex
Recruitment of phagocytes (e.g., neutrophils)
and activation of mast cells by anaphylatoxins C5a, C4a,
C3a.
Figure 8-8
C3 contains a thioester bond
Figure 8-10
•Complement system - complement activation occurs mainly via the
alternative pathway. This is the non-antibody mediated pathway.
•initial recognition of the pathogen involves component C3b binding
covalently to any one of several polysaccharides on the surfaces of
pathogens.
•The deposition of C3b on the pathogen cell surface serves three major
functions:
C3b
Phagocytosis by complement receptors CR1,
CR3, CR4
Lysis by membrane-attack complex
Recruitment of phagocytes (e.g., neutrophils)
and activation of mast cells by anaphylatoxins C5a, C4a,
C3a.
Figure 7-44 part 2 of 2
Pattern recognition receptors - receptors for common components of multiple
different types of pathogens.
Pattern recognition receptors recognize common features of several different
ligands. These common features are referred to as pathogen-associated molecular
patterns (PAMPs).
PAMP
Pattern recognition
receptor
PAMP’s include things like LPS, peptidoglycans from bacterial cell walls,
mannose, flagellin, pillin, glycolipids and zymosan from fungi, bacterial DNA
(nonmethylated CpG), double-stranded RNA (from viruses), etc.
There are two functional classes of patternrecognition receptors:
1. endocytic pattern-recognition
receptors – promotes phagocytosis.
Includes:
•mannose receptor (a sugar common
on the end of bacterial polysaccharides,
but not human ones)
•scavenger receptor (binds sialic acidrich molecules)
•CD14 – receptor of LPS and LPSbinding protein complexes
2. Signaling pattern recognition receptors – binding of ligand
promotes production of cytokines. Includes a family of receptors referred to as
Toll-like receptors.
Humans have 10 different toll-like receptors. Each binds a
different class of PAMP.
Different TLRs directly or indirectly bind different
microbial molecules.
TLR-2 recognizes peptidoglycan and lipoproteins
TLR-3 recognizes double-stranded RNA
TLR-4 recognizes lipopolysaccharide
TLR-5 recognizes bacterial flagellin
TLR-9 recognizes bacterial DNA.
All toll like receptors signal through common pathways to
regulate the expression of cytokine genes
Figure 8-14
E. The activated macrophages secrete a battery of
cytokines and chemokines that function to initiate the
inflammatory response and to recruit other effector cells to the
site of infection.
cytokines (IL-1, IL-6, IL-8 (CXCL8), IL12, TNF-a)
bacteria
lipid mediators (prostaglandins, leukotrienes, etc.)
TLR
tissue macrophage
complement C3a, C4a, C5a
mast cells
chemokines (e.g., CXCL8 (IL-8))
recruit neutrophils
histamine, lipids, TNF-a
Due to the release of these various inflammatory mediators, blood
vessels near site of infection increase in diameter (vasodilation)
and exhibit enhanced permeability (capillary endothelial cells
contract and fluid enters site of inflammation) causing swelling
and redness (inflammation). They trigger platelet activation and
clotting to restrict the infection to a limited area. They also attract
other effector cells (more monocytes and neutrophils) to the site
of infection.
TNF-a acts on vascular endothelial cells to increase vascular permeability.
TNF-a induces vascular endothelial cells to make platelet-activating factor,
which promotes blood clotting to block local blood vessels to restrict pathogen from
entering blood.
The excessive release of TNF-a by macrophages into the blood stream, as can
occur in response to blood-borne pathogens (e.g., a bacterial infection that enters the
wider circulation), can produce a dangerous condition known as sepsis.
Instead of local blood vessel dilation, systemic vasodilation can occur with
massive leakage of fluid into tissues and widespread blood clotting. Causes septic shock
and can lead to organ failure and death.
CXCL8 is an example of a chemoattractant or chemokine.
Small, 90-130 residue polypeptides. Some are produced all the time and
some are produced selectively during an infection to help determine where a cell
will go in the body. Over 50 chemokines and 15 chemokine receptors.
Classified based on the sequence around cysteines as the CC group
(Cys’s are adjacent) or the CXC group (one amino acid separates the two Cys)
(there are also minor groups of C and CXXXC chemokines). Receptors for the CC
group are termed CCR’s (e.g., CCR1, CCR2, etc.) and for the CXC group are
termed CXCR’s (e.g., CXCR1, CXCR2, etc.). Chemokine receptors are G-protein
coupled receptors.
IL-8 is a CXC chemokine that binds CXCR1 and CXCR2 to recruit
neutrophils.
C
C
CC
CXC
C
C
E. The activated macrophages secrete a battery of
cytokines and chemokines that function to initiate the
inflammatory response and to recruit other effector cells to the
site of infection.
cytokines (IL-1, IL-6, IL-8 (CXCL8), IL12, TNF-a)
bacteria
lipid mediators (prostaglandins, leukotrienes, etc.)
TLR
tissue macrophage
chemokines (e.g., CXCL8 (IL-8))
complement C3a, C4a, C5a
recruit neutrophils
mast cells
histamine, lipids
Neutrophils are the most abundant of the cells recruited from the blood stream
to the site of an infection.
neutrophils – most abundant of the white blood cells – also known as
polymorphonuclear leukocytes (odd shaped nuclei). Found in blood and not
in normal tissue, are recruited into infected tissues by cytokines released by
activated macrophages.
neutrophils are short-lived cells that die within hours causing the
formation of pus at sites of infection. Bacteria that efficiently recruit
neutrophils are pyogenic or pus-forming.
The recruited neutrophil must move from the blood stream, through the wall of
the blood vessel, into the tissue. This process is known as extravasation –
Two features are important for the cell to move from the blood stream
into a particular organ or tissue:
1) The cell must recognize where it wants to bind to the wall
of the blood vessel and then bind there and then
2) it must cross through the wall into the tissue.
Extravasation occurs in four steps:
1) rolling
2) arrest and adhesion
3) transendothelial migration and
4) movement to central region of infection
Figure 8-19 part 2 of 2
Figure 8-19 part 1 of 2
Cell adhesion molecules involved in extravasation
1.
Rolling – selectins on neutrophils bind sialyl-Lewisx carbohydrates on
endothelial cells.
2.
Tight binding – integrins (heterodimers of a and b integrin subunits) are
activated by chemoattractants binding to receptors on the cell surface.
Activated integrins like LFA-1 or CR3 on neutrophils (Mac-1 on
monocytes) bind to adhesion molecules like ICAM-1 (intercellular cell
adhesion molecule-1) and VCAM-1 (vascular cell adhesion molecule-1).
ICAM-1 and VCAM-1 expression are induced by TNF-a and IL-1.
Figure 8-19 part 3 of 3
Neutrophils can phagocytose
and kill bacteria, fungi and
even some enveloped viruses
using Fc receptors (once Ab’s
are made) or complement
receptors. Contain
phagosomes with lots of
degradative enzymes and
other toxic substances like
NO, oxygen radicals, etc.
They cannot replenish these
and they die by undergoing
apoptosis.
Systemic effects of IL-1, IL-6 and TNF-a.
Known as endogenous pyrogens, they act on the hypothalamus to increase body
temperature (stimulate production of the prostaglandin PGE2 in the brain).
Stimulate the acute-phase response.
Act on hepatocytes (liver cells) to produce acute-phase proteins like Creactive protein and mannose-binding lectin.
C-reactive protein and mannose-binding protein bind to a wide variety
of microorganisms. C-reactive protein recognizes phosphorylcholine groups on multiple
bacterial capsular polysaccharides. Mannose-binding protein recognizes mannose residues.
Can opsinize a bacterium to stimulate phagocytosis via Fc receptors and activate
complement for lysis or uptake by phagocytic cells.
Hypothalamus
Local inflammatory
Response
PGE2
IL-1, IL-6, TNF-a
Liver
CRP, MBL
fever
CRP can bind C1q to initiate the classical pathway of complement
activation in the absence of antibody. MBL activates MBL-associated
protease (MASP) to cleave C4 and C2 to initiate complement activation.
Known as the lectin pathway of complement activation.
Innate immune responses to viral infections
The initial defense against viral infections also includes innate immune
responses, which mostly involve interferons and NK cells.
Many cells, when infected by a virus, produce IFN-a and IFN-b in
response to a double-stranded RNA binding to TLR3.
IFN-a/b binds to the IFN receptors on neighboring cells and induces a
state of viral resistance by inhibiting specific protein synthesis.
Figure 8-25
Oligoadenylate synthetase dsRNA-dependent protein kinase (PKR)
dsRNA
ATP
2’-5’A(n)
eIF-2 (active)
eIF-2-P (inactive)
ATP ADP
RNaseLi
RNaseLa
mRNA
Protein Synthesis
Figure 8-26
NK or natural killer cells are large lymphocytes distinct from T or B cells important for
fighting viral infections. Function both by killing virally infected cells and by
producing cytokines. Killing function enhanced by IFN-a/b. Cytokine production
(IFN-g) is enhanced by macrophage-derived IL-12. IFN-g activates macrophages. NK
cells turned off by IL-10 from cytotoxic T cells
Virally infected cell
NK cell
IL-12
macrophage
IFNa/b
IFN-g
IL-10
Cytotoxic activity
Cytotoxic T cell
Figure 8-28
NK cell mediated killing is a function of inhibitory and activating
signals received by NK cell receptors from ligands on the target cell.
Two main classes:
1). Killer cell immunoglobulin-like receptors (KIRs). Those
that activate cell killing are referred to as natural cytotoxicity receptors
(NCRs),
2). NK-cell lectin-like receptors – NKG receptors.
Activating and inhibitory receptors are present in both structural
classes.
NK cell activating receptors trigger cell killing.
NK inhibitory receptors prevent cell killing.
Usually engagement of an inhibitory receptor will prevent killing by an
engaged activating receptor.
Figure 8-29
Both KIRs and NKGs are
polymorphic, especially the KIRs. NKGs
are encoded by genes in the natural killer
complex (NKC) while KIR genes are
encoded by genes in the leukocyte receptor
complex (LRC).
Figure 8-31
Different receptors are expressed
nearly randomly on surfaces of NK cells
from same individual leading to multiple
subpopulations. Must have at least one
inhibitory receptor that can prevent killing
of autologous cells.
Ligands for activating receptors
1) NKG2D binds MICA and MICB – class 1-like heavy chains
encoded by genes in the HLA region. Not expressed on normal cells, but are
expressed in response to stress. Often a marker of infected, damaged or
cancerous cells. (This is a rare exception in that NKG2D is actually dominant
over inhibitory receptors.)
2) KIR2DS –binds HLA-C molecules with specific amino acid
substitutions. May enhance killing of cells with a certain HLA-C allotype
3) NKp30, 44, 46 – main activating NCRs. Normal ligands (e.g., for
killing cancer cells) are unknown. NKp44 and NKp46 can bind viral
hemagglutinins
Ligands for inhibitory receptors
1). Recognize MHC class I ligands. Both KIRs and NKGs
recognize MHC I-peptide complexes; but usually the peptide itself is
irrelevant since most of it doesn’t contact the receptor.
2) KIR2DL binds HLA-C molecules of a certain allotype.
3) NKG2A functions as a heterodimer with CD94 and binds HL-E
that has bound a peptide derived from the leader sequence of HLA-A, B
Figure 8-32
Figure 8-33
Specialized T and B cells with a limited antigen receptor repertoire are
poised at major sites of possible infection to ward off pathogens.
1. gd T cells have TCR’s composed of g and d chains of very
limited diversity. They are found in highest abundance in epithelial tissues (in
any given tissue, these cells have pretty much the same TCR’s). Recognize
nonpeptide microbial antigens like prenylpyrophosphates and alkylamines and
MICA and MICB, autologous proteins upregulated by transformed, infected or
stressed epithelial cells.
2. NK T cells – subpopulation of T cells bearing both T cell
and NK cell markers. Have a very limited TCR (a:b) repertoire that recognizes
lipid antigens presented by CD1D, a class I-type molecule. NK T cells are
known for their ability to secrete lots of IL-4 (stimulates TH2 responses) and
IFN-g (TH1 responses). Recent evidence suggests that they are present normally
in an “activated” state due to presentation of endogenous ligands and then
respond quickly to IL-12 production from macrophages or dendritic cells
encountering foreign PAMPs through toll-like receptors. They likely provide a
crucial link between the innate and adaptive immune systems.
B-1 lineage B cells have a limited set
of variable regions and recognize
general polysaccharide antigens in a
T cell-independent fashion. Often
found in body cavities rather than
lymph nodes – generate rapid IgM
responses.