immuno3 &4 q innate immunity & complement
TRANSCRIPT
8/7/2019 Immuno3 &4 Q Innate Immunity & Complement
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LECOM-Pharmacy School
Immunology 3 & 4
Dr. Saber Hussein
Innate Immunity & Complement
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O bjectives
1. The early defense against infections and cancer 2. Recognition of microbes by the innate immune system
3. Components of innate immunity
± Physical and chemical barriers (e.g. epithelial barrier, stomach
acidity) ± Phagocytes: neutrophils and monocytes/macrophages
± Natural killer cells
± The complement system
± Cytokines of innate immunity
± Other plasma proteins of innate immunity
4. Microbes evasion of the innate immunity
5. How does innate immunity stimulate the acquired
immunity?
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Innate Immunity
Natural, none-adaptive
Nonspecific to an antigen but recognize and fight
microbes
Phagocytes: Monocytes, macrophages, PMNneutrophils
Natural killer (NK) cells
Complement system
Exterior defenses: Skin, Stomach acidity, Mucus,
Cilia, Microflora, Lysozyme in tears, Flushing of
urinary tract
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Cytokines of Innate Immunity
Cytokines are small soluble proteins produced by many cells such as
macrophages
They mediate immune and inflammatoryreactions
They are the tool of communication among
leukocytes and between those and other cells
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Cytokines produced by macrophages
Tumor necrosis factor (TNF)
Interleukins (IL):
± IL-1
± IL12 ± IL-10
± IL-6
± IL-15
± IL-18
Type I interferons:
± IFN-E
± IFN- F
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Cytokines of Innate ImmunityCytoki e ri cipal cell
so rce
ri cipal cell lar targets
iologic effect
T acrophage, T cell ndothelial cell: activation
eutrophil: activation
ypothalamus: fever
any cell types: apoptosis
I -1 acrophage,endothelial cell,
epithelial cell
ndothelial cells: activation
I -12 acrophages
endritic cellscells T cells: I -K
synthesis, increased cytolytic
activityI -K cells, T cells Activation o macrophages
Type I
I sI -E acrophages
I - F ibroblasts
All cells: antiviral activity,
increased I expression
cells: activation
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Innate Immunity
Natural, none-adaptive, Nonspecific
Phagocytes: Monocytes,macrophages, PMNneutrophils
Natural killer (NK) cells
Complement system
Exterior defenses: Skin,
Stomach acidity, Mucus,Cilia, Microflora,Lysozyme in tears,Flushing of urinary tract
Physical Barriers
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Functions of activated macrophages Macrophages may be
activated by signals from
many surface receptors.
± Receptor for bacterial
endotoxin (LPS), which
transduces signals via an
attached Toll-likereceptor
± Receptor for the most
important macrophage-
activating cytokine, IFNK
Signals from activating receptors stimulate the production of several proteins, which
mediate the important functions of macrophages.
Different M* surface receptors may stimulate distinct or overlapping responses
Common feature is that they stimulate the production of transcription factors, which
result in the production of various proteins
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Functions of Natural killer (NK) cells
NK cells kill host cellsinfected by intracellular
microbes
± eliminating reservoirs of
infection. NK cells secrete IFNK in
response to IL-12
produced by macrophages
IFNK activates the
macrophages to kill
phagocytosed microbes
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Reticuloendothelial system & Normal flora
Reticuloendothelial system & Competition by Normal flora
Normal flora on
Oral cavitySkin
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Soluble Factors &
Physiological responses Soluble Factors:
1. Lysozyme
2. Complement
3. ntiproteinases
4. C-reactive protein
5. DN se6. RNases
Physiological responses:
± Chemotactic factors from
infecting agents
Bacteria F-Met
peptides
Injured tissue
± Mast cells & PMN
± Leukotrienes &
± Histamines
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Mechanisms of
killing
Toxic oxygen
± Oxygen radicals
± Hydrogen peroxide
± Hypochlorous acid(HOCl)
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Innate & adaptive immunityInnate Immunity
Pathogen recognized by receptors
encoded in the germline Receptors have broad specificity,
i.e., recognize many relatedmolecular structures called P MPs(pathogen-associated molecular
patterns) P MPs are essentialpolysaccharides &polynucleotides that differ littlefrom one pathogen to another butare not found in the host (mannose)
Receptors are PRRs (patternrecognition receptors)
Immediate response
No memory of prior exposure
Occurs in all metazoans?
Adaptive Immunity
Pathogen recognized byreceptors generated randomly
Receptors have very narrowspecificity; i.e., recognize a
particular epitope
Most epitopes are derived from
polypeptides (proteins) andreflect the individuality of the
pathogen
Receptors are B-cell (BCR ) andT-cell (TCR ) receptors for
antigen Slow (3 -5 days) response(because of the need for clonesof responding cells to develop)
Memory of prior exposure
O
ccurs in vertebrates only
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Innate
&daptive
Immunity
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C-Reactive
Protein
CRP belongs to the pentaraxin
family of proteins
± so-called because it has five identical
subunits, encoded by a single gene on
chromosome 1, which associate to form a
stable disc-like pentameric structure
It reacts with the somatic Cpolysaccharide of St rept ococcus
pneumoniae
In the presence of calcium, CRP
specifically binds to phosphocholine
moieties
± phosphocholine is found in phospholipid
membranes of many organisms
Pentameric structure
of CRP
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CRP role in innate immunity
Binding phosphocholine gives CRP a host-defensive
role because:
± Phosphocholine is found in microbial polysaccharides
CRP-binding activates the classicalcomplement pathway
Opsonizes ligands for phagocytosis
± It neutralizes the pro-inflammatory platelet-activating
factor (PAF)
± It down-regulates polymorphs (neutrophil, eosinophil,
basophil)
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CRP made in the liver CRP is exclusively made in the liver
Secreted in increased amounts within 6 hours of an
acute inflammatory stimulus (e.g. infection)
The plasma level can double at least every 8 hours,
reaching a peak after about 50 hours fter effective treatment or removal of the inflammatory
stimulus, levels can fall almost as rapidly as the 5-7-
hour plasma half-life of labeled exogenous CRP
The only condition that interferes with the "normal"CRP response is severe hepatocellular impairment
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Defensins
Definition: ± family of abundant, modestly potent
cationic proteins that is found
in the primary granules of neutrophils and
in the lysosomes of some mononuclear phagocytes
Bactericidal
± can kill fungi and viruses too
One defensin is chemotactic for monocytes
± Neutrophils help to attract the "second wave" of leukocytes-
Mononuclear phagocytes
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Defensins
ll of the following are protected by defensins
1. our epithelial surfaces
2. skin
3. lining of the GI tract
4. lining of the genitourinary tracts
5. lining of the nasal passages and lungs
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Leukocytes extravasation
Blood vessel
Infected tissue
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Complement
Alternative Pathway
Classic Pathway
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O bjectives
1. Define complement
2. ctivation of the classical pathway
3. ctivation of the lectin pathway
4. ctivation of the alternative pathway
5. Describe the three functions of complement in
body defense
6. Complement deficiencies and disease
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The complement system: (Chapter 2)
The enzymatic cascade ctivation of the complement cascade
1. The alternative pathway
2. The classical pathway
3. The lectin pathway
naphylactic and chemotactic products of thecomplement system
Membrane attack complex
Evasion of innate immunity by microbes
Role of innate immunity in stimulating adaptiveimmune responses
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What is Complement?
Non-immunoglobulin serum proteins
Involved in:
i. Control of inflammation
ii. Stimulation of phagocytosis
iii. ctivation of cell lysis
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O psonization (³Eat Me´ tag) & phagocytosis Preparation for eating
Phagocytosis facilitating process
O psonins are deposited on the g (bacteria or virus infected cell)
Important opsonins can label bacteria:
IgG
Complement fragments (e.g. C3b)
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Sites of synthesis Hepatocytes
Macrophages, various tissues
Epithelial cells, GI tract
Monocytes, in blood
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Functions of complement Direct killing of bacteria & virus-infected
cells by lysis mediated by MAC
I ndirect killing by opsonization followed
by phagocytosis & intracellular killing
Immunization does NOT increase
complement concentration in the serum
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Role of C3 in bacterial
clearance and killing
1. C3 bound to bacteria as C3b or iC3b binds to CR1 onerythrocytes, which transport
bacteria through circulation
2. C3 acts as focus for the
deposition of lytic M C on bacterial cell membrane
3. It ligates complement receptor on phagocytes
4. Complement, in turn, activates
the phagocyte leading to Bacterial phagocytosis,
Respiratory burstgeneration and
Bacterial killing
intermediate
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Activators of the alternative
pathway (AP) Lipopolysaccharides (LPS)
Bacterial cell walls
Cell walls of yeasts
Aggregated IgA
Cobra venom NO need for A b-Ag complex or IgM for
activation
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Activation cascade
of the
Alternative
Pathway
C3b binds foreign substance
C3b + Serum¶s Factor B C3bB
Factor D cleaves Factor B C3bBb C3bBb acts as C3 convertase:
C3 C3a + C3b
± Properdin regulates the process; stabilizes C3bBb.
± Factor I & H inactivate free C3b
AlternativePathway
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Activation of Classical Pathway (CP)
CP is activated by: ± Antigen-IgG complex
± Pentameric IgM
Non-activators of CP: ± IgG4
± IgA
± IgE
± They lack C1q
receptors they
cannot bind C1q
Classical pathway
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Steps of CP activation
Step 1:A
ctivation of C1 ± C1q-FcIgG activates C1r &C1s
± C1s activates C4 C4a +C4b
Step 2: Activation of C4
± C4 C4a + C4b Step 3: Activation of C2 by
C4b ± C4b + C2 C4b2a (C3-
convertase) + 2b
Step 4: Activation of C3
Step 5: Activation of C5,C6 & C7
Step 6: Activation of C8 &C9
Classical pathway
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Complement
Classic Pathway
Alternative
Pathway
Common Pathway
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MAC & Cell Lysis
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Split Products and Their Activity
Activities of complement fragments
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The Lectin Pathway (LP)
Activator: Mannose-binding lectin (MBL), a plasma protein that is similar to C1q
MBL binds to terminal mannose (sugar) on the
surface glycoprotein of microbes This lectin activates the classical pathway
proteins
Difference between LP and CP: ± LP activation does not require antibodies
Therefore, LP activation is part of the innate immune
system
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Three functions of complement in host defense
1. Opsonization:
± C3b binds to microbes and so enables the phagocytes to grab the microbe, via their C3breceptor, and phagocytose it
2. Chemotactic activity of C5a:
± This complement fragment attracts neutrophilsand monocytes to the site of infection
± C5a promotes inflammation at the site of complement activation
3. Formation of membrane attack complex(MAC)
± MAC forms a pore (hole)in the membrane of themicrobe leading to the loss of cellular contents, lysis
of the microbe and death of the microbe
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Complement Proteins¶
Deficiencies Alternative pathway defects Susceptibility
to H aemophilus influenzae
Defects of F act or D & P roperdin increase
N eisseria infection
C5 deficiency, less severe consequences,
but increases susceptibility to N eisseria gonorrheae & N. meningitidis
l
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Complement &
disease pathogenesis
Complement may cause disease pathogenesis by:
1. Systemic production of anaphylaxis such as after Gram-negative sepsis
2. Insertion of MAC into hostcell membrane leading tocellular activation andstimulation of membranearachidonic acid metabolism
3. Fixation of C3b to immunecomplexes located in tissuescausing recruitment andactivation of tissue andcirculatingWBCs
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Heritable angioedema (HA
E) C1-inhibitor deficiency
Autosomal dominant trait inheritance
Edema in various organs & tissues
Especially bad:
± Edema of intestine and throat
Treatment
± Epinephrine for emergency treatment
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A
cquired angioedema Caused by an autoantibody to C1 inhibitor,
This leads to inactivation of C1 inhibitor
± A result similar to HAE:
C1 inhibi t or becomes deficient