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Innate Immune Response (Ch14)
Although the complement system
has traditionally been considered
part of the innate immune system,
research in recent decades has
revealed that complement is able
to activate cells involved in both
the adaptive and innate immune
response. Complement triggers
and modulates a variety of
immune activities and acts as a
linker between the two branches
of the immune response. In
addition, the complement system
maintains cell homeostasis by
eliminatiing cellular debris and
immune complexes.
Katie Ris-Vicari
Immune System: Innate and Adaptive Immunity
§  To microbes, human body is nutrient-rich
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But most of our internal systems are sterile (gut doesn’t count)
Innate immunity is routine protection
Skin, mucous membranes prevent entry
Sensor systems detect invaders, general microbe pattern
recognition
•  Adaptive immunity develops throughout life: antigens cause
response, system produces
antibodies to bind
•  Can also destroy host cells
Overview of Innate Defense System
First lines of Defense
•  Physical Barriers
–  Skin
–  Mucous membranes
•  Antimicrobial substances
–  Lysozyme
–  Peroxidase enzyme
–  Lactoferrin
–  Defensins
•  Normal Flora
•  Physical Barriers: body’s
borders
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•  Skin
–  Difficult to penetrate
–  Dermis: tightly woven fibrous
connective tissue
–  Epidermis: many layers of
epithelial cells
•  Outermost are dead, filled
with keratin
– Repels water, Continually
slough off along with
any attached microbes
Nucleus
Basement membrane
Connective
tissue
Stratified epithelium
• Skin (the outer cell layers are embedded with keratin)
• Lining of the mouth, vagina, urethra, and anus
Cilia
Mucus-
producing cell
Columnar cell
Columnar epithelium
• Passages of respiratory system
• Various tubes of the reproductive systems
Skin as the first line of defense
•  Intact skin protects
–  Epidermis
–  Dermis
First-Line Defenses
•  Physical Barriers (continued…)
•  Mucous Membranes line the inside of the body
–  Digestive, respiratory, genitourinary tracts
–  Constantly bathed in secretions (e.g., mucous)
–  Peristalsis of intestines, mucociliary escalator of
respiratory tract remove microbes
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Mouth
Eye
Respiratory tract
Digestive tract
Urogenital tract
Skin
Anus
Mucous
membranes
Skin
Ciliated cells are important…where?
•  Antimicrobial
Substances
–  Protect skin, mucous
membranes
–  Salt on skin
–  Lysozyme degrades
peptidoglycan
–  Peroxidase enzymes break
down hydrogen peroxide
–  Lactoferrin binds iron
–  Defensins form pores in
microbial membranes
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Antimicrobial factors
in saliva (lysozyme,
peroxidase, lactoferrin)
Lysozyme in tears
and other secretions
and in phagocytes
Removal of inhaled
particles
Normal microbiota
Mucus, cilia
Physical barrier
of skin, salty
residue, fatty acids,
normal microbiota
Acid in stomach
(low p H)
Rapid pH change
from stomach to
upper intestine
Normal
microbiota
Flushing of
urinary tract
pH and normal
microbiota of vagina
Microbial Barriers
•  Normal flora (biota) play a role in keeping the
body protected
•  Competitive exclusion—take up spaces, and
nutrients
•  Toxic compounds
•  Propionibacterium degrade lipids, produce fatty acids
•  E. coli may synthesize colicins in intestinal tract
–  Kill Salmonella and Shigella
•  Lactobacillus in vagina produce low pH—prevents
infections
Cells of the Immune System
•  Formation=hematopoiesis
•  Blood cells originate from hematopoietic stem cells
•  In bone marrow
•  Stem cells develop into particular types of cells
because induced by different colony-stimulating
factors (CSFs)
–  Move around body, travel through circulatory systems
–  Some reside in tissues
–  Three general categories
•  Red blood cells (erythrocytes) carry O2
•  Platelets (from megakaryocytes) involved in clotting
•  White blood cells (leukocytes)--defense
Hematopoietic stem cell
(in bone marrow)
Common
myeloid progenitor
Common
lymphoid progenitor
Selfrenewal
Monoblast
Erythroblast Megakaryoblast Putative
mast
cell
precursor
Lymphoblasts
Myeloblast
Megakaryocyte
Red blood cell
Platelets
(erythrocyte) (thrombocytes)
Basophil
Natural
Monocyte
T cell B cell
Eosinophil
Neutrophil
killer (NK) cell
Granulocytes
Lymphocytes
Macrophage
Mast cell
Dendritic cell
White blood cells (leukocytes)
The Cells of the Immune System
•  Four types of leukocytes (white blood cells)
–  Granulocytes contain cytoplasmic granules
•  Neutrophils engulf and destroy bacteria, other
material
•  Basophils involved in allergic reactions,
inflammation
Selfrenewal
–  Mast cells similar;
found in tissues
•  Eosinophils fight
parasitic worms
–  Also involved in
allergic reactions
Common
myeloid progenitor
Erythroblast
Megakaryoblast
Putative mast
cell precursor
Common
lymphoid progenitor
Myeloblast
Monoblast
Lymphoblasts
Megakaryocyte
Eosinophil
Red blood cell
(erythrocyte)
Platelets
(thrombocytes)
Basophil
Neutrophil
Monocyte
Natural
killer (NK) cell
Lymphocytes
Granulocytes
Mast cell
T cell
Macrophage
Dendritic cell
White blood cells (leukocytes)
B cell
The Cells of the Immune System
•  Four types of leukocytes (cont…)
–  Mononuclear Phagocytes
Selfrenewal
•  monocytes (circulate in
Common
blood) and these develop myeloid progenitor
into Macrophages and Dendritic
cells as they leave blood stream
•  Often named after location
where found in body
Monoblast
Monocyte
–  Dendritic Cells
•  Sentinel cells, function as “scouts”
•  Engulf material in tissues, bring it to
cells of adaptive immune system for
“inspection”
Macrophage Dendritic cell
Dendritic cells
•  Branched cells, important in adaptive
immunity
•  Develop from monocytes, engulf material
and bring it to other cells for analysis
Four types of leukocytes (cont…)
Lymphocytes
Responsible for adaptive
immunity
B cells, T cells highly
specific in recognition of
antigen
Generally reside in
lymph nodes,
lymphatic tissues
Natural killer (NK) cells
lack specificity
Common
lymphoid progenitor
Lymphoblasts
Natural
T cell
killer (NK) cell
B cell
Lymphocytes
How do cell coordinate—communicate?
•  Communication allows coordinated response
–  Surface receptors --“eyes” and “ears” of cell
•  Binding to specific ligand induces response
•  Often span the membrane
–  Adhesion molecules allow cells to stick to other cells
•  E.g., endothelial cells can adhere to phagocytic
cells, allow them to exit bloodstream
–  Cytokines—communication between cells
•  Produced by cell, diffuse to others, bind to receptors
--induce changes -- growth, differentiation,
movement, cell death
•  Act at low concentration; effects local, regional,
systemic
Cell Communication
–  Cytokines
•  Chemokines: chemotaxis of immune cells
•  Colony-stimulating factors (CSFs): multiplication and
differentiation of leukocytes
•  Interferons (IFNs): control of viral infections,
regulation of inflammatory response
•  Interleukins (ILs): produced by leukocytes; important
in innate and adaptive immunity
•  Tumor necrosis factor (TNF): inflammation,
apoptosis
Cytokines and their function
Sensor systems in the blood,
tissues and cells
•  Can detect signs of tissue damage or
microbial invasion
•  Respond by
–  Detecting parts of bacteria/viruses using pattern
recognition receptors (PRRs)
–  Directly destroy bacteria using complement
–  Recruit other components of host defense
Pattern Recognition Receptors (PRRs)
•  Pattern recognition receptors (PRRs) detect
pathogen-associated molecular patterns
(PAMPs), “see” signs of microbial invasion
–  Cell wall (lipopolysaccharide, peptidoglycan,
lipoteichoic acid, lipoproteins), flagellin subunits,
viral RNA molecules
–  Also called MAMPs (for microbe-associated)
–  Some are DAMPs (for danger-associated), which
indicate host cell damage
Pattern Recognition Receptors
•  Toll-Like receptors (TLRs)
–  Membrane bound receptors which detect
bacterial parts
•  NOD-like receptors (NLRs)
–  Cytoplasmic proteins detect bacterial parts
•  RIG-like receptors (RLRs)
–  Cytoplasmic proteins detect viral RNA
Pattern Recognition Receptors (PRRs)
Toll-like receptors (TLRs) in membranes of sentinel
cells
Phagosome
or endosome
(e.g., macrophages,
dendritic cells, cells lining
sterile body sites)
Cells “see” PAMPs
in extracellular
environment
--signal transmitted to
nucleus
--Induces gene
expression, e.g.
inflammatory response,
antiviral response
Detects
Detects lipopolysaccharide
(LPS)
peptidoglycan
Detects
flagellin
Outside
of cell
TLRs in cytoplasmic membrane
Cytoplasm
TLRs in phagosomal or endosomal membrane
Lumen of
endosome
Detects
dsRNA
Detects
bacterial DNA
Detects
ssRNA
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Pattern Recognition Receptors (PRRs)
– NOD-like receptors (NLRs found in
cytoplasm
•  Detect bacterial components --cell invasion; some
detect damage
•  Unleash series of events
NLR - Detects flagellin
to protect host
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RLR - Detects dsRNA
–  Some at expense of cell
•  Some NLRs join
cytoplasmic proteins to
form an inflammasome
–  Activates inflammatory
response
RLR - Detects
uncapped ssRNA
NLR - Detects
peptidoglycan
NLR - Detects compounds
that indicate cell damage
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Virus
ssRNA
dsRNA
Fig.14.9
Long dsRNA
activates genes
for IFN synthesis.
IFN
IFN
IFN
Cell 1: Cell is infected by a
virus; viral replication
produces long dsRNA,
which induces the
synthesis and secretion of
interferon (IFN).
IFN diffuses to
neighboring
cells.
Virus infects
Cell 1: Productive
infection; cell is destroyed neighboring
cells.
as a result of infection.
IFN
iAVP
IFN activates
genes for iAVP
synthesis.
iAVP
Cell 2: Interferon induces synthesis of a
group of inactive antiviral proteins (iAVP).
These have no effect on the cell unless they
are activated.
iAVP
AVP
Induction of
programmed
cell death
(apoptosis)
Cell 2: Infection of cell (detected by the
presence of long dsRNA) results in activation
of the antiviral proteins, leading to apoptosis.
Although the cell dies, the virus does not
have the opportunity to replicate, thus
preventing viral spread.
Complement Proteins are part of
the Complement system
•  Consists of a collection of 9 interacting
proteins found in blood and tissues
•  Activation of these proteins promote
–  Opsonization
–  Inflammatory response
–  Lysis of foreign cell
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Alternative pathway
Lectin pathway
Triggered by
Triggered by
Mannose-binding lectin (MBL) binding to
microbial invaders
Antibodies binding to microbial invaders
Triggered by
C3b binding to microbial invaders
Classical pathway
Antibody
C3b
MBL
Formation of C3 convertase
Splits C3
C3
Inflammatory response
C3a and C5a induce changes that
contribute to local vascular permeability
and attract phagocytes.
C3a
Opsonization
C3b binds to microbial cells,
functioning as an opsonin.
C3b
C3b
C5
C5a
Combines with C3
convertase to form an
enzyme that splits C5
C5b
C5b
Lysis of foreign cells
C5b combines with complement
C6
C9
proteins C6, C7, C8, and C9
C7
C9
C9
C9
to form membrane attack
C8
complexes that insert
into cell membranes.
Summary of the
system and roles of
the complement
components C1 – C9
Regulation of the complement system
What have we covered so far?
•  The innate immune system is composed of –  Cells
–  Chemicals released by cells to communicate
with each other
–  Receptors to recognize invaders
–  Responses to kill invaders, and to interact with
the adaptive immune elements.
•  What happens during phagocytosis?
How do phagocytes work?
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1
Chemotaxis
C5a
Microbes
C3b
2
Phagocyte
Lysosomes
Recognition
and attachment
6
Pseudopod
Phagosome
C3b
Phagolysosome
C3b receptors
on phagocyte
Digestive
enzymes
4
3
Engulfment
Phagosome maturation and
phagolysosome formation
(top): © Meckes/Ottawa/SPL/Photo Researchers, Inc.
5
Destruction
and digestion
Exocytosis
Inflammation response
•  Purpose?
–  Contain a site of damage, localize the response,
eliminate the invador and restore tissue
function.
•  What are the key cells involved
–  Macrophages (residents initially detect trouble),
Neutrophils (rapid response team)
•  What activates the inflammation response?
•  What are the symptoms?
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Proinflammatory
chemicals
Bacteria
Blood vessel
Inflammatory
mediators are
released in
Resident
macrophage response to
microbial
components
and tissue
damage.
Phagocytic
cells destroy
and remove
invaders.
Neutrophil
Recruited
macrophage
Neutrophil
Monocyte
Normal blood flow in the tissues
as the injury occurs.
Neutrophils are the first phagocytes
recruited to the site.
As the infection is brought under
control, macrophages ingest dead
cells and debris.
(a)
Tighter
adherence
Diapedesis
Loose adherence;
cells tumble to a halt.
Inflammatory mediators cause small blood vessels to dilate. The phagocytic cells
tumble to a halt and then squeeze between the endothelial cells and enter the tissues.
(b)
Inflammation response steps
1.  Macrophages detect and cause an alarm—produce
cytokines to attract other cells (T-cells, and Neurtophils).
All granulomas
2.  Become activated Macrophages and can interact with
antibodies, and fuse to become GIANT cells—help to wall
off area. 3.  Neutrophils –early recruits to the site—move faster into the
site and are more effective at killing than macrophages. But
live only 1-2 days.
4.  Neutrophils release NET—neutrophil extracellular traps.
DNA and granule content—catches and kills bacteria
outside the cells.
Inflammation steps
•  Macrophages--Involves TLRs (detect PAMPs) and
NLRs(detect DAMPs)—release inflamatory mediators
(cytokines, histamines…)
•  TNF-tumor necrosis factors—help make proteins to increase
phagocytosis and activate the complement system. •  Increase coagulation of blood and blood vessel leakiness,
allows macrophages and neutrophils through
•  In the fluid there is transferrin (binds Fe), complement system
proteins, and antibodies.
•  When things seem under control, neutrophils slow entrance and
macrophage clean up cell debris, etc.
Fever is a nonspecific response
•  Il-1 increases T lymphocytes
•  Decreases available iron
•  Increases cellular reactions
pyroptosis