Download Lesson 10: Innate Immunity/ Nonspecific Defenses of the Host

Lesson 10: Innate Immunity/
Nonspecific Defenses of the Host
March 24, 2015
Overview
• Our bodies are constantly being attacked by
microbes
– Susceptible—the inability to ward off disease
– Immunity—ability to fight off a disease
• Immune system—is a set of biological structures
and systems that protect an organisms from
invading pathogens
– Innate Immunity
– Adaptive Immunity
• Innate Immunity—refers to defenses that are
present at birth
– The body’s first line of defense against invading
microorganisms
– Always present to provide a rapid response to
protect against disease
– No memory response present
• Multiple infections with same organism would produce
similar response
• Components of Innate Immunity
– First line of defense
• Skin and mucous membranes
– Lacrimal glands (eye), saliva, urine, vaginal secretions
– Mucous is secreted by goblet cells in epithelial lining
– Second line of defense
•
•
•
•
•
Natural killer cells
Phagocytes
Inflammation
Fever
Antimicrobial substances
• Serves as the body’s early-warning system
– Designed to prevent microbes from gaining access
into the body
– The microbes that slip past the skin and mucous
membranes usually are eliminated by the innate
immune system
• Also referred to as “non-specific immunity”
• Responses of the innate system are activated by
protein receptors (Toll-like receptors) on the
plasma membrane of defensive cells
• Toll-like receptors (TLRs) recognize various
components found on/in pathogens (pathogenassociated molecular patterns)
• Examples of PAMPs
–
–
–
–
Lipopolysaccharide (LPS)
Peptidoglycan
Flagella
DNA
• Each TLR can recognize a specific PAMP
– Multiple TLRs can be used to bind one PAMP
– 13 TLRs have been identified. Function of two are
unknown
• Binding of TLR to PAMP induces a chemical response
– Cytokines—proteins released by the cell to signal an
infection has taken place
– Cytokines regulate the intensity and duration of an
immune response
– One role of cytokines is to recruit other immune cells to
the site of the infection
• Cytokines function in both Innate and
Adaptive immunity
– Cytokines recruits macrophages and dendritic
cells to the site of the infection
– Cytokines activate T-cells and B-cells involved in
adaptive immunity. (stimulates antibody
production)
• Adaptive immunity—the portion of the
immune system that “remembers” an
attacking pathogen
– Activated when innate immunity fails to stop an
invading microbe
– Slower activation than innate immunity but
contains a memory component
– Specific immunity “Particular response for a
specific microbe”
• Components of adaptive immunity
– T-cells (T-lymphocytes)
– B-cells (B-lymphocytes)
• Lymphocytes are a type of white blood cell
Figure 16.1 An overview of the body’s defenses.
First line of defense
• Intact skin
• Mucous membranes
and their secretions
• Normal microbiota
Second line of defense
• Phagocytes, such as neutrophils,
eosinophils, dendritic cells, and
macrophages
• Inflammation
• Fever
• Antimicrobial substances
Third line of defense
• Specialized lymphocytes:
T cells and B cells
• Antibodies
Innate Immunity
• The first line of defense against an invading
pathogen is the skin and mucous membranes
– Physical factors—provide a physical barrier
• Skin
• Mucous membranes
– Chemical factors—secrete chemicals that inhibit
growth or eradicates the bacteria
Physical Factors
• Skin
– Largest organ in the body
– Dermis—skin’s inner,
thicker portion. Composed
of connective tissue
– Epidermis—skin’s outer,
thinner layer. Direct
contact with the external
environment
• Keratin—protective layer
of protein
epidermis w/
keratin
epidermis
dermis
• Anti-microbial properties of the skin
– Shedding of the top layer of epidermis aids in the
removal of microbes (sloughing)
– Dryness of the skin prevents microbial colonization
• Populations in humid climates have a greater incidence of
skin infections
• Athletes Foot Fungus (Trichophyton spp)
– Compactness of the cells prevents pathogen passage
(tight junctions)
– pH of skin is between 3-5
• Mucous membranes
– Consists of epithelial
layer and connective
tissue
– Line the gastrintestinal,
respiratory, and
genitourinary tracts
– Goblet cells secretes
mucous (slightly viscous
glycoprotein)
• Prevents colonization
Mucus
Epithelial
Layer
Connective
Tissue
Other Physical Barriers
• Lacrimal apparatus (tear ducts) washes microbes
and other particulates from the eyeball
• Saliva dilutes the numbers of microbes and
washes them from the teeth and mucous
membranes of the mouth
• Hair aids in filtering the inhaled air by trapping
microbes, dust, and pollutants
Other Physical Barriers
• Cilia are hair-like structures on cells that help
propel particulates out of the lower
respiratory tract (ciliary escalator)
– Toxins in cigarette smoke impair cilia function
Figure 24.7 Ciliated cells of the respiratory system infected with Bordetella pertussis.
B. pertussis
Cilia
© 2013 Pearson Education, Inc.
Other Physical Barriers
• Cilia are hair-like structures on cells that help
propel particulates out of the lower
respiratory tract (ciliary escalator)
– Toxins in cigarette smoke impair cilia function
• Epiglottis is a small flap of cartilage in the
larynx
• Earwax traps microbes in the external ear
Other Physical Barriers
• Urine/vaginal secretions functions by
mechanically cleaning the urethra and vagina,
respectively
• Peristalsis, defecation, vomiting, diarrhea all
act to remove microbes and toxins from the
body
– Contraction of gastrointestinal muscles is an effort
of the body to remove toxins (stomach pains)
Chemical Factors
• Sebaceous (oil) glands secretes sebum that forms
a protective film over the skin surface
– Sebum contains unsaturated fatty acids that prevents
the growth of certain pathogens
– Contributes to acidic pH (3-5) of the skin
• Perspiration (sweat) eliminates certain wastes
and microbes from the body
– Also contains lysozyme—enzyme that breaks down
the cell wall of Gram (+) bacteria and some Gram (-)
bacteria
• Found in tears, saliva, nasal secretions, tissue fluids, & urine
• PEPTIDOGLYCAN!!!!
• Earwax is a mixture of secretions rich in fatty
acids (lowers pH)
– Sebaceous glands
– Sweat glands
• Saliva contains lysozyme, urea, and uric acid
that inhibit microbial growth
– Immunoglobin A (antibody) that prevents
microbial attachment to cells
• Gastric juice
– Produced by stomach glands.
– Very acidic (pH 1.2-3.0)
– Destroys microbes and their toxins
• Vaginal Secretions
– Contains glycogen that is digested by Lactobacillus
acidophilus, resulting in lactic acid (pH 3-5)
• Urine
– Contains lysozyme that lowers pH thus inhibiting
microbial growth
Normal Microbiota
• The normal flora also acts as a first line of
defense against invading pathogens
– Microbial antagonism
• Changes in pH
– Prevents Candida albicans growth in the vagina
• Oxygen availability
• Production of bacteriocins that inhibit growth of
pathogens
– E. coli production of bacteriocins prevent Shigella and
Salmonella growth
• Competition for nutrients
• Probiotics—live microbial cultures applied to
or ingested to exert a beneficial effect
– Prebiotics (chemicals that selectively promote
growth of beneficial bacteria)
– Studies have shown that the introduction of
certain lactic acid bacteria can prevent the growth
by Salmonella enterica
Innate Immunity: Nonspecific
Defenses of the Host
Second Line of Defense
• If a microbe escapes the first line of defense,
the body begins mounting a second wave of
defense
– Production of phagocytes
– Inflammation
– Fever
– Antimicrobial substances
Formed Elements in Blood
• Blood consists of plasma (fluid) and formed
elements (cells and cell fragments)
• Cells of the blood
– Erythrocytes
– Leukocytes (white blood cells)
• Granulocytes
• Agranulocytes
• During an infection, the number of leukocytes
can increase (leukocytosis) or decrease
(leukopenia)
Table 16.1 Formed Elements in Blood (Part 1 of 2)
Insert Table 16.1
If possible, break into multiple slides
Table 16.1 Formed Elements in Blood (Part 2 of 2)
Insert Table 16.1
If possible, break into multiple slides
Differential White Cell Count
• Percentage of each type of white cell in a sample
of 100 white blood cells
Neutrophils
60–70%
Basophils
0.5–1%
Eosinophils
2–4%
Monocytes
3–8%
Lymphocytes (NK cells, T and
B cells)
20–25%
Lymphatic System
• Is part of the circulatory system that functions by carrying a
clear liquid (lymph) towards the heart
• Transports leukocytes and antigen-presenting cells to and
from lymph nodes
• Lymph nodes are organized collection of lymphoid tissue
through which lymph passes before circulating back into
the blood
• Lymph nodes are primarily found in the neck, chest, armpit,
pelvis, groin, and intestines
Figure 16.5a The lymphatic system.
Right
lymphatic
duct
Right
subclavian
vein
Thoracic
(left
lymphatic)
duct
Left
subclavian
vein
Tonsil
Thymus
Heart
Thoracic duct
Spleen
Lymphatic vessel
Small intestine
Large intestine
Red
bone marrow
(a) Components of lymphatic system
Peyer’s patch
Lymph node
Figure 16.5b-c The lymphatic system.
Venule
Tissue cell
Blood
Interstitial fluid
Blood capillary
One-way opening
Arteriole
Blood
Lymphatic capillary
Interstitial
fluid (between cells)
Lymph
Tissue cell
Lymphatic capillary
Relationship of lymphatic capillaries to tissue cells
and blood capillaries
Lymph
Details of a lymphatic capillary
Phagocytosis
• Ingestion of microbes or particles by a cell,
performed by phagocytes
– Phago: from Greek, meaning eat
– Cyte: from Greek, meaning cell
• Neutrophils and eosinophils function in
phagocytosis
• Monocytes mature into macrophages
– Fixed macrophages
– Wandering (circulating) macrophages
Figure 16.6 A macrophage engulfing rod-shaped bacteria.
Macrophage
Bacterium
Pseudopods
Mechanism of Phagocytosis
1. Chemotaxis—chemical attraction of
phagocytes to microbes
2. Adherence—attachment of the phagocyte’s
plasma membrane to the microbe or other
foreign particle
– Action is enhanced with opsonins
3. Ingestion—uptake of microbe into the cell
4. Digestion—breakdown of microbe via
digestive enzymes in lysosomes
Figure 16.7 The Phases of Phagocytosis.
A phagocytic macrophage
uses a pseudopod to engulf
nearby bacteria.
Pseudopods
Phagocyte
Cytoplasm
1 CHEMOTAXIS
and
ADHERENCE
of phagocyte to
microbe
2 INGESTION
of microbe by phagocyte
Microbe
or other
particle
Details of
adherence
3 Formation of phagosome
(phagocytic vesicle)
4 Fusion of phagosome
with a lysosome
to form a phagolysosome
Lysosome
PAMP (peptidoglycan
in cell wall)
Digestive
enzymes
Partially
digested
microbe
5 DIGESTION
of ingested
microbes by
enzymes in the
phagolysosome
Indigestible
material
6 Formation of
the residual body
containing
indigestible
material
TLR
(Toll-like receptor)
Plasma membrane
7 DISCHARGE of
waste materials
Pg. 461 of
textbook
Microbial Evasion of Phagocytosis
Inhibit adherence:
M protein, capsules
Streptococcus pyogenes, S. pneumoniae
Kill phagocytes: Leukocidins
Staphylococcus aureus
Lyse phagocytes:
Membrane attack complex
Listeria monocytogenes
Escape phagosome
Shigella, Rickettsia
Prevent phagosome–
lysosome fusion
HIV, Mycobacterium tuberculosis
Survive in phagolysosome
Coxiella burnettii
Inflammation
• Damage to the body’s tissues triggers a local defensive
response called inflammation
– Not only generated by microbes
• Inflammation is characterized by four signs/symptoms
–
–
–
–
Redness
Swelling (edema)
Pain
Heat
• Binding of microbial structures stimulate the Toll-like receptors
of macrophages and they begin producing TNF-alpha
• Activation of acute-phase proteins (complement, cytokine,
and kinins)
• Vasodilation (histamine, kinins, prostaglandins, and
leukotrienes)
Chemicals Released by Damaged Cells
Histamine
Vasodilation, increased permeability
of blood vessels
Kinins
Vasodilation, increased permeability
of blood vessels
Intensify histamine and kinin effect
Prostaglandins
Leukotrienes
Increased permeability of blood vessels,
phagocytic attachment
Figure 16.8a-b The process of inflammation.
Bacteria entering
on knife
Bacteria
Epidermis
Blood vessel
Dermis
Nerve
Subcutaneous
tissue
(a) Tissue damage
1 Chemicals such as histamine, kinins,
prostaglandins, leukotrienes, and cytokines
(represented as blue
dots) are released by
damaged cells.
2 Blood clot forms.
3 Abscess starts to form
(orange area).
(b) Vasodilation and increased
permeability of blood vessels
Figure 16.8c The process of inflammation.
Blood vessel
endothelium
Monocyte
4 Margination—
phagocytes stick
to endothelium.
5 Diapedesis—
phagocytes
squeeze between
endothelial cells.
Insert Fig 16.8c
6 Phagocytosis of
invading bacteria occurs.
Red
blood
cell
Macrophage
(c) Phagocyte migration
and phagocytosis
Bacterium
Neutrophil
Fever
• Abnormally high body temperature
• Hypothalamus is normally set at 37°C
• Gram-negative endotoxins (LPS) cause
phagocytes to release interleukin-1 (IL-1)
• Hypothalamus releases prostaglandins that reset
the hypothalamus to a high temperature
• Body increases rate of metabolism, chills begin
and shivering occurs, which raise temperature
• Vasodilation and sweating: body temperature
falls (crisis)
The Complement System
• 30+ proteins produced by the liver and are
located in blood serum throughout the body
– Serum proteins are activated in a cascade
• Activated by
– Antigen–antibody reaction (Classical)
– Complement C3 binds the factors B, D, P on a
pathogen (Alternative)
– Liver produces Lectins that bind to carbohydrates
Effects of Complement Activation
• Opsonization, or immune adherence: enhanced
phagocytosis
– C3a and C5a
• Membrane attack complex: cytolysis
– C5b, C6, C7, C8, C9 (multiple copies)
• Attract phagocytes
– C5a (chemoattractant)
Figure 16.9 Outcomes of Complement Activation.
1 Inactivated C3 splits into activated
C3
C3a and C3b.
Pg. 468 of
textbook
2 C3b binds to microbe, resulting
in opsonization.
C3b
C3a
C3b
proteins
3 C3b also splits C5
into C5a and C5b
mast cells to release
histamine, resulting
in inflammation;
C5a also attracts
phagocytes.
opsonization
C5
Enhancement of phagocytosis
by coating with C3b
C5a
C5b
C5a receptor
Histamine
C5a
Insert Fig 16.9
Mast cell
4 C5b, C6, C7, and C8 bind
together sequentially and
insert into the microbial
plasma membrane, where
they function as a receptor
to attract a C9 fragment;
additional C9 fragments are
added to form a channel.
Together, C5b through C8
and the multiple C9
fragments form the
membrane attack complex,
resulting in cytolysis.
5 C3a and C5a cause
C6
C3a receptor
C3a
inflammation
C7
C8
Increase of blood vessel
permeability and chemotactic
attraction of phagocytes
C9
Microbial
plasma
membrane
Channel
C6
C7
C5b
C8
C9
Formation of membrane
attack complex (MAC)
C6
C5b
C7
C8
C9
Cytolysis
cytolysis
© 2013 Pearson Education, Inc.
Bursting of microbe due to inflow of extracellular fluid through
transmembrane channel formed by membrane attack complex
Figure 16.10 Cytolysis caused by complement.
Insert Fig 16.10
Figure 16.11 Inflammation stimulated by complement.
C5a
C5a receptor
Histamine
Phagocytes
Neutrophil
Histaminecontaining
granule
Insert Fig 16.11
Histaminereleasing
mast cell
C3a
C3a receptor
C5a
Macrophage
Figure 16.12 Classical pathway of complement activation.
Microbe
Antigen
C1 is activated
by binding to
antigen–antibody
complexes.
Antibody
C1
Activated C1 splits
C2 into C2a and
C2b, and C4 into
C4a and C4b.
C4
C2
Insert Fig 16.12
C2b
C2a
C2a and C4b combine
and activate C3, splitting
it into C3a and C3b (see
also Figure 16.9).
Opsonization
C3b
Cytolysis
C4b
C4a
C3
C3a
Inflammation
Figure 16.13 Alternative pathway of complement activation.
Lipid-carbohydrate
complex
Microbe
C3 combines with
factors B, D, and P
on the surface of
a microbe.
B
D
P
C3
Insert Fig 16.13
This causes C3 to
split into fragments
C3a and C3b.
C3b
C3a
Inflammation
Opsonization
Cytolysis
Key:
B B factor
D D factor
P P factor
Figure 16.14 The lectin pathway of complement activation.
Microbe
Carbohydrate
containing
mannose
Lectin
Lectin binds to
an invading cell.
Bound lectin
splits C2 into
C2b and C2a
and C4 into
C4b and C4a.
C2
C2b
C4
C2a and C4b combine
and activate C3
(see also Figure 16.9).
Opsonization
C4b
C2a
C4a
C3
C3b
Cytolysis
C3a
Inflammation
Some Bacteria Evade Complement
• Capsules prevent C activation
– Disallows Ab from binding to bacteria thus preventing
C1 binding
• Surface lipid–carbohydrate complexes prevent
formation of membrane attack complex (MAC)
– Modification of sugars on the bacterial membrane
abrogates C5b-C9 from binding to surface
• Neisseria gonorrhoeae
• Enzymatic digestion of C5a
– Gram positive cocci (Streptococcus pyogenes)
Interferons (IFNs)
• Interferons—class of similar anti-viral proteins
produced by certain animal cells and function to
abrogate viral multiplication
– Host cell specific and not viral specific
• IFN- and IFN-: produced by virally-infected cells
and causes neighboring cells to produce anti-viral
proteins that inhibit viral replication
– Oligoadenylate synthetase—degrades viral mRNA
– Protein kinase—inhibits protein synthesis
• IFN-: produced by lymphocytes and causes
neutrophils and macrophages to phagocytize
bacteria
– Produce iNOS (nitric oxide) that inhibits ATP production
Figure 16.15 Antiviral action of alpha and beta interferons (IFNs).
1
Viral RNA from
an infecting virus
enters the cell.
Pg. 471 of
textbook
2 The infecting virus
5 New viruses released by the
replicates into
new viruses.
Viral RNA
virus-infected host cell infect
neighboring host cells.
3 The infecting virus
also induces the
Infecting
host cell to produce
virus
interferon mRNA
(IFN-mRNA), which
is translated into
alpha and beta interferons.
Viral RNA
Nucleus
Translation
Insert Fig 16.15
Transcription
Transcription
IFN-mRNA
4 Interferons released by the
virus-infected host cell bind
to plasma membrane or
nuclear membrane receptors on
uninfected neighboring host
cells, inducing them to
synthesize antiviral proteins
(AVPs). These include
oligoadenylate synthetase
and protein kinase.
Alpha
and beta
interferons
Translation
Virus-infected
host cell
Neighboring host cell
Antiviral
proteins
(AVPs)
6 AVPs degrade
viral mRNA and
inhibit protein
synthesis—and
thus interfere
with viral
replication.
Innate Immunity
• Iron-binding
proteins
– Bind free-iron in
serum
– Siderophores—
proteins that
microbes secrete
to bind iron
• Antimicrobial peptides
– Chain of 15-20 amino
acids
– Lyse bacterial cells
– Production triggered by
protein and sugar
molecules on surface of
microbes
KNOW TABLE ON PAGE 474