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INNATE IMMUNITY
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Aims
Know key properties of innate
immunity.
Know components made up the
innate immune system.
Understand mechanism(s) by which
the innate immunity use to protect
body.
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Innate immunity
Innate immunity
The two principal types of reactions of the innate immune system are inflammation
and antiviral defense.
The innate immune system responds in essentially the same way to repeat
encounters with a microbe, whereas the adaptive immune system mounts stronger,
more rapid and thus more effective responses on successive encounters with a
microbe
The innate immune system recognizes structures that are shared by various
classes of microbes and are not present on normal host cells Innate immune
receptors are specific for structures of microbes that are often essential for the
survival and infectivity of these microbes.
The innate immune system also recognizes molecules that are released from
damaged or necrotic host cells. Such molecules are called damage-associated
molecular patterns (DAMPs).
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Innate immunity and adaptive immunity
Innate immunity and adaptive immunity
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Properties of innate immunity
Naturally exits, inherited from one to
another generation.
Always present and immediately react as the
microbe enters the body.
Utilize the same mechanism to fight
different microbes (non-specific).
No memory, reaction is not stronger after each
encounterment.
Components of innate immunity
Epithelia (skin and mucous
membranes).
Phagocytes, NK cell.
Plasma proteins, including
complements.
Cytokines.
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Mechanisms of innate immunity
Physical and chemical mechanisms:
Physical barries of skin and mucous membrane.
Chemical barries of the secreting fluid.
Cellular mechanisms:
Phagocytosis by phagocytes.
Killing by NK cell.
Humoral mechanisms:
Lysis by complements.
Cytokines.
Mechanisms of innate immunity
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Physical and chemical mechanisms
Skin and
mucous membranes
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Roles of epithelia in innate immunity
Abbas A. K and Lichtman A. H
Basic Immunology 3rd Ed © Saunders 2011
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Mechanisms of innate immunity
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Epithelial Barriers
gastrointestinal
COMMON PORTALS OF ENTRY BY MICROBES: skin, GI tract,
respiratory tract.
These 3 portals are lined by continuous epithelia. These cells also
produce peptide antibiotics. In addition, intraepithelial lymphocytes (T
cell lineage) express antigen receptors of limited diversity
Intraepithelial lymphocytes recognize microbial structures and
serve as sentinels against agents trying to breach epithelia.
The epithelial layers that insulate the interior of the body from outside
pathogens—the skin and epithelial layers of the mucosal tracts and
secretory glands—constitute an anatomical physical barrier that is highly
effective in preventing pathogens from entering the rest of the body.
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What happens when the physical and
chemical barriers are breached?
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Function of epithelia in innate immunity
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Cellular mechanisms
Leukocyte Players of Innate Immune
Responses
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Cellular mechanisms
Phagocytosis
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Phagocytosis steps
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Phagocytosis
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How phagocyte get out of
the blood vessel?
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How do phagocytes recognize microbes?
Mannose Scavenger Mannose Scavenger Toll like receptor
CD14
receptor Mac-1 receptor receptor Mac-1 receptor
C’ Fc C’ Fc
Neutrophil Macrophage
• These cell have surface receptor for microbes, that can bind to
microbes (PRR). Pattern recognition receptors
Microbe
• These receptor recognise unique structure on microbe only (MP). pattern
• Receptors for C’ and Fc to cache C’ or Ab coated microbe.
22 C' = complement system receptor
Fc = antibody receptor
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Phagocytosis process
Arginine
NO
Inducible nitric
ROI O oxide synthase
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(INOS)
Oxidase
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How phagocyte capture microbe
Direct
capture with
PRR
C’ coated microbe
(opsonization by C’)
(via C’ receptor)
Y Antibody coated microbe
(opsonization by antibody)
(via Fc receptor)
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Neutrophils and monocyte
The two types of circulating phagocytes, neutrophils and monocytes, are blood cells that are
recruited to sites of infection, where they recognize and ingest microbes for intracellular killing
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Macrophages
ingest and destroy microbes
clear dead tissues and initiate the process of tissue
repair
produce cytokines that induce and regulate
inflammation
Macrophages may be activated by two different
pathways that serve distinct functions: classical and
alternative
Classical macrophage activation is induced by
innate immune signals , such as from TLRs, and by
the cytokine IFN-γ (toll like receptors)
Alternative macrophage activation occurs in the
absence of strong TLR signals and is induced by the
cytokines IL-4 and IL-13; these macrophages, called
M2
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Dendritic cells
As sentinels in tissues which serve two main functions: initiate inflammation and stimulate
adaptive immune responses.
Capture protein antigens and display fragments of these antigens to T cells.
Constitute an important bridge between innate and adaptive immunity.
Mast cells
present throughout the skin and mucosal barriers.
can be activated by microbial products binding to TLRs and by components of the complement
system as part of innate immunity or by an antibody-dependent mechanism in adaptive immunity.
synthesize and secrete lipid mediators (e.g., prostaglandins and leukotrienes) and cytokines (e.g.,
tumor necrosis factor [TNF]), which stimulate inflammation.
Provide defense against helminths and other pathogens, as well as protection against snake and
insect venoms
Responsible for symptoms of allergic diseases
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Innate lymphoid cells
are tissue-resident cells
produce cytokines similar to those secreted by helper T lymphocytes but do not express T cell antigen
receptors (TCRs).
are often stimulated by cytokines produced by damaged epithelial and other cells at sites of infection.
provide early defense against infections in tissues
their essential roles in host defense or immunological diseases, especially in humans, are not clear.
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NK cells
NK cells recognize infected and stressed cells and respond by killing these cells and by secreting the
macrophage-activating cytokine IFN-γ
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NK cell kills target cells
NK KILLS INFECTED HOST CELLS,
THUS ELIMINATING MICROBIAL
RESERVOIR
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NK works in colaboration with macrophage
Macrophage ingests microbes and makes IL-12. IL-12
activates NK cell to make IFN-, and IFN- activates
macrophage to kill ingested microbes. BEAUTIFUL!!!
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When NK cell kills other cell?
NORMAL
ABNORMAL
Abbas A. K and Lichtman A. H Basic Immunology 2nd Ed © Saunders 2004
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Activating and Inhibitory receptors
on NK cells
ACTIVATING RECEPTORS recognize cell surface molecules on
stressed cells (viruses, IC bacteria, DNA damage, malignant
transformation, tumour cells)… tell NK to kill.
INHIBITORY RECEPTORS specific for class I MHCs tell NK not to
kill.
Viruses have mechanisms which block expression of MHC class I
molecules. This mechanism evades CD8+ CTLs but inhibits the
inhibitory NK receptors. Thus, NK cells are still activated and
continue to eliminate virus-infected cells. cytotoxic T lymphocytes = CTLs
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The complement system – C’
Bordet’s experiment (1910)
Injection
Cholaera
Cholaera
serum
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+
Fresh serum
+
560C
inactivated
serum Non-
injected
rabbit
Bordet’s experiment serum
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The complement system – C’
Collection of circulating membrane associated proteins (mainly
proteolytic enzymes)
C’ activation pathways:
Alternative pathway (innate) is triggered when complement proteins are
activated on microbial surfaces. Microbes don’t have regulatory proteins
and can’t control it.
Classical pathway (humoral adaptive) is triggered after Abs bind to
microbes and other Ags.
Lectin pathway (innate immunity) activated when mannose-binding
lectin binds to terminal mannose residues on microbial surface
glycoproteins (activates proteins of the classical pathway but is innate).
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C’ pathways
Alternative pathway and
Lectin pathway belong to
innate immunity;
Classical pathway belongs
to humoral (adaptive)
immunity
Abbas A. K and Lichtman A. H
Basic Immunology 2nd Ed © Saunders 2004
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Beginning steps
Abbas A. K and Lichtman A. H
Basic Immunology 2nd Ed © Saunde rs 2004
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Final steps
(common for all pathways)
3 pathways have different
beginnings but share same
late steps and effector
functions
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Biological effects of C’
Opsonization: C3b coats microbes, promotes
phagocytosis.
Lysis of bacteria: formation of MAC that penetrates
the cell membrane and causes either lysis or
microbial apoptotic death.
Chemotaxic: some C’ fragments are
chemoattractants for phagocytes and eventually
other leukocytes (ie. C5a, C3a).
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Biological effects of C’
Abbas A. K and Lichtman A. H Basic Immunology 2nd Ed © Saunders 2004
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Antimicrobial Proteins and Peptides
Kill Would-Be invader
Among the antimicrobial proteins
produced by the skin and other epithelia in
humans
Several are enzymes and binding
proteins that kill or inhibit growth of
bacterial and fungal cells.
Lysozyme is an enzyme found in saliva,
tears, and fluids of the respiratory tract
that cleaves the peptidoglycan
components of bacterial cell walls.
Lactoferrin and calprotectin are two
proteins that bind and sequester metal
ions needed by bacteria and fungi, limiting
their growth.
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Antimicrobial Proteins and Peptides
Kill Would-Be invader
Antimicrobial peptides are generally less than 100 amino acids long.
These peptides are an ancient form of innate immunity present in vertebrates,
invertebrates, plants, and even some fungi.
Antimicrobial peptides generally are cysteine-rich, cationic, and amphipathic
(containing both hydrophilic and hydrophobic regions).
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Cytokines of Innate Immunity
Interleukins: most are produced by leukocytes, act on leukocytes (though not all).
Cytokines are secreted in small amounts in response to an external stimulus and bind
to high-affinity receptors on target cells.
act on nearby cells (paracrine actions)
act on the cells that produce them (autocrine actions)
may be active distant from their site of secretion (endocrine actions).
The principal sources of cytokines are activated Dendritic cells and Macrophages
most produced in small amounts
bind with high affinity to target cells
can act distant from site of secretion
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Macrophage cytokines
Abbas A. K and Lichtman A. H Basic Immunology 2nd Ed © Saunders 2004
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Other Plasma Proteins
Plasma mannose-binding lectin (MBL) – opsonizes
and activates complement
C-reactive protein (CRP) – opsonization
Circulating levels of many plasma proteins rapidly
increase after infection – acute phase response
All are leading to imflamation
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Cytokines of innate immunity
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Notes
Extracellular bacteria and fungi combated by
phagocytes, complement, acute phase proteins
Intracellular bacteria and viruses combated by
phagocytes, dendritic cells, NK cells with help
from cytokines
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Innate immunity stimulates
adaptive immunity
Innate immune responses
generate molecules that
serve as second signals
(together with antigens) to
activate B and T
lymphocytes.
This microbe-dependent
second signal requirement
ensures no response to
harmless substances.
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2 signals regulation
Antigen (often referred to as “signal 1”)
and molecules produced during the innate
immune response (“signal 2”) function
cooperatively to activate antigen-specific
lymphocytes.
The requirement for microbe-triggered
signal 2 ensures that the adaptive immune
response is induced by microbes and not by
harmless substances.
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These second signals not only stimulate
adaptive immunity but also guide the response
Intracellular pathogens need to be
eliminated by T cells thus T cells are
stimulated by “T-cell costimulators” on
dendritic cells and macrophages.
Extracellular pathogens (ie. blood-borne)
need to stimulate B cells and do so by
“complement system co-stimulators”.
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