Innate Immunity
Azad k. kaushlk, 8vSc (Ponors), MvSc, uSc (arls)
unlverslLy of Cuelph
Azad Kaushik (Illustrations from Kuby Immunology, 7th Edition)
Anatomical barriers to infection
!
Several barriers, both physical and chemical, exist to
prevent pathogens from gaining access to tissues
"
Should those barriers be breached, innate immune
system receptors recognize the threat
!
Conserved pathogen-associated molecular patterns
(PAMPs) found on microbes
"
Aging, dead, or damaged self structures can also be
recognized
!
Damage-associated molecular patterns (DAMPs)
"
Pattern recognition receptors (PRRs) recognize these
structures and target them for clearance
1
2
Anatomical barriers to infection
Anatomical barriers to infection
!
Barriers are just one difference between innate and
adaptive immune responses
3
4
Anatomical barriers to infection
!
Epithelial barriers prevent pathogen entry into the
bodys interior
"
Skin
"
Mucosal membranes
Anatomical barriers to infection
!
Epithelial layers produce protective substances
"
Acidic pH
"
Enzymes and binding proteins
"
Antimicrobial peptides
5
6
Phagocytosis
!
Defined as engulfment and internalization of
materials such as microbes for their clearance
Phagocytosis: accessory cells (Macrophage, neuLrophlls eLc.)
a. chemoLaxls
b. adherence Lo cell wall
c. formauon of phago-lysosome
d. proLeolyuc dlgesuon, and
e. ellmlnauon by exocyLosls.
7
8
Phagocytosis
!
Microbes are recognized by
receptors on phagocytes
"
May recognize PAMPs
directly
"
May recognize soluble
opsonin protein bound to
microbes
Phagocytosis
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Phagocytosis
!
Opsonins
"
Mannose-binding lectin (Collectin)
"
H-ficolin
"
C1 bound to Antibody or LPS
Phagocytosis
!
Ingested materials are taken into phagosomes
"
Phagosomes are fused with lysosomes or
granules
!
Destruction occurs through enzyme degradation,
antimicrobial proteins, and toxic effects of reactive
oxygen and reactive nitrogen species (ROS and RNS)
Induced cellular innate responses
!
Families of PRRs recognize a variety of PAMP ligands
"
TLRs
"
CLRs
"
RLRs
"
NLRs
!
Signaling pathways are activated, contributing to innate/
inflammatory responses
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Induced cellular innate responses
!
Toll-like receptors (TLRs) recognize many types of
pathogen molecules
"
Homologous to fruit fly Toll receptor
"
Dimers with extracellular leucine-rich (LRR)
domains that bind PAMPs and DAMPs
Induced cellular innate responses
!
TLRs recognize many types of pathogen molecules
"
Of 13 TLRs in mice and humans, some are in
lysosomes and some are surface bound
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Induced cellular innate responses
"
Location helps determine what each binds
!
TLR binding of
PAMPs activates
signaling pathways
Induced cellular innate responses
!
C-type lectin receptors (CLRs)
"
Heterogeneous population of surface PRRs
expressed on Macrophages, dendritic cells, PMNs,
B and T cells
"
Recognize cell wall components
!
Sugars/polysaccharides of bacteria/fungi
"
Trigger a variety of pathways
!
Some similar to those activated by TLRs
!
RIG-I-like receptors (RLRs; Retinoic Acid inducible gene)
"
RNA helicases
"
Function as cytosolic PRRs
"
Recognize viral double-stranded RNAs
"
Trigger signaling pathways
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Induced cellular innate responses
!
NOD-like receptors (NLRs)
"
Large family of cytosolic PRRs
"
Activated by intracellular PAMPs
"
Can also sense changes in intracellular environment
!
Activates caspase-1 protease
!
Caspase-1 cleaves IL-1/IL-18
into active forms for release
!
PRR signaling pathways activate expression of
various genes
"
Antimicrobial peptides
"
Type I interferons (potent antiviral activity)
"
Cytokines (inflammatory IL-1, TNF-!, and IL-6)
"
Chemokines
"
Enzymes: iNOS and COX2
Induced cellular innate responses
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Induced cellular innate responses
Induced cellular innate responses
!
PRR signaling pathways activate expression of a
variety of genes
"
Type I interferons (potent antiviral effects)
Inflammatory responses
!
Proinflammatory cytokines and chemokines
triggered by innate responses to infection, damage,
or harmful substances
!
Early components of inflammation include:
"
Increased vascular permeability
"
Recruitment of neutrophils and other leukocytes
from the blood to the site of damage/infection
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Inflammatory responses
Inflammatory responses
!
Later stages of inflammation are the acute phase
responses (APRs)
"
Induced by proinflammatory cytokines (IL-1, TNF-
!, and IL-6)
"
APR involves:
!
Increased synthesis/secretion of antimicrobial
proteins from the liver
!
MBL
!
CRP
!
Complement components
!
Liver acute phase proteins activate other
processes that help eliminate pathogens
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22
Natural killer (NK) cells
!
NK cells are lymphocytes with innate immune
functions
"
Express a set of receptors for self proteins
induced by:
!
Infections
!
Malignant transformations
!
Other stresses
"
Activated NK cells perform one of two functions:
!
Kill the altered self cell
!
Produce cytokines that induce adaptive responses
against the altered self cell
Interactions between the innate and adaptive
immune systems
!
A constant interplay between the two
systems exists
"
Several innate systems have been co-opted by
adaptive immunity to contribute to antibody-
mediated pathogen elimination
!
Opsonization
!
Complement activation
"
Some lymphocytes express TLRs, but use them
as co-stimulatory receptors
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Interactions between the innate and adaptive
immune systems
!
A constant interplay between the two systems exists
"
Dendritic cells are a key bridge
!
They bring antigens from the site of infection and
present them to T cells in lymph nodes
!
This activates the T cells, allowing them to
differentiate into particular pathogen-specific
subsets for the best antigen clearance
! T
H
cell subsets
! T
C
cells
Ubiquity of innate immunity
!
Innate immunity is evolutionarily older
"
TLRs are unique to animals, BUT
"
PRRs with leucine-rich repeats (LRRs) are found in
virtually all plants and animals
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iClick Questions
27
Indicate whether each of the following
statements is true (A) or false (B):
i. Low pH in stomach is not a host defense
mechanism
ii. Destruction occurs through enzyme degradation
only in the phagosome
iii. Mannose-binding lectin acts as opsonin
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