Lec 04- Innate Immunity (Part 1) Flashcards
What is the function of innate immunity?
- Initial host defense response to pathogens that prevents, controls, or eliminates infection
- Eliminates damaged cells and initiates tissue repair process
- Controls adaptive responses
Innate immunity may keep the infection in check until _______.
more specialized adaptive immune responses are activated
Steps of damaged cell elimination
1- RECOGNIZES and responds to host molecules that are stressed, damaged, and dead host cells
2- CLEARS cell debris by phagocytosis
3- STIMULATES and controls tissue remodeling
How does innate immunity control adaptive responses to intracellular vs. extracellular pathogens?
- Provides danger signals»_space; alert adaptive immune system to respond
- Reacts in distinct ways to different microbes»_space; influences the type of adaptive immune response
Innate Immunity component:
Cellular and chemical barriers
- skin
- mucosal epithelia
- antimicrobial molecules
Innate immunity component:
Blood proteins
- complement
- acute phase proteins
- cytokines
- others
Innate immunity component:
Cells
- phagocytes (macrophages/neutrophils)
- dendritic cells
- natural killer cells
- innate lymphoid cells
3 Major Type of Defenses of Innate Immunity
-Inflammation
> Leukocytes and plasma proteins
-Physical barriers
> Skin and epithelial cells
-Anti-viral responses
> Inhibition of viral replication
Specificity:
Innate vs. Adaptive
Innate:
- Pathogen-associated molecular patterns (PAMPs)
- Damage-associatd molecular patterns (DAMPs)
Adaptive:
-Fine structures of microbial and non microbial Ags
Receptors:
Innate vs. Adaptive
Innate = Pattern recognition receptors (PRRs)
Adaptive = Greater diversity of BCRs and TCRs generated by somatic recombination
Distribution of receptors:
Innate vs. Adaptive
Innate = NONCLONAL (identical receptors on various cells)
Adaptive = CLONAL (identical on a single cell, but different between 2 cells)
Discrimination of self and non-self:
Innate vs. Adaptive
Innate = YES
Adaptive = YES
Where are PRRs located?
- extracellularly
- endosomes
- cytosol
What are the 5 families of microbial PRRS?
1- TLR family (surface and endosomal) 2- CLRs family 3- NOD-like receptors (NLRs) family 4- RIG-like receptors (RLRs) family 5- Cytosolic DNA sensors (CNS) family
PRRs on the cell surface bind PAMPs from __________.
extracellular pathogens
What do endosomal TLRs recognize?
nucleic acids of phagocytized microbes
Which family of PRRs is an evolutionarily conserved family?
TLRs
TLRs can form _______ or ________.
homodimers or heterodimers
What do TLRs recognize?
Both PAMPs and DAMPs
Which TLRs are expressed on the cell surface?
TLRs: 1 2 4 5 6
Which TLRs are expressed in endosomes?
TLRs: 3 7 8 9
Which TLRs use the adapter protein MyD88 and activate the transcription factors NF-kB and AP-1?
TLRs: 1 2 5 6
Which TLR uses the adaptor protein TRIF and activates the IRF3 and IRF7 transcription factors?
TLR3
Which TLR can activate both pathways?
TLR4
Which TLRs in the endosome use My D88 and activate both NF-kB and IRF7?
TLRs:
7
9
All TLRs signal through MyD88 except _______.
TLR3
Which TLRs also engage TIRAP?
TLR4 and the TLR2 subfamily (TLR 1,2,6)
Which TLR signals through TRIF?
TLR3
What is used in conjunction with TRAM in the TLR4-MyD88 independent pathway?
TRIF
TLRs are expressed on ______ cells
Immune cells
including macrophages and dendritic cells
Microbial lipoproteins activate mammalian immune cells through ________.
TLR2
LPS activates cells via ______.
TLR4
Through which TLR do bacterial DNA sequences containing unmethylated cytosine-guanosine dinucleotides (CpGs) work?
TLR9
TLR-dependent signaling pathways activate ______ which results in transcription of pro-inflammatory genes.
NF-kB
Which cytokine controls the adaptive T cell immune response?
IL-12
Activation of TLRs triggers ____.
antimicrobial pathways that directly kill the pathogen
What are the 2 ways activation of TLRs can be detrimental to the host?
- can contribute to tissue injury by inducing apoptosis
- can lead to life-threatenting septic shock
Where is the secreted from of IL-1b and IL-18 produced?
in the inflammasome
From which family is the NLRP subfamily?
14 NOD-like receptors
How do NLRPs respond to cytosolic PAMPs and DAMPs?
- binding other proteins
- forming signaling complexes (inflammasomes)
How do inflammasomes activate the enzyme caspase-1?
by recruitment to the complex
What is caspase-1?
a protease with cysteine residue in the active site
What is the main function of caspase-1?
to cleave the inactive cytoplasmic precursor forms of IL-1b and IL-18
What are the secreted forms of IL-1b and IL-18?
proinflammatory cytokines
What kind of complexes make up the scavenger receptor family?
Trimeric complexes of type II transmembrane polypeptides
What are the 3 extracellular structural domains of the scavenger receptor family?
1- SR cysteine-rich (SRCR) domain
2-The collagen-like domain, which is implicated in the binding of polyanionic ligands
3-The a-helical coiled-coil domain, believed to assist in receptor trimerization
What are the 3 domains on the Macrophage mannose receptor (MMR) and DEC-205?
1- cyesteine-rich N terminal domain
2- fibronectin-like domain
3- multiple calcium-dependent lectin domains that bind various carbohydrate ligands
What do scavenger receptors mediate?
the uptake of oxidized lipoproteins into cells
Which scavenger receptors are expressed on macrophages and mediate the recognition/phagocytosis of microorganisms?
SR-A and CD36
CD36 also functions as what?
- a coreceptor in TLR2/6 recognition
- response to bacterially derived lipoteichoic acid and diacylated lipopeptides
SRs bind bacterial constituents based on _______ of bacterial LPS, lipoteichoic acid, nucleic acids, b-glucan, and proteins
negative charges
SRs KO mice have increased _________ with several microbial pathogens
increased susceptibility to infection
Receptors for carbohydrates belong to the _________ family.
C-type lectin family because they bind to carbohydrates
All receptors contain a conserved carbohydrate recognition domain for recognition of ______, ______, and ______.
- microbial mannose
- N-acetylglucosamine
- b-glucans
EUK carbohydrates are most often terminated by _______ and _______.
galactose and sialic acid
Where are soluble lectins found?
- blood
- extracellular fluids
Where are integral membrane protein lectins found?
- surfaces of macrophages
- dendritic cells
- some tissue cells
Function of receptors for carbohydrates
- facilitate the phagocytosis of microbes
- secretion of cytokines that promoted subsequent adaptive immune responses
What do mannose receptors recognize on microbial surfaces?
- terminal D-mannose
- L-fructose
- N-acetyl-D-glucosamine sugars
The mannose receptor is involved in __________ of microbes.
phagocytosis of microbes
3 types of epithelial barriers
- physical barrier to infection
- killing of microbes by locally produced antibiotics
- killing of microbes and infected cells by intraepithelial lymphocytes
What are defensins?
-small cationic antimicrobial peptides
What do defensins contain?
- cationic regions
- hydrophobic regions
What produces defensins?
- epithelial cells of mucosal surfaces
- granule-containing leukocytes (neutrophils, natural killer cells, CTLs)
What stimulates defensin synthesis?
- cytokines
- microbial products
To what do defensins have direct toxicity?
Microbes
including:
- bacteria
- fungi
- enveloped viruses
Function of defensins
regulate activation of cells involved in inflammatory response to microbes
What produces cathelicidins?
-neutrophils
-barrier cells in the:
> skin
> GI tract
> respiratory tract
What are cathelicidins synthesized as?
Cleaved into?
Synthesized as: an 18-kD 2-domain precursor protein
Cleaved into: 2 protective peptides
To what do cathelicidins have direct toxicity?
- Microorganisms
- Activation of leukocytes
What is LL-37?
- The C-terminal fragment of cathelicidins
- Can bind and neutralize LPS
- Binds to DNA blocking AIM2 inflammasome activation
Functions of Anti-microbial Peptides (AMP)
- Wound repair
- Initiation of TLR9 activation
- Recruitment of T cells
- Mast cell de-granulation and histamine release»_space; vasodilation
- Recruitment of immature dendritic cells
- Promotion of angiogenesis
- Anti-endotoxin activity
- Killing microbes
Where do innate lymphoid cells (ILCs) develop?
from common bone marrow precursor
The common bone marrow precursor is identified by ______.
the Id2 transcription factor
What are the 3 subsets of Id2?
T-bet (ILC1)
GATA-3 (ILC2)
RORyt (ILC3)
How are the 3 subsets of Id2 distinguished?
by expression of distinct transcription factors and cytokines produced
Which cytokines does ILC1 produce?
IL-2
IL-18
Defense against viruses
Which cytokines does ILC2 produce?
IL-25
IL-33
Allergic inflammation
Which cytokines does ILC3 produce?
IL-1
IL-23
Intestinal barrier function
Lymphoid organogenesis
Functions of natural killer cells
- RECOGNIZE ligands on infected cells or stressed cells
- KILL infected or stressed host cells
- ELIMINATE reservoirs of infection
- RELEASE intracellular pathogens for phagocytosis
What do natural killer cells respond to and secrete?
Respond to: IL-12 produced by macrophages
Secrete: IFN-y
Function of IFN-y
activates macrophages to kill phagocytized microbes
What are Killer cell immunoglobulin (Ig) like receptors (KIRs)?
NK-cell activating receptors
Function of Killer cell immunoglobulin (Ig) like receptors (KIRs)?
- recognize ligands on target cells
- activate protein tyrosine kinases (PTKs)
What inhibits activation signal of natural killer cells?
The inhibitory receptors that:
- Recognize class I MHC molecules
- Activate protein tyrosine phosphatases (PTPs)
Do NK cells kill class I MHC-expressing healthy cells?
NO!
MHC
major histocompatability complex
Any inhibition of class I MHC expression on infected cells leads to what?
- NK cell inhibitory receptor not engaged
- The activating receptor functions unopposed to trigger activation of NK cells
KARs
Killer Activation Receptors
NCR
Natural Cytotoxicity Receptors
-(with stimulation) mediate NK killing and release of IFN-y
