Lecture 4 Flashcards
What is the reaction of innate immunity?
eliminates damaged cells and initiates the process of tissue repair:
-recognizes and responds to host molecules related to stressed, damaged, and dead host
innate immunity
initial host defense response to pathogens that prevents, controls, or eliminates infection:
-may keep the infection in check until more specialiezed adaptive immune repsonses are activated
What clears cell debris?
phagocytosis
What stimulates and controls tissue remodeling?
innate immunity
Innate immunity controls?
adaptive responses
- intracellular vs extracellular pathogens
- provides the danger signals that alert the adaptive immune system to response
- reacts in distint ways to different microbes thereby influcencing the type of adaptive immune response
cellular and chemical barriers
skin, mucosal epithelia, antimicrobial molecules
blood proteins
complemetn, acute phase proteins, cytokines, others
cells
phagocytes(macrophages, neutrophils), dendritic cells, natural killer cells, innate lymphoid cells
Liver is major responder to these acute phase proteins
components
T cells were-natural killer cells, innate lymphoid cells,
innate immunity
inflammation, physical barriers, anti viral responses
leukocytes and plamsa proteins
inflammation
skin and epithelial cells
physcial barriers
inhibition of viral replication
anti-viral reponses
innate immunity specficity
pathogen-assocaited mollecular patterns (PAMPs)
damage-associated mollecular patterns (DAMPs)
adaptive immunity specificity
Fine structures of microbial and non microbial Ags
Innate immunity receptors
patterna recognition receptors (PRRs)
Adaptive immunity receptors
greater diversity of BCRs and TCRs generated by somatic recombination
Distribution of receptors innate immunity
nonclonal: identical receptors on vaious cell
Distribution of receptors with adaptive immunity
clonal: identical on a single cell, but different btw two cells
innate immunity discrimination of self and non self
Yes
adaptive immunity discrimination of self and non self
Yes
Nucleic Acids
- ssRNA
- dsRNA
- CpG- unmethylated CpG DNA seuqneces
- Virus
- Virus
- Virus, bacteria
Protiens
Pilin
Flagellin
- bacteria
- bacteria
Cell wall lipids Lipoplysaccharides (LPS) Lipoteichoic acid (LTA)
- Gram negative bacteria
- gram positive bacteria
Carbohydrates
mannan
glucans
fungi, bacteria
fungi
Damage Assocaited molecular patterns
Stress induced proteins
HSPs
crystals
monosodium urate
nuclear proteins
HMGB1
innate immunity inducers inflammation
pathogens sd
Exogenous ligands (PAMPs)
- nucleic acid
- Lipid
- Proteins
Sensors Pattern Recognition receptors inflammation
Toll-like receptors
NOD-like receptors
C-type lectin and so forth
mediators inflamation
TNF alpha
IL-6
IL-1Beta
Homeostatic inflammation Cell/ECM-derived molecules
inducers
Nuclecic Acids (ATP)
Lipid
Protein
inflammation causes
a lot of macrophages, it is unable to get rid of them.
Where can microbial PRRs be located?
extracellular in endososoems or cytosol
5 families of microbieal PRRs
TLR family: surface, endosomal CLRs family NOD-like receptors (NLRs) family RIG-like receptors (RLRs) family Cytosolic DNA sensors (CDS) family
Which cell expresses toll like receptor 9??
macrophages
What bind pathogen assocaited molecular patterns from extracellular pathogens?
PRRs on the cell surface
What recognize nucleic acids of phagocytized microbes?
endosomal TLRs
NOD
nucleotide-binding oligomerization domain
CLR
C type lectin receptor
RIG
retinoic acid inducible gene
TLR’s location
surface and endosomal membranes of DCs, phagocytes, B cells, endotheial cells
Ex TLRs 1-9
Ligands= microbial Ags(LPS, peptidoglycans, viral nucleic acids)
NLRs llocation
cytosol of phagocytes, epithelial cells and others
NLR’s example NOD1/2
bacterial cell wall peptidoglycans
NLRP family (inflammasomes)
intracellular crystals (urate, silica); changes in concentrations of ATP and ions lysosomal damage
RLRs location
cytosol of phagocytes and other cells
ex RIG-1, MDA-5
Viral RNA
CDSs location
cytosol of many cell types
ex AIM2; Sing assocaited CDSs
bacterial and viral DNA
CLRs location
plasma membranes and phagocytes
mannose receptors
microbial carbohydrates w terminal mannose or fructose
homodimers or heterodimers
TLRs
evolutionalrily conserved family of PRRs expressed on many cell types
TLRs
What do TLRs recognize?
PAMPs and DAMPs
Whare TLRs are express on the cell surface?
1,2,4,5,6
What TLRs are expressed in endosomes?
3,7,8,9
DNA containing un methylated ctyosine-guanosine dinucleotides
CpG
receptor homology domain
TIR, TOLL/IL-1
TLR1;TLR2
bacterial lipopeptides
TLR2
bacterial peptidoglycans
TLR4
LPS
The only anti inflammatory cytokine is?
L10 not dependent on
TLR5
bacterial flagelin
TLR2;TLR6
bacterial lipopeptides
TLR3
dsRNA
TLR7
ssRNA
TLR8
ss RNA
TLR9
CpG DNA
TLR structure
Leucine rich repeat motifs
cysteine rich flanking motifs, TIR domain
What adaptor protein does TLRs 1, 2, 5 and 6 use?
MyD88
MyD88 activates?
the transcription factors NF-kB and AP-1
What adaptor ptoein does TLR3 use/
TRIF
What does TRIF activiate?
IRF3 and IRF7 transcription factos
TLRs 7 ad 9 can activate
both pathways
TLRs 7 and 9 in the endosome use
MyD88
MyD88 activates
NF-KB adn IRF7
Major TLF signaling pathways?
MyD88, with expetion of TLR3
TLR4 and the TLR2 subfamily(TLF1, TLR2, TLR6) engage?
TIRAP
How does TLR3 signal?
TRIF
What is TRIF used in conjuction with?
TRAM in the TLR4-MyD88-independent pathway
What are functional roles of TLRs?
influence adaptive repsone–>T cells–>cell mediated immunity
direct antimicrobial response–> bacterial death
tissue injury–> apoptosis of host cells or septic shock
What is produced in the inflammasome?
secreted form of IL-1B and IL-18
What are proinflammatory cytokines?
IL-1B and IL-18
What is the main function of caspase-1?
to cleave the inactive ctyoplasmic precursor forms of two homologous ctyokines called IL-IB and IL-18
What does inflammasomes activate?
the enzyme caspase-1(a protease w cysteine residue in the active site)
a subfamily of 14 NOD-like receptors
NLRP(pyrin-domain-containing protines)
What respond to cytosolic PAMPs and DAMPs by binding other proteins and forming signaling complexes?
inflammasomes
Caspase
important in apoptosis
macrophage mannose receptor (MMR) and DEC-205
a) a cysteine- rich N terminal domain
b) a fibronectin-like domain
c) multiple calcium-dependent (C-type)lectin domains that bind various carbohydrate ligands
The scavenger receptor (SR) family
trimeric complexes of type II transmembrane polypeptides
Have 3 distince extracellular structural domains
a) SR cysteine-rich (SRCR) domain (absent in SR-A II)
b) the collagen-like domain, which is implicated in the binding of polyanionic ligands
c) the alpha- helical coiled-coil domain (absent in MARCO), which is believed to assist in receptor trmerization
What is a group of receptors mediated the uptake of oxidiezed lipoprotiens into cells?
SRs
What are expressed on Mo and mediate recognition/phagocytosis of microorganisms?
SR-A and CD36
What functions as a coreceptor in TLR2/6 recogintion and repsonse to bactrailly derived lipoteichoic acid and diacylated lipopeptides?
CD36
SRs bind various bacterila constituets based on?
negative charges of bacterial LPS, lipoteichoic acid, nucleic acids, B-glucan and proteins…. only bacteria has sugars
What are c-type lectin receptors?
receptors for carboydates
What is the mannose receptor involved in?
phagocytosis of microbes
What do mannose receptors recognize?
terminal D-mannose, L-fucos, and N-acetyl D glucosamine sugars on microbial surface
What does carbohydrate receptors contain a conserved carbohydrate recognition domain for?
microbial mannose, N-acetylglucosamine, and B-glucans
Some of the lectins are soluble proteins found in?
the blood an dextracellular fluids
Other lectins are integral membrane proteins found on
the surfaces of macrophages, dendritic cells, and some tissue cells
What doe receptors for carbohydrates facilitate?
the phagocytosis of the microbes and the secretion of cytokines that promote subsequence adaptive immune repsones
what prevent approach and deny entry of pahtogens at skin and mucous membranes?
physical barriers for innate immunity
What remove debris and pahtogens?
pagocytes
destroys absnomal cells
immunological surveillance
What immune cells are TLRs expressed on?
mcarophages and dendritic cells
What do microbial lipoproteins activate?
mammalian immune cells through TLR2
What does LPS activate?
TLR4
What do bactreial DNA sequences containing unmethylated cytosine-guanomsine dinucleotides(CpGs) work through?
TLR9
What does TLR dependent signaling pathways activate?
NF-KB which results in transcription of pro inflammatory genes
What controsl the adaptive T cell immune response?
Cytokine IL-12
What does activation of TLRs trigger?
antimicrobial pathways that directly kill the pathogens
In what way can actiavtion of the TLRs be detrimental to the host?
- can contribute to tissue injury by inducing apoptosis
- can lead to life thratening symptoms of septic shock
What does epithelia at the portals of entry of microbes provide?
physical barriers, produce antimicrobial substances, and harbor intraepithelial lymphocytes that are believed to kill microbes and infected cells
small cationic peptides that contain both cationic and hydrophobic regions
defensins
What are defensins produced by?
epithelial cells of mucosal surfaces and by granule containign leukocytes, including neutrophils, NK cells, and CTLs
Why is synthesis of defensins stimulated by?
cytokines and microbial products
Defensin A and B are produced by
different cell types
What have direct toxicity to microbes, including bacteria, fungi and enveloped viruses?
defensins
How do defensisn kill microbes?
By inserting into and disrupting functions of the microbail membranes
What regualted activation of cells involved in the infalmmatory repsonse to microbes?
antimicrobial peptides defensins
What are produced by neutrophils and barrier epithelial cells in the skin, gastrointestinal tract and respiratory system?
antimicrobial peptides cathelicidins
What are antimicrobial peptides cathelicidins synthesized as?
18-kD two domain precursor protine and is proteolytically cleaved into two protective peptides
Whay would synthesis and cleavage of antimicrobial peptides cathelicidins be stimulated by?
cytokinds and microbial products
What are the mechanisms of antimicrobial peptides cathelicidins?
direct toxicity to microorganisms and the activation of leukocytes
What can bind and neutralize LPS?
C-termal fragment called LL-37
What plays an anti inflammatory role by beinding to DNA and blocking AIM2 inflammasome activation?
LL-37
What are common at sites in the body that are exposed to the external environment, such as the skin?
mast cells
Why are mast cells found in close proximity to blood vessels?
They can regualte vacular permeability and effector- cell recruitment
How can mast cells regulate the behavior of neighboring cells?
Effector cells through the release of mediators
What are lipid mediators?
prostaglandins, leukotrienes, platelet-activating factors
Mast cells release what preformed mediators?
histamine heparin proteases chondroitin sulfates TNF antimicribial peptides
What effect does lipid mediators have?
- recruitment and activation of monocytes and macrophages
- migration and activation of dendritic cells
What effect do preformed mediators have?
- recruitment and activation of T cells
- recuritment and activation of neutrophils, basophils and eosinophils
- phagocytosis and or antimicrobial activity
- effects on epithelial cells, tight juction protiens, etc..
Functions of monocyte/macrophages
1.activation
2.chemotaxis, tissue inflammation
3. phagocytosis, scavenger function, tissue repair
4effector function
5. antigen presentation
6. immunomodulation
Where do dendritic cells arise from?
A common precursor cell of the myeloid lineage in the bone marrow
What do Dcs further differentiate into?
classical DCs and plamacytoid Dcs
What may arise from monocytes in infalmed tissues?
inflammatory DCs
tissue-redient DCs, the skin, appears early in life and may develop from embryonic precursors
Langerhans cells
What is the matruation of DCs dependent on?
Flt2 ligand, which binds to the Flt3 tyrosine kinase receptor on the precursor cells
Dendritic cells are the most improtant for activation of?
naive T cells
Play a major role in inate responses to infections and in linking innate and adaptive immune repsonses?
DCs
WHat have long membraneous projections and phagocytic capabilites?
DCs
DCs are part of the …. lineage?
Myeloid and arise from a precursor that can also differentiate into monocytes
Does to Mo and Dcs express?
receptors that recognize Ags typically made by microbes and no mammalian cells
What do activated DCs also secret?
cytokines
Where do classical DCs reside?
The skin, mucosa and organ parenchyma
Where do cassical DCs micrate upon actiatioini by microbes?
to LNs where they display microbial protein Ags to T lymphocytes
What are early cellular repsonders to viral infections?
plamacytoid DCs
What does plamacytoid DCs recgonize and produce?
They recognize nucleic acids of intracellular viruses and produe soluble proteins type I interferons, aka IFN-alpha/beta
What have potent antiviral activites?
IFN-ALpha/beta
DC may also derive from
ciruclating monocytes
What do innate lymphoid cells develop from?
Common bone marrow precursor identified by the Id2 transcription factor
What are the 3 major subsets of innate lymphoid cells?
distinguished by expression of distince transcription factors and by cytokines produced
ILC1–>
IL-12 and IL-18
defense against viruses
ILC2–>
IL-25 and IL-33
allergic inflammation
ILC3–>
IL-1 and IL-23
intestinal barrier function; lymphoid organogensesis
What is the function of NK cells?
Recgnize ligands on infected cells or cells undergoing other types of stress
NK cells kill htos…
infected or stressed host cells
what eliminate reservoirs of infection and thus release intracellular pahtoges for phagocytosis?
NK
What do NK cells respond too?
IL-12 produced by macrophages and secrete IFN-gamma
What activates the macrophages to kill phagocytized microbes?
IFN-gamma
When NK cells recognize ligands on targe cells, they?
activate protein tyosine kinases (PTKs)
What are NK cell activating receptors called?
killer cell immunoglobulin (Ig) like receptors (KIRs)
What do Nk cells not kill?
I MHC expressing healthy cells
