B3.004 Innate Immunity Flashcards
pathogen
a microbe that is causing disease
necrotic
dead cells or tissue from injury or disease
apoptosis
cell death as a normal and controlled part of an organism’s growth and development
cytokines
soluble proteins important in cell signaling
chemokine
cytokine that attracts a particular cell into an environment
opsonization
coating a microbe with molecules that can be recognized by receptors on a phagocyte
phagocytosis
process by which a cell engulfs a solid particle
roles of the immune system
defense against infections defense against tumors injure cells induce pathogenic inflammation recognize and respond to tissue grafts and newly introduced proteins
overview of innate immunity
natural or native immunity
present in all individuals at birth
immediate response upon infectious encounters
restricted response without memory
receptors encoded in germline
does not react against host in normal circumstances
innate immunity defense at the site of microbial entry
epithelium of skin, GI tract, and respiratory tract
-physical barrier, antimicrobial molecules, lymphoid cells
innate immunity defense in tissues where microbes breach
macrophages, dendritic cells, and mast cells secrete cytokines
-initiation of inflammation
phagocytes destroy microbes, eliminate damaged cells
innate immunity defense in blood
plasma proteins (complement) promote microbial destruction
innate immunity defense in viruses
induce production of interferons from infected cells to inhibit infection of other cells
induce killing by NK cells
process of innate immunity microbial recognition
recognize structures shared by classes of microbes not present on host cells
enhanced function through the adaptive immune system
PAMPs
pathogen-associated molecular patterns
microbial molecules, shared by microbes of the same type
not on normal host cells
stimulate innate immune response
4 classes of PAMPs essential for survival/infectivity
LPS endotoxin- gram - bacteria
peptidoglycans - bacteria
terminal mannose residues - opportunistic infections
unmethylated CG-rich DNA - intracellular viral infections
DAMPs
damage associated molecular patterns
released from damaged or necrotic host cells
present in injury or infection
PRRs
pattern recognition receptors
innate immune receptors that recognize PAMPs and DAMPs
where are PRRs expressed?
phagocytes
dendritic cells
others
why are cellular receptors present on different cellular compartments?
cell surface to detect extracellular microbes
vesicles where microbes are ingested
cytosol to sense cytoplasmic microbes
what are TLRs and what do they bind?
toll like receptors
extracellular microbes: proteins, lipids, and polysaccharides on cell surfaces
endosomes: nucleic acids
how do TLRs function?
activate transcription factors to stimulate expression of genes encoding cytokines, enzymes, and other proteins
-NFKB family promotes other items involved in fighting infections
extracellular TLRs
1 - bacterial lipopeptides 2 - lipopeptides, peptidoglycans 4 - LPS 5 - flagellin 6 - lipopeptides
intracellular TLRs
3- dsRNA
7- ssRNA
8- ssRNA
9- CpG DNA
run through the steps involved in TLR signaling
- TLR engagement by bacterial or viral molecules
- recruitment of proteins that activate transcription (NFKB and IRFs)
- increased expression of cytokines, adhesion molecules, co-stimulators
- production of type I interferon (IFN alpha and beta)
- generate inflammation
- stimulate adaptive immunity
- antiviral activity
what are NLRs and what do they bind?
NOD-like receptors
family of cytosolic receptors that sense DAMPs and PAMPs in the cytoplasm that contain:
-central NOD (nucleotide oligomerization domain)
-different N-terminal domains
NOD-1 and NOD-2
contain N-terminal CARD (caspase related domains)
- bacterial peptidoglycans in the cell wall
- activated NFKB
NLRP-3
recognizes microbial products, substances associated with cell damage, and endogenous substances in cells in large quantities
enhances production of IL-1b
what is the inflammasome?
NLRP-3 oligomerizes with inactive form of caspase 1
what causes the creation of the inflammasome?
pathogenic bacteria extracellular ATP bacterial products crystals K+ efflux ROS viral DNA
what is the function of the inflammasome?
once activated, the caspase 1 cleaves an IL-1 B precursor leading to activation of IL-1 B and thus generation of fever
what are some results of inflammasome dysregulation?
gout- urate crystal deposits
auto-inflammatory syndromes (periodic fever syndrome if inflammasome is always active)
what are the 4 primary goals of innate immunity
- accumulation/activation of leukocytes and plasma proteins at the site of infection or injury
- kill extracellular microbes
- eliminate damaged tissues
- defend against intracellular infected cells
- NK cells
- cytokines (type 1 interferons) block viral replication in host cells
components of innate immunity
epithelial barrier phagocytes (neutrophils and monocytes/macrophages) dendritic cells mast cells innate lymphoid cells NK cells lymphocytes w limited diversity complement plasma proteins cytokines
what are the functions of the epithelial barrier?
- mechanical barrier of tightly adherent cells
- produce mucous to trap and expel pathogens
- chemical barrier that produces peptide antibiotics such as defensins and cathelicidins
- intraepithelial lymphocytes kill microbes
what are the basic steps of leukocyte recruitment?
- rolling (selectins)
- stable adhesion by integrin binding
- migration through endothelium (diapedesis)
- recruitment to injury by chemokines
most abundant leukocyte in blood
neutrophils
why do neutrophils increase in number rapidly during infection?
stimulated by cytokines secreted by other cells during infections causing hematopoietic stem cells to proliferate and mature neutrophil precursors
first cell to respond to infections
neutrophils
dominant cell of inflammation
neutrophils
how long to neutrophils live?
only a few hours in tissues
dead ones form pus
2 goals of neutrophils
phagocytose microbes in blood and tissues to destroy them
dominant cell of inflammation
what is a band neutrophil?
immature neutrophil
increase in number when the immune system is overwhelmed
describe the steps of an oxidative burst
- microbe is recognized by PRRs and phagocytosis occurs
- membrane closes forming a phagosome
- phagosome fuses with lysosome forming phagolysosome
- phagocyte oxidase converts molecular oxygen into several enzymes: superoxide anions and free radical ROSs
- ROSs work with inducible nitric oxide synthase and lysosomal proteases to destroy microbes
chronic granulomatous disease
cant produce ROS, so you can’t fight infection despite the presence of neutrophils
what cells differentiate into macrophages in the tissues?
monocytes
where are monocytes found?
all connective tissues and organs
how long to monocytes live?
prolonged survival in tissues
what are the functions of monocytes?
ingest microbes in blood and tissues
clear dead tissues
initiate tissue repair
what are the functions of macrophages?
cytokine production that regulates and induces inflammation
phagocytose microbes because of recognition of cell surface receptors
clear dead tissues
initiate repair process
activated by PRRs
respond to cytokines
what is classical macrophage activation?
macrophages activated by immune signals such as TLRs and cytokine IFN-gamma
activated macrophages destroy microbes and induce inflammation (ROS, NO, lysosomal enzymes, IL-1,12,23
what is the alternative macrophage activation pathway?
activation by cytokines IL-4 and IL-13
activated macrophages incite tissue repair and termination of inflammation (IL-10 and TGF-B)
what are dendritic cells and how do they function?
antigen presenting cells
production of cytokines
bridge innate and adaptive immunity by presenting to T-cells
what is present within mast cells
abundant cytoplasmic and vasoactive granules
where are mast cells found
skin and mucosal epithelial
how mast cells activated?
microbial products binding to TLRs antibody dependent (allergic reactions)
how do mast cells impact inflammation?
release vasoactive amines (histamine and tryptase)
-increase capillary permeability
synthesize and secrete lipid mediators and cytokines
-stimulate inflammation
what is the function of NK cells?
identify infected and stressed cells and kill them
- empty cytoplasmic granules into the extracellular space near the infected cell
- granules enter the cell and activate enzymes to induce apoptosis
what type of infections to NK cells fight?
intracellular microbial infections
what do NK cells secrete?
IFN-gamma to activate macrophages
how are NK cells activated?
by cytokines from macrophages and dendritic cells
IL-15 - development and maturation of NK cells
IL-12 and type I IFNs- enhance NK cell killing function
describe ITIMs and their mechanism of action
immunoreceptor tyrosine-based inhibitory motifs (ITIMs)
become phosphorylated on tyrosine residues when receptors bind MHC I (self molecule)
counteract ITAMs blocking NK cell activation
describe the mechanism of action of ITAMs
immunoreceptor tyrosine-based activating motifs (ITAMs)
become phosphorylated on tyrosine residues and recognize their activating ligands
promote activation of cytosolic protein tyrosine kinase
activate other substrates involved in downstream signaling pathways causing cytotoxic granule exocytosis and production of IFN-gamma
when do NK cells act against tumor cells?
when they have stress from DNA damage and malignant transformation
describe NK cell ADCC (antibody dependent cellular cytotoxicity)
antibodies recognize viral glycoproteins expressed on the surface of cells infected w enveloped viruses
NK cells recognize antibodies and kill antibody coated cell
therapeutic intervention in treating tumor cells
alternative pathway of the complement system
triggered when activated complement proteins on microbial surfaces are uncontrolled due to lack of regulatory proteins
innate immunity
classical pathway of the complement system
triggered by antibodies bound to microbes/antigens
adaptive immunity
lectin pathways of the complement system
mannose binding lectin binds to terminal residues on microbial cell surface glycoproteins
innate immunity
3 main functions of complement system
- opsonization and phagocytosis
- inflammation
- cell lysis
describe the formation and function of the MAC
C5 convertase causes proteolysis of C5 to C5b
C5b binds with C6-9
forms a pore in the cell membrane
causes and influx of water and ions and cell death
what is the acute phase response?
plasma proteins of innate immunity increase rapidly with infection
collectins
mannose binding lectins (MBLs)
-recognize microbial carbs, and coat them for phagocytosis
-activation of complement by the lectin pathway
surfactant
-soap like substance in the lung protective from infectious microbes
C-reactive protein (CRP)
binds phosphorylcholine on microbes, opsonizes them for phagocytosis by macrophages
activated classical complement pathway proteins
what are interleukins?
cytokines of innate immunity
soluble proteins that cause signaling to generate immune and inflammatory reactions - stimulated by infection
cytokines responsible for recruitment of neutrophils and monocytes
TNF
IL-1
chemokines
cytokines responsible for fever by acting on hypothalamus
TNK
IL-1 (predominant)
cytokines responsible for acute phase response protein synthesis from the liver (CRP and fibrinogen)
IL-6
cytokines responsible for thrombus formation
TNF at high conc
cytokines responsible for hypotension
TNF at high conc
cytokines responsible for septic shock
high TNF
IL-12 from dendritic cells and macrophages
type 1 interferon
important in viral infections
binds to the virus
blocks enzymes necessary for viral replication
how does type 1 interferon block viral replication?
inhibition of protein synthesis
degradation of viral RNA
inhibition of viral gene expression
source of TNF
macrophages
T cells
mast cells
source of IL-1
macrophages dendritic cells endothelial cells some epithelial cells mast cells
source of chemokines
macrophages dendritic cells endothelial cells T lymphocytes fibroblasts platelets
sources of IL-12
dendritic cells
macrophages
sources of IFN-gamma
NK cells
T lymphocytes
sources of Type 1 IFNs
IFN alpha: dendritic cells, macrophages
IFN beta: fibroblasts
sources of IL-10
macrophages
dendritic cells
T cells
sources of IL-6
macrophages
endothelial cells
T cells
sources of IL-15
macrophages
others
sources of IL-18
macrophages
sources of TGF-beta
many cell types
principal targets and effects of TNF
endothelial cells: activation (inflammation, coagulation) neutrophils: activation hypothalamus: fever liver: synthesis of acute phase proteins muscle, fat: catabolism (cachexia) many cell types: apoptosis
principal targets and effects of IL-1
endothelial cells: activation
hypothalamus: fever
liver: synthesis of acute phase proteins
T-cells: Th17 differentiation
principal targets and effects of chemokines
leukocytes: increased integrin affinity, chemotaxis, activation
principal targets and effects of IL-12
NK cells and T cells: IFN-gamma production, increased cytotoxic activity
T cells: Th1 differentiation
principal targets and effects of IFN-gamma
activation of macrophages
stimulation of some antibody responses
principal targets and effects of type 1 IFNs
all cells: antiviral state, increased MHC 1 expression
NK cells: activation
principal targets and effects of IL-10
macrophages/dendritic cells: inhibition of cytokine and chemokine production, reduced expression of costimulators and class 2 MHC molecules
principal targets and effects of IL-6
liver: synthesis of acute phase proteins
B cells: proliferation of antibody producing cells
principal targets and effects of IL-15
NK cells: proliferation
T cells: proliferation
principal targets and effects of IL-18
NK cells and T cells: IFN-gamma synthesis
principal targets and effects of TGF-beta
inhibition of inflammation
T cells: differentiation of Th17, regulatory T cells
deficiencies associated with chronic granulomatous disease
defective production of ROS
mutations in genes encoding components of the phagocyte oxidase enzyme
deficiencies associated with leukocyte adhesion deficiency-1
absent or deficient expression of B2 integrins causing defective leukocyte adhesion dependent function
mutations in gene encoding B chain of B2 integrins
deficiencies associated with leukocyte adhesion deficiency-2
absent or deficient expression of leukocyte ligands for endothelial E and P selectins, causing failure of leukocyte migration into tissues
mutations in gene encoding a protein required for synthesis of E and P selectin ligands
deficiencies associated with complement C3 deficiency
defect in complement cascade activation
mutations in C3 gene
deficiencies associated with complement C2,C4 deficiency
deficient activation of classical pathway of complement leading to failure to clear immune complexes and development of lupus like disease
mutations in C2 or C4 gene
deficiencies associated with Chediak-Higashi syndrome
defective lysosomal function in neutrophils, macrophages, and dendritic cells, and defective granule function in NK cells
mutation in a gene encoding a lysosomal trafficking regulatory protein
deficiencies associated with HSV-1 encephalitis
defective antiviral immunity in CNS
mutations in TLR3 gene
deficiencies associated with recurrent pyogenic bacterial infections
defective innate immune responses to pyogenic bacteria
mutations in MyD88 gene
