Innate immune response Flashcards
what do innate system recognize
Receptors for bacterial endotoxin ( lipopolysaccharide)
Recognize terminal mannose residues on bacteria and fungi
recongize DsRNA
recongize unmethylated CG-rich oligonuceoltides in mcicrobial DNA
Recognize PAMPs
recognize DAMPs ( high mobility group box protien 1 (HMBG1)
What are TLRs and the function
Cellular receptor for microbes and damaged cells and they recongize nucliec acid in endosomes and products of extracellular microbes and once recognizing it will activate transcription factors for proinflammatory cytokines and interferons regulatory factors
Mutation in MyD88
adaptor protien of downstream of TLRs will cause recurrent bacterial pneumonia
NLR function
they sense DAMPs and PAMPs in the cytosol and promtoe inflammation but only recognize lipids
- contail Nucelotide oligomerization domain ( NOD)
what are the function of NOD1 and NOD2
NOD1 and NOD2 have N terminal caspase domain and recoginze peptides from bacterial cell wall and generate signlas activating NF-kB which promotes proinflammatory cytokines ( TNF, IL1)
where do you find NOD2
intestinal paneth cells in small bowel and it expresses defensins
mutation in NOD2
inflammatory bowel disease and it may cause crohns disease
what are inflammasomes
multiprotien complexes that assemble in cytosole in response to microbes and generate pro IL1beta and pro IL18 which are cleaved by caspase 1 to become active inducing acute inflammation and fever
NLRP3 inflammasome receptor
( NOD like receptor family pyrin domain containing 3) is expressed in innat eimmune cells including macrophage and neutrophilsw
what induces formation of NLRP3
uric acid by DNA breakdown,
Cholesterol crystals
ATP ( mitochonrdrial damage)
reduced intracellular K ( plasma membrane damage)
ROS
what is pyroptosis
induced by inflammsome formation and is swelling of cells and loss of plasma membrane integrity and release of infalmmtorycytokines
Gain of function mutation, loss of function mutation of NLRP3 will cause what disease
autoinflammatory syndromes ( uncontrolld spontanous inflammation)
Gout
Deposit of urate crystals and IL1beta production
arterioschlerosis
inflammation by cholesterol
Familila mediaterranean fever
mutation in MEFV gene leading to dysfunction of pyrin cuaseing over activation of inflammasomes
RIG like receptors
sense viral RNA and induce type 1 IFN by interacting with MAVS which initaite trasncription factor to make IFN1
Cytosolic DNA sensorys
recognize DsDNA in cytosole and produce IFN type 1 and autophage
how do CDCs stimulate IFN
by STING pathway
DsDNA bind to cyclic GMP_AMP synthase and binds to endoplasmic reticulum and stimulatory of interferon gene ( STING) and causes epression of IFN1
activtaed also by RIG
The components of innate immunity ?
Epithelial barriers
neutrophils
monocytes
macrophages
Monocytes
DC
Mast cells
Neutrophils
Origin: hematopoietic stem cells in the bone marrow.
Markers: Neutrophils express CD15 (also known as Lewis X antigen), CD16 (FcγRIII), CD66b, CD11b/CD18 (β2 integrins), and CD62L (L-selectin).
Function: First line of defense (innate immunity). Neutrophils fight bacterial and fungal infections by phagocytosis, degranulation, production of reactive oxygen species (ROS), and neutrophil extracellular traps (NETs) to trap and kill pathogens.
Mechanism of Action: PHAGOCYTOSIS. They detect pathogens through pattern recognition receptors (PRRs) such as TLRs & NLRs. Then, they undergo chemotaxis by chemokines C5a and IL-8, then recognize and engulf pathogens through opsonization and form phagosomes.
Activation Receptors: Fcγ receptors (FcγR1 opsonization of FcγRIIB inhibit inflammation that bind to antibody-opsonized pathogens (IgG1 and IgG3), complement receptors (CR1 and CR3) that recognize complement-coated microbes, and formyl peptide receptors (FPRs) that detect bacterial peptides.
Inhibition Receptors: immunoglobulin-like receptor (ILT)-3
Inhibition of Neutrophil Activation: interleukin-10 (IL-10) and (TGF-β)
* Mutations: Chediak-Higashi syndrome: defective vesicle fusion and lysosomal function in neutrophils and macrophages.
NK cells
Origin: lymphoid progenitor cells in the bone marrow. They also develop in secondary lymphoid tissues.
Markers: CD56 and CD16 (FcγRIII). (CD16 when they mature).
* Function: for viral infections and tumor cells—> direct killing of infected or transformed cells, production of cytokines (IFN-γ) to enhance immune responses.
Mechanism of Action: Direct killing of virally infected cells or tumor cells; they release perforin to make holes in the cell membrane and facilitate entry of granzymes B to induce apoptosis in target cells. Also, NK cells express death ligands (such as Fas ligand) that trigger apoptosis in target cells.
- Activation Receptors: Activated through antibody-dependent cellular cytotoxicity (ADCC) by engaging FcγRIII (CD16) to recognize and kill antibody-coated target cells (IgG) and NKG2D receptors.
Inhibition Receptors: killer immunoglobulin-like receptors (KIRs), which recognize MHC class 1 on healthy cells.
NK cell–activating cytokines: (IL-15), type I IFNs, and (IL-12).
Cytokines released by NKs (IFN-γ) to activate macrophages.
Monocytes
kidney-shaped or oval nucleus with abundant light cytoplasm
Toll-like receptors (TLRs) (e.g., TLR2, TLR4,
TLR9) - recognize PAMPs
2. Fc receptors (FcRs) (e.g., FcγRI, FcγRII,
FcγRIII) - bind to IgG
3. Complement receptors (CRs) (e.g., CR1, CR3,
CR4) - Bind to C3b
4. Scavenger receptors—facilitate wound
recognition and phagocytic disposal of host
cell debris by macrophages at wound sites
5. Mannose receptors—range of carbohydrates
present on the surface and cell walls of
micro-organisms
6. Dectin-1—β-glucan receptor on fungal wall
7. CD14—Co-receptor with TLR4 for LPS
8. CCR2—Chemokine receptor important in
monocyte recruitment
9. NOD-like receptors (NLRs) - Intracellular
sensors of pathogens
10. SIRPα - Inhibitory receptor
Macrophages
Neuclues is large or round and abdudnt and with phagocytic cytoplasm
has same function and receptors as Monocytes
Eosinophils
biloped neucleus
bright orange red cytoplasm
FcyR
FceR
CCR3
IL5R
CR3
TLR
NK cells
large and round nucleus
scant cytoplasm
. Killer immunoglobulin-like receptors (KIRs) -
control development and function of NK cells
2. NKG2D - Activating receptor for stress-induced
ligands
3. CD16 (FcγRIII) - for IgG, mediates
antibody-dependent cellular cytotoxicity
(ADCC)
4. Natural cytotoxicity receptors (e.g., NKp30,
NKp44, NKp46)
5. CD94/NKG2A - Inhibitory receptor
Natural kiler cells
it kills cells and cancer by cytokine IFN-y
MHC1 inhibits NK cells so when a virus decreases expression of MHC1 it will get activated
what do NK cells secrete
how is it activated
IFNy activating macrophages
IL15, IFN1 and IL12 enhacne development and maturation an IFN1 and IL12 enhance killing function
inflammation steps
1- recruitment
2- phagocytosis and destruction
3- TIssue repair
Recruitment of phagocytes steps
1- Rolling: TNF and IL1 express ahesion molecules E selection and P selectin
neutrphils and mononcytes express ligands for them and causing them to roll to site of infection
2- Firm adhesion: leukocyte express integrins lie LFA-1 and VLA4 and endothelial cells produce chemokines causing also rolling on indothelim
TNF and IL1 act on enodthelim to make ICAM1 and VCAM1 to bind to integrins
3- Leukocyte migration: directed by concetration graidentof chemoattracts
Phagocytosis and desctruction of microbes
neutrophils and macrophage eat the microbe and destroy it by pattern recogniton receptors
it kills phagocytes by ROS and iNOS which makes NO
and makes lysosomal proteases
