2. Innate immunity Flashcards
Receptors involved in tight binding of neutrophils
- s-Le^x => E-selectin
- CXCL8R (IL-8 R) => chemokine CXCL8 (IL-8)
- LFA-1 (alphaL:beta2) (integrin) => ICAM-1
Involved in tethering and rolling of neutrophils
Selectins (E-selectin)
Involved in tight binding of neutrophils
Integrins (ICAM-1)
Anti-microbial effects of neutrophils
1) Phagocytosis (intravesical killing which can be oxygen dependent or independent, degrad. by lysosomal enzymes)
2) Degranulation (frustrated phagocytosis)
3) NETs (extracellular DNA trap
4) (Superoxide production)
Types of transendothelial migration
Paracellular and transcellular
Neutrophil swarm
Coordinated chemotaxis. Steps:
1) Scouting (DAMPs and/or PAMPs)
2) Amplification (Cluster of necrotic neutrophils, gets an ECM devoid region at the injury site)
3) Stabilization (Monocytes appear)
Immature dendritic cells
- Reside in peripheral tissues
- High phagocytic activity
- Macropinosome
Mature dendritic cells
Appears when immature dendritic cell has taken up an antigen in case of pathogen invasion/inflammation
- In deep cortex of lymph node
- Present antigens to T cells
- No phagocytic activity
- Costimulation
Human dendritic cell populations
1) Myeloid
- Conventional DC1 (cDC1)
- Conventional DC2 (cDC2)
2) Plasmocytoid DC (pDC)
3) Monocyte derived DC
Monocyte derived DC functions
- TNF
- iNOS
- Bacterial antigens
- Secondary immune responses
Zipper hypothesis of Fc mediated phagocytosis
Fc receptor connected to actin, stretches and wraps around the pathogen
Frustrated phagocytosis
- Phagocyte attaches to surface via Fc receptors
- Lysosomes moves to attached surface
- Lysosomal contents released into extracellular space
Maturation of phagosome
“Phagolysosome”
Fusion of phagosome with endosomes and lysosomes
- Endosome enters cell via endocytosis with a clathrin-coated pit
- Lysosomes from golgi, contains hydrolytic enzymes
Surface receptors of phagocytes
- Opsonic receptors: Fc and complement receptors
- PRRs
Opsonization
Facilitation of phagocytosis by binding of antibody or a complement protein to the antigen
- Then phagocytic cells can take up antigen through complement receptor and/or Fc receptor
Used to split antibody
Papain (-> Fab and Fc)
Fc receptors
- Fcg
- Fce
- PolyIg
- FcRn (neonatal)
Fcg receptor
- Bind IgG
- Facilitate phagocytosis
- Zipper mechanism, respiratory burst of macrophages
- May suppress function of B cells (FcR IIb)
Fce receptor
- Bind IgE
- High affinity form on mast cells and basophils
- Plays role in allergy
PolyIg receptor
- Bind polymeric antibodies (IgA)
- Plays a role in transcytosis through epith. of mucus membrane
FcRn receptor
- Neonatal
- Bind IgG
- Transfer of passive immunity to fetus
- Protects IgG from degradation
Intravesical killing - Oxygen dependent microbicidal activity
1) Peroxidase-independent
- NADPH oxidase
2) Peroxidase dependent
- Lysosome with myeloperoxidase
- Catalase from peroxisomes
Intravesical killing - The nitric oxide pathway
1) IFNγ -> activate inducible NOS -> NOS w/tetrahydrobiopterin -> L-arginine + O2 to NO
2) TNF skip first step, rest same as IFNγ
Pus content
Alive + dead neutrophils and tissue debris
CGD
Chronic granulomatosis disease
- Phagocyte oxidase deficiency
- Granuloma formation, skin infections, gingivitis
Innate-like cells (between innate and adaptive)
- iNKT cells
- MAIT cells
- γδ T cells
- Innate like cells (ILCs)
- B1 B cells
- Marginal zone B cells
NK cells
- Kill virus infected and tumor cells
- No B nor T cell receptor
- Have activating and inhibitory receptors
- Attacks cells with no MHC class I, that contain activating ligands
- Might attack cells with MHC class I if they have activating ligands (depends on balance)
Inhibitory NK cell receptor
NKG2A (ITIM receptor)
- Ligand: HLA-E with leader peptides from HLA-A, -B, -C and -G
Activating NK cell receptor
NKG2D
- Ligand: MICA, MICB, ULBP
γδ T cell effects
- Lysis of infected and stressed cells
- Cytokine and chemokine production
- B cell help and IgE prod.
- Priming of αβ T cells via antigen presentation
- Dendritic cell maturation
- Regulation of stromal cell function via growth factor production
Innate lymphoid cells (ILCs)
Type I: IFNγ producers (NK cell)
Type II: Th2 cytokines producers
Type III: IL17 or IL22 producers
Pattern recognition receptors (PRRs)
1) Membrane PRRs
2) Secreted PRRs
3) Intracellular PRRs
- Vesicular
- Cytosolic
Membrane PRRs
1) Lectin R
2) NK cell R
3) Scavenger R
4) Complement R
5) Toll like R
Membrane PRRs on macrophages
- Mannose R
- LPS R (CD14)
- TLR-2 and -4
- Glucan R
- Scavenger R
Toll-like receptors (TLR)
- Horse-shoe shape
- Leucine-rich repeats
- PAMP recognition
- Very conserved structures
TLR signal transduction pathway
- Ligand binds
- > Binding of MyD88 adaptor
- > Ser/Thr kinase cascade
- > Phosphorylation of IB degradation
- > NFB translocation to nucleus!
- Induces expression of costimulatory molecules and cytokines (induces increased MHC- and B7 expression in T cells)
Membrane-bound TLRs
- Recognize bacteria
- TLR1:TLR2
- TLR2
- TLR4 (recognize LPS, contains MD2)
- TLR5
- TLR2:TLR6
Intracellular TLRs
- Recognize viruses
- TLR3
- TLR7
- TLR8
- TLR9
Secreted PRRs
Soluble lectins
- Ficolins
- Lung surfactant
- MBL
- Pentraxins (CRP, SAP)
- Cationic peptides
- Antimicrobial peptides (defensins)
- Cathelicidines
- Lipid transporter proteins
- Mindin
- Lipocalin
- C type lectins: C1q, MBL
Cytosolic PRRs
- NOD-like receptors (NLR)
- RIG-I-like receptors
RIG-I-like receptors
- Cytosolic PRRs
- Virus recognition
- Helicase domain
- Cytoplasmic dsRNA recognition
NOD-like receptors (NLR)
- Intracellular bacteria
- Cytoplasmic peptidoglycan recognition
- 20 members
- 4 subfamilies: NLRA, NLRB, NLRC, NLRP
Inflammasome constituents
Cytoplasmic multiprotein oligomer
- NLR
- ASC (CARD + pyrin domain)
- Caspase 1
- Activated by PAMPs or DAMPs
Inflammasome secretions
IL-1β and IL-18 (and IL-33)
(RICK via NOD/IPAF)
-> Inflammatory response via NF-κB or MAPK pathways)
Inflammasomopathies
Autoinflammatory disorders
- IL-1β secretion
- Ex: Gout, Type II Diabetes, Muscle-Wells Syndrome (MWS)
TLR location on gut epithelial cells
Intracellularly on the basolateral surface
Natural immunity of bacteria
Anti-nucleic acid defence
- Prod. restriction endonucleases (cut phage DNA into smaller, non-infectious fragments)
Natural immunity of bacteria - Natural CRISPR Pathway
1) DNA invasion
2) Incorporation into CRISPR (of the invading DNA)
3) Pre-crRNA transcription
4) Guide RNA formation
5) Cas9 activation
6) Target binding
7) Target cleavage (of the invading DNA)
Time course of immune response
0-4 hrs: Innate immunity
4-96 hrs: Early induced response
>96 hrs: Adaptive immune response (T/B cells)
Innate immunity receptor characteristic
Fixed in genome
Types of macrophages
1) Tissue-resident
- Osteoclasts, Kupffer cells, histiocytes, microglia
2) Recruited
- M1: Classically activated by IFNγ
- M2: Alternatively activated by IL-4 and IL-13
M1 macrophage
- Classically activated by IFNγ
- Proinflammatory
- Prod. IL-1, TNF and IL-12
- Promote Th immunity
- Antitumor immunity
M2 macrophage
- Alternatively activated by IL-4 and IL-13
- Regulate wound healing
- Prod. IL-1ra, decayIL-1RII, IL-10
- Suppress T cell responses
- Suppress host defense
- Suppress antitumor immunity
Elimination of apoptotic cells by macrophages
1) “Find me” (MCP-1, IL-8)
- Apoptotic cells send attraction signals
2) “Eat me” (Phosphatidylserine++)
- Receptors on phagocyte (bridging protein R, PS R++)
3) “Tolerate me”
- Ingest w/o starting huge reaction
