5 - Induced Responses of Innate Immunity Flashcards
The innate immune system recognises microbial elements that are often essential for survival of microbes
- Ensures that the targets of innate immunity cannot be discarded by microbes in an effort to evade recognition by the host
- Host cell pattern recognition receptors (PRRs) recognise pathogen associated molecular patterns (PAMPs)
Examples of target of innate immunity that is indispensable for microbes
- Double stranded viral RNA (essential intermediate in life cycle of viruses)
- LPS and lipoteichoic acids
Cellular locations of pattern recognition receptors of the innate immune system
Extracellular, Cytosolic and endosomal
Toll like receptors
- Family of PRRs expressed on many cell types that recognise products of a wide variety of microbes and molecules released by dying cells
- 9 different functional TLRs in humans (TLR1-TLR9)
Examples of bacterial products that bind to TLRs
LPS (gram -‘ve) and lipoteichoic acid (game +’ve)
Examples of nucleic acids that bind to TLRs
- dsRNA
- ssRNA
- Unmethylated CpG dinucleotides
How is ssRNA distinguished from host/self ssRNA
By their location within endosomes and by high guanosine and uridine content
End result of TLR recognition of microbial ligands
- Expression of genes whose products are important for inflammatory and antiviral responses
- Ligand induced TLR dimerisation brings the TIR domains of the cytoplasmic tails of each protein close to one another
- Leads to recruitment of TIR domain containing adaptor proteins which facilitate the recruitment and activation of various protein kinases
- Leads to activation of different transcription factors
Major transcription factors that are activated by TLR signaling pathways
- Nuclear factor kB(NF-kB)
- Activation protein 1 (AP-1)
- Interferon response factor 3 (IRF3)
- IRF7
C type lectin receptors
Cellular receptors that recognise carbohydrates on the surface of microbes facilitate the phagocytosis of the microbes and the secretion of cytokines that promote inflammation and subsequent adaptive immune responses
Where are c type lectin receptors found
- Integral membrane proteins found on the surfaces of macrophages, DCs, and some tissue cells
- Other lectins are soluble proteins in the blood and extracellular fluids
Types of plasma membrane C type lectins with specificities for different carbohydrates
- Mannose
- Glucose
- N-actylglucosamine (GlcNAc)
- β-glucans
Inflammatory response
- Bacteria trigger macrophages to release cytokines and chemokines which cause vasodilation
- Leukocytes move to periphery of blood vessel as a result of increased expression of adhesion molecules by endothelium
- Leukocytes extravasate at site of infection
- Neutrophils engulf and kill the microbes
- Blood clotting occurs
When do blood monocytes differentiate into tissue macrophages
- During inflammation
- Monocyte binds adhesion molecules on vascular endothelium near site of infection and receives chemokine signal
- Monocyte migrates into tissue
- Monocyte differentiates into macrophage
Adhesion molecules that control immune cell movement
- Selectins
- Integrins
- Immunoglobulin superfamily
Selectins
- Bind carbohydrates
- Initiate leukocyte-endothelial interaction
- e.g. P selectin
Integrins
- Located on phagocyte
- Bind to cell adhesion molecules and extracellular matrix
- Strong adhesion
- E.g. LFA-1
Immunoglobulin superfamily
- Various roles in cell adhesion
- Ligand for integrins
- e.g. ICAM-1
Multistep process of neutrophils leaving blood and migrating to sites of infection
- Rolling adhesion, tight binding, diapedesis, and migration
- Binding of a chemokine such as CXCL8 (IL-8) to its receptor on the neutrophil
triggers activation of integrin LFA-1 - Inflammatory cytokines such as TNF-⍺ are also necessary to induce expression of adhesion molecules such as ICAM-1,
ligand for the integrin, on vascular endothelium - Tight binding between ICAM-1 and integrin arrests
rolling and allows neutrophil to squeeze between endothelial cells that form blood vessel wall
Phagocytosis
- Phagocyte receptors bind to PAMPs and opsonins including antibody molecules and complement proteins
- Ingested foreign particles are enclosed within phagosome that breaks away from plasma membrane
- Phagosome fused with lysosome to create phagolysosome that contain antimicrobial molecules
What antimicrobial molecules do phagolysosomes contain
- Reactive Oxygen Species (ROS)
- Nitric oxide
- Proteolytic enzymes
Important cytokines and chemokines secreted by dendritic cells and macrophages in response to bacterial products
- IL-1β
- IL-6
- CXCL8 (IL-8)
- IL-12
- TNF-⍺
Local effects of IL-1β
- Activates vascular endothelium
- Activates lymphocytes
- Local tissue destruction
- Increases access of effector cells
Systemic effects of IL-1β
- Fever
- Production of IL-6
Local effects of TNF-⍺
- Activates vascular endothelium
- Increases vascular permeability (leads to increased entry of IgG complement, and cells to tissues and increased fluid drainage to lymph nodes
Systemic effects of TNF-⍺
- Fever
- Mobilisation of metabolites
- Shock
Local effects of IL-6
- lymphocyte activation
- Increased antibody production
Systemic effects of IL-6
- Fever
- Induces acute phase protein production
Local effects of CXCL8
- Chemotactic factor that recruits neutrophils, basophils, and T cells to site of infection
Local effects of IL-12
- Activates NK cells
- Induces the differentiation of CD4 T cells into Th1 cells
Excess TNF production
- Leads to sepsis
- Macrophages activated in liver and spleen secrete TNF-⍺ into bloodstream
- Systemic edema causing decreased blood volume, leading to collapse of vessels
- Disseminated intravascular coagulation leading to wasting and multiple organ failure
- Death
Acute phase proteins
Produced by hepatocytes in response to cytokines produced by macrophages in the presence of bacteria (e.g. C reative protein and mannose binding lectin)
C-reactive protein
Binds phosphocholine on bacterial surfaces, acting as an opsonin, and also activating complement
Mannose binding lectin
Binds mannose residues on bacterial surfaces, acting as an opsonin, and also activating complement
What is the major way by which the innate immune system blocks viral infections
By inducing the expression of type 1 interferons
Type 1 interferons
- Large family of structurally related cytokines that mediate the early innate response to viral infections
- Most important are IFN-α and IFN-β
What produces IFN-α
Major source is plasmacytoid DCs but also produced by mononuclear phagocytes
What produces IFN-β
Many cell types in response to viral infection
Outcomes of interferons
- Inhibition of viral protein synthesis
- Degradation of viral RNA
- Inhibition of viral gene expression and virion assembly
Antiviral response
- Production of IFN-α, IFN-β, and IL-12 (1-5 days)
- NK-cell mediated killing of infected cells (1-6 days)
- T-cell mediated killing of infected cells (2-10+ days)
NK cells
- Cytotoxic cells that play important roles in innate immune responses, mainly against viruses and intracellular bacteria
- Innate lymphoid cells (ILCs)
How can NK cells be differentiated from T cells
As they do not express CD3, (T cell receptor)
Why are NK cells referred to as lymphoid cells and not lymphocytes
Because they do not express clonally distributed diverse antigen receptors like T lymphocytes
Functions of NK cells
Kill infected cells and to produce IFN-γ, which activates macrophages to destroy phagocytosed microbes (important for intracellular bacteria)
How do NK cells kill other cells
Activated NK cells produce perforin, a protein that facilitates the entry of
granzymes into the cytosol of target cells, to initiate a sequence of signalling events that induce apoptosis
Activating and inhibitory receptors of NK cells
- Activating receptors recognise ligands on infected and injured cells, stimulating killing activity of NK cells
- Inhibitory receptors recognise ligands on healthy normal cells, shutting off NK cell activity
Antibody dependent cellular cytotoxicity (ADCC)
- Anti-viral function of NK Cells
- Antibodies bind to virus infected cells
- NK cells bind to antibodies with CD16 receptor
- NK cells release cytotoxic granules and antiviral cytokines to kill infected cells
Two signal hypothesis of stimulation of adaptive immunity
- Activation of lymphocytes requires two distinct signals
- First signal is the antigen
- Second is molecules produced during innate immune responses (e.g. complement, costimulator)
- Ensures that adaptive response are induced when there is a dangerous infection and not harmless antigens (including self)
Examples of two signal hypothesis
- IL-12 stimulates the differentiation of naive CD4+ T cells to the Th1 subset
- IL-6 promotes the production of antibodies by activated B cells
What TLRs detect bacterial lipopeptides
TLR1, 2 and 6
What TLRs detect bacterial peptidoglycan
TLR2
What TLRs detect LPS
TLR4
What TLRs detect bacterial flagellin
TLR5
What TLRs detect dsDNA
TLR3
What TLRs detect ssRNA
TLR7 and 8
What TLRs detect CpG DNA
TLR 9
TLR structure
- Leucine rich repeat motifs
- Cysteine rich flanking motif
- TIR domain
