Innate Immune System Flashcards
Why do humans have both the innate and adaptive immune systems?
- Need the innate immune system as it provides immediate and early protection. Does not require earlier ‘memory’ of the pathogen
- Need the adaptive immune system as it provides ‘memory’ of an infection, making recovery faster the next time we’re faced with the same challenge. Provides ‘ sterile’ immunity
- Innate system alone may not be strong enough to protect from certain pathogens
- Adaptive immune response alone is too slow to protect from a new pathogen.
List some components of innate immunity.
- PHYSICAL BARRIERS: skin, mucosal surfaces
- CHEMICAL BARRIERS: pH, secreted factors
- PHAGOCYTES: monocytes/granulocytes/neutrophils
- INFLAMMATION
- ACUTE PHASE RESPONSE
- CYTOKINES/CHEMOKINES
- COMPLEMENT PROTEINS
- NATURAL KILLER CELLS (NK CELLS)
Describe cytokines and chemokines.
- Both are glycoprotein hormones that are components of innate immunity.
CYTOKINES:
- act to modify the behaviour of cells in the immune response
- most (not all) of them are called interleukins (eg. IL-1)
EXAMPLES
- IL-1 - produced by macrophages and keratinocytes, acts upon lymphocytes and liver, enhances response, induces acute-phase protein secretion
- IL-6 - same as IL-1 but produced by macrophages and dendritic cells
- CXCL-8 (IL-8) - produced by macrophages and dendritic cells, acts upon phagocytes, acts as a chemoattractant for neutrophils
- IL-12 - produced by macrophages and dendritic cells, acts upon naive T cells, has proinflammatory roles and involved in cytokine secretion
- TNF-α - produced by macrophages and dendritic cells, acts upon vascular endothelium, induces changes in endothelium and changes in cell-cell junctions with increased fluid loss
CHEMOKINES:
- act as chemotactic factors, ie. they create concentration gradients which attract (or occasionally repel) specific cell types to a site of production/infection
How do macrophages detect microbes?
- Macrophages have phagocytic receptors that bind microbes and their components.
- Receptors detect substances that are usually presented on pathogens and not on normal host cells (non-self).
5 types of receptors:
Complement
Mannose
Lipid
Scavenger
Dectin-1
Phagocytes also recognise target pathogens in the following way
- By detecting phosphatidylserine on exterior membrane surface (cells undergoing apoptosis)
* By detecting “atypical sugars” (e.g. mannose, fucose, b-glucan) on cell surfaces
* By detecting complement proteins bound to the pathogen surface
* By Scavenger receptors
Describe protein-associated molecular patterns (PAMPs).
PAMPs are small molecular motifs conserved within a class of microbes and present on pathogens but not host cells. A vast array include:
- glycans/ abnormal glycosylated proteins
- lipopolysaccharides - found on outer membrane of Gram-negative bacteria
- bacterial flagellin
- lipoteichoic acid
- peptidoglycan - along with lipoteichoic acid, found on outer membrane of Gram-positive bacteria
- abnormal nucleic variants normally associated with viruses, such as double-stranded RNA
- Pattern recognition occurs through PAMPs
Describe damage-associated molecular patterns (DAMPs).
- Molecules released by stressed cells undergoing necrosis.
- Vary greatly depending on the type of cell and injured tissue.
- Some are proteins - heat-shock proteins and cytokines.
- Non-protein DAMPs include ATP, heparin sulfate and DNA.
Describe Pattern Recognition Receptors (PRRs).
They are host factors that specifically recognise a particular type of PAMP. They are germ-line encoded.
There are several classes of PRR, but functionally they are :
- EXTRACELLULAR: they recognise PAMPs outside of a cell and trigger a coordinated response to the pathogen
- INTRACELLULAR (CYTOPLASMIC): they recognise PAMPs inside a cell and act to coordinate a response to the pathogen
- SECRETED: they act to tag circulation pathogens for elimination
Describe how the interferon system works.
- A virus infects a cell, which then becomes known as the primary infected cell.
- The virus will multiply inside the cell, and, after the cell dies, it will release the viral progeny.
- However, as the primary infected cell is dying, it releases interferons.
- These interferons are picked up by other healthy cells, and they induce the transcription of >400 antiviral genes.
- Put the healthy cells in an antiviral state, meaning that viruses cannot affect them.
List the five PPRs, their ligands, and the outcome of their activation.
RECEPTOR: Lectin receptors
LIGAND: terminal mannose, fucose
OUTCOME: phagocytosis
RECEPTOR: scavenger receptors
LIGAND: bacterial cell walls, modified low-density lipoproteins
OUTCOME: phagocytosis
RECEPTOR: Toll-like receptors (TLRs) (surface or endosomal)
LIGAND: lipopolysaccharides together with CD14 (LPS), lipoproteins, unmethylated CpG, flagellin, dsRNA, and ssRNA (in endosomes)
OUTCOME: phagocytosis, inflammation, cytokine release (TNF, IL-1, IL-12), enhanced killing: reactive oxygen species, NO
RECEPTOR: NOD-like receptors (NLRs) (cytoplasmic)
LIGAND: peptidoglycan from Gram-positive and negative bacteria, some viral DNA, and RNA
OUTCOME: inflammation, cytokine release (IL-1, IL-8)
RECEPTOR: RIG-like receptors (RIG-1 and MDA5) (cytoplasmic)
LIGAND: dsRNA and 5’-triphosphate RNA
OUTCOME: type I interferon production
Describe complement proteins.
- System of secreted proteins made in the liver that recognize PAMPs on the surface of microbes and tag them.
- Microbes are then cleared by phagocytosis, opsonised (C3 sticks to pathogen membranes), or have holes punched in them.
There are three ways of activating them:
- recognition of LPS and other PAMPs by the C1q component of the ‘classical’ pathway
- non-host glycosylation is recognized by MBP (mannan/mannose-binding protein) and other lectins to activate the ‘lectin’ pathway
- membranes that are recognized as “non-self” activate the ‘alternative’ pathway
Complement activation involves a proteolytic cascade.
Describe the structure of natural killer (NK) cells.
- Large granular lymphocytes.
- Make up about 4% of WBCs.
- Lymphocyte-like, but larger with granular cytoplasm.
- Kill certain tumour cells and virally-infected cells.
- Target cell destruction is caused by cytotoxic molecules called granzymes and perforins.
How are NK cells activated?
- Activated by infection of cells.
- Possess the ability to recognize and lyse virally-infected cells and certain tumour cells.
- NK cell has an MHC receptor on its surface.
- With an uninfected cell, it will present the ligand for the MHC receptor, stimulating an inhibitory signal that prevents the NK cell from killing it.
- With an infected cell, they do not present this ligand, so the inhibitory signal is not presented, thus the NK cell stimulates cell death in two ways.
- The first way is that it releases perforin and cytotoxic granules into the infected cell, and the second way is that it engages the cell’s death receptors.
APPLICATION IN CMV
CMV has four gene products which reduce the expression of Class 1 MHC molecules and two class I MHC homologues (UL18 & M144), that give a negative signal to NK cells
NK cells bind HLA-E which carries in its groove a peptide from the leader sequence of classical class I MHC molecules. This same peptide sequence is found on the leader sequence of human CMV. Thus, whilst MHC class I molecules are downregulated in hCMV infected cells, HLA-E is up regulated
There are many specific diseases associated with inherited defects associated with innate immunity. List a few.
- complement - core defects (eg. C3) linked to the development of autoimmune diseases such as lupus
- complement - non-core defects linked to susceptibility to specific types of pathogens such as Neisseria (meningitis)
- macrophage deficiencies - chronic granulomatous disease (CGD); no oxidative burst for bacterial killing
- macrophage deficiencies - IRF8 (transcription factor) mutations linked to susceptibility to TB
- Aicardi-Goutieres syndrome is associated with constitutive production of inflammatory cytokines (defect in regulation of cytokines)
- lack of interferon-responsiveness - sensitivity to viral infections (eg. measles)
Compare the innate and adaptive immune systems.
- in the innate system, there are macrophages, neutrophils, dendritic cells; in the adaptive system, there are lymphocytes
- the innate system acts faster than the adaptive system. Maximal activity of adaptive system and antibody/memory lymphocyte production begins long after beginning of infection while innate system reaches high activity very soon after
- the innate system does not hold or generate any ‘memory’, while the adaptive system does
- the innate system has low specificity, while the adaptive system is very specific
- the innate system recognises a small number of microbial ligands that are highly conserved between pathogens; the adaptive system recognises billions of possible antigens
- the innate system recognises based on germ-line encoded receptors evolved by natural selection which don’t change; the adaptive system recognises based on receptors that are generated randomly within the individual, they can’t be inherited
Give the sites of microbe entry
Conjunctiva
Capillary
Scratch, injury
Skin
Anus
Urinogenital tract
Alimentary tract
Respiratory Tract
