Innate Immunity Flashcards
Why do we need both the innate and adaptive immune systems?
We need the innate immune system as it provides immediate and early protection. We 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.
The innate system alone may not be strong enough to protect us from certain pathogens, and the adaptive immune response alone is too slow to protect us 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 of them are glycoprotein hormones that affect the immune response.
CYTOKINES:
- act to modify the behaviour of cells in the immune response
- most (not all) of them are called interleukins (eg. IL-1)
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 ‘see’ microbes?
Macrophages have phagocytic receptors that bind microbes and their components.
They detect substances that are usually presented on pathogens (non-self).
Describe protein-associated molecular patterns (PAMPs).
PAMPs are small molecular motifs conserved within a class of microbes. A vast array include:
- glycans
- lipopolysaccharides
- bacterial flagellin
- lipoteichoic acid
- peptidoglycan
- nucleic variants normally associated with viruses, such as double-stranded RNA
Describe damage-associated molecular patterns (DAMPs).
DAMPs are molecules released by stressed cells undergoing necrosis. They vary greatly depending on the type of cell and injured tissue.
Some of these endogenous danger signals 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 either:
- 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. These put the healthy cells in an antiviral state, meaning that now, 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.
A system of secreted proteins made in the liver that recognise PAMPs on the surface of microbes and ‘decorate’ or ‘tag’ them. The microbes are then cleared by phagocytosis, “opsonised” (C3 sticks to pathogen membranes) or they 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 recognised by MBP (mannan/mannose-binding protein) and other lectins to activate the ‘lectin’ pathway
- membranes that are recognised as “non-self” activate the ‘alternative’ pathway
Complement activation involves a proteolytic cascade.
Describe the structure of natural killer (NK) cells.
They are large granular lymphocytes. They make up about 4% of WBCs. They are lymphocyte-like, but larger with a granular cytoplasm.
They kill certain tumour cells and virally-infected cells. Target cell destruction is caused by the cytotoxic molecules called granzymes and perforins.
How are NK cells activated?
Natural killer (NK) cells are activated by loss-of-self. NK cells possess the ability to recognise and lyse virally-infected cells and certain tumour cells.
An 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 stops the NK cell from killing it. However, 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.
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 aspects of the innate and adaptive immune system.
- in the innate system, we have macrophages, neutrophils, dendritic cells; in the adaptive system, we have lymphocytes
- the innate system acts faster than the adaptive system
- the innate system does not hold any ‘memory’, while the adaptive system does
- the innate system is not specific, while the adaptive system is very specific
- the innate system has a small number of microbial ligands that are highly conserved between pathogens; the adaptive system has billions of possible antigens
- the innate system has germ-line encoded receptors evolved by natural selection which don’t change; the adaptive system has receptors that are generated randomly within the individual, they can’t be inherited
