Lecture 11: The cellular arm of the innate immune response Flashcards
Monday 4th October 2024
What makes up the cellular arm of innate immunity?
- Phagocytes
- Interferons
- Natural killer cells
What are the 3 major classes of phagocyte?
Neutrophil
Eosinophil
Macrophage
Give 2 types of granulocytes
Neutrophils and Eosinophils
Why are neutrophils and eosnophils granulocytes?
Because their cytoplasm is granular. They contain numerous lysosomes and secretory vesicles (or granules)
Phagocytes seek, engulf and destroy
Phagocytes seek, engulf and destroy
What is another name for neutrophils?
polymorphonuclear leucocytes
Why are neutrophils also called polymorphonuclear leucocytes?
Because of their multilobed nucleus
What is the most common type of granulocyte?
Neutrophils
Describe neutrophils
multi-lobed nucleus
They phagocytose and destroy microorganisms, especially bacteria, and thus have a key role in innate immunity to bacterial infection.
short-lived cells
abundant in blood
not present in normal healthy tissues.
They are very sensitive to cleaved complement proteins, detecting them at concentrations as low as 10-11 M.
What are neutrophils rapidly recruited to sites of infection by?
activated macrophages
peptide fragments of cleaved complement proteins (
and by some PAMPs
Describe macrophages
Macrophages are much larger and longer-lived than neutrophils.
They recognize and remove senescent, dead, and
damaged cells in many tissues, and are able to
ingest large microorganisms such as protozoa.
What do eosinophils help to do?
Destroy parasites
Modulate allergic inflammatory responses.
Attack cells covered in complement
What do phagocytes do?
They display cell-surface receptors for PAMPS and chemicals produced by the immune response
They have cell-surface receptors for PAMPs, TLRs, receptors for antibodies, and receptors for complement C3b protein
Binding of ligands to any of these receptors
‘activates’ phagocytes: this enhances killing power
and also causes release of cytokines to attract more
white blood cells. It also induces actin polymerisation
at the site: the phagocyte’s plasma membrane
surrounds the pathogen in an attempt to engulf it in
a large membrane enclosed phagosome.
Binding of ligands to any of these receptors
‘activates’ phagocytes: this enhances killing power
and also causes release of cytokines to attract more
white blood cells. It also induces actin polymerisation
at the site: the phagocyte’s plasma membrane
surrounds the pathogen in an attempt to engulf it in
a large membrane enclosed phagosome.
What are the granules?
The ‘granules’ are dense membrane-bound lysosomal derivatives.
They fuse with the phagosome membrane and release their contents (lysozyme, acid hydrolases) in an attempt to digest the pathogen’s cell walls.
The granules also contain defensins, which destabilise the pathogen’s membranes.
What does NADPH oxidase do?
NADPH oxidase complexes form on the phago-lysosomal membrane.
A respiratory burst (a transient increase in oxygen consumption) by the phagocyte allows the NADPH oxidase complexes to produce highly toxic oxygen-derived compounds such as: Superoxide
“Most macrophages survive this chemical and enzymatic barrage, but neutrophils normally do not”. Is this true?
Yes, Neutrophils appear to be suicide squads and will even use their own DNA to accomplish their task, ejecting it in a sticky web that can trap bacteria, preventing their escape from the killing frenzy.
What is pus made up from?
Dead neutrophils/pathogens
What is the usual colour of pus?
Typically white/cream in colour but can be green/yellow because of release of copper-containing compounds and myeloperoxidase from the dead neutrophils
What does the addition of sialic acid to capsule components do?
Addition of sialic acid to capsule components avoids complement attack and subsequent engulfment e.g. Neisseria gonorrhoeae (already discussed)
Can gonnorhoea be engulfed?
No. Even when it is, it produces a virulence factor that protects against the respiratory burst
“Some bacteria survive and replicate inside neutrophils by expressing virulence factors that protect against the respiratory burst, at least until the neutrophils themselves die and release the ingested bacteria”. Is this true?
Yes
“Some bacteria can neutralise actin polymerisation and therefore phagocytosis by injecting a toxin that disrupts assembly of the actin cytoskeleton e.g. Yersinia pestis, the causative bacterium of plague”. Is this true?
Yes
“Some bacteria can survive inside macrophages, which usually survive the killing frenzy, and can hitch a ride as the macrophages migrate away, converting a local invasion into a severe systemic disease e.g. Salmonella enterica serovar Typhi”. Is this true?
Yes
What aids the killing frenzy?
Inflammation
Is it true that the symptoms if inflammation have been recognised for a long time medically?
Yes
What are the symptoms of inflammation?
Pain
Redness
Heat
Swelling
Dolor meanin
Pain
Rubor meaning
Redness
Calor meaning
Heat
Turgor meaning
Swelling
Describe how inflammation occurs
- Blood vessels dilate, reducing blood pressure, and leading to local swelling and the accumulation of components of the complement cascade, such as C3.
- Activation of TLRs in epithelia and activated
macrophages contribute to inflammation:
the macrophages also secrete cytokines
including chemokines that attract neutrophils.
What can go wrong with inflammation?
Systemic release of inflammatory cytokines can lead to excessive blood vessel dilation, resulting in sudden lowering of blood pressure (shock).
What happens in widespread inflammation?
If widespread inflammation, swelling and blood clotting occurs, this is referred to as septic shock.
This can lead to a significant decrease in blood pressure, which can mean the blood supply to vital organs such as the brain, heart and kidneys is reduced.
If not treated quickly, sepsis can eventually lead to multiple organ failure and death
“There is not much opportunity for the cell to display virus-encoded PAMPs at the cell surface.” Because of this, what does the innate immune system generally rely on when it comes to viruses?
The innate immune system generally relies on:
Recognition of CpG motifs in viral DNA by TLR9: TLRs are usually found on the plasma membrane, but some are also active on internal membranes, where they aid in detecting internal pathogens
Recognition of viral dsRNA that is an intermediate in the life-cycle of many viruses
When double stranded RNA is detected by TLR9, what is activated?
Interferons
IS it true that interferons are key cytokines in antiviral activity?
yes
Describe the steps involved when double stranded RNA induces interferon production ?
Infection with dsRNA Virus:
The infected cell produces Interferon-alpha (IFN-α) and Interferon-beta (IFN-β) in response to the viral dsRNA.
Autocrine Action: The interferons induce changes within the same infected cell.
Autocrine Action: The interferons induce changes within the same infected cell.
IFN-γ (Interferon-gamma) is mainly produced by T cells when they recognize their specific antigen.. Is this true?
Yes
How do interferons limit viral replication ?
① make the virally-infected cell and its neighbours into much less efficient factories for making new viruses:
warn neighbouring cells of infection and induce expression of other cytokines: communication between cells is increased
activate a ssRNA nuclease, which degrades host ssRNA non-specifically, reducing host and virus protein synthesis.
activate other mechanisms that shut down host cell synthesis in neighbouring cells by inhibiting the process of translation
②limit viral spread by promoting apoptosis of the infected cell
③ upregulate the display of viral peptides on the outer membrane of the infected cell: this provides signals for recognition by activated T cells (see later)
④ stimulate expression of the immunoproteasome to process and destroy viral proteins
⑤ They also provide a call for help, attracting NATURAL KILLER CELLS and also activating macrophages.
⑥ They also fight cancers locally
Is it true that Interferons can inflame the tongue and cause dysfunction in taste bud cells, restructuring or killing taste buds entirely?
Yes
NK (natural killer) cells
Many viruses (and cancers) down-regulate the expression of immune system recognition molecules on the cell surfaces.
A cell with unusually low expression of these molecules is therefore likely to be infected or transformed.
NK cells recognise their targets by monitoring the level of expression of these molecules at the cell surface.
NK cells are also attracted to virally-infected cells by IFNs
NK cells then persuade such cells to commit suicide: the target cells die by APOPTOSIS.
In summary, natural killer cells detect low presentation of proteins and induce apoptosis
In summary, natural killer cells detect low presentation of proteins and induce apoptosis
What happens when natural killer cells induce apoptosis?
Apoptosis results in cell fragmentation and phagocytes will engulf the ‘apoptotic bodies’ that are left behind
