Lecture 11: The cellular arm of the innate immune response

Question 1

What makes up the cellular arm of innate immunity?

Answer 1

• Phagocytes
• Interferons
• Natural killer cells

Question 2

What are the 3 major classes of phagocyte?

Answer 2

Neutrophil
Eosinophil
Macrophage

Question 3

Give 2 types of granulocytes

Answer 3

Neutrophils and Eosinophils

Question 4

Why are neutrophils and eosnophils granulocytes?

Answer 4

Because their cytoplasm is granular. They contain numerous lysosomes and secretory vesicles (or granules)

Question 5

Phagocytes seek, engulf and destroy

Answer 5

Phagocytes seek, engulf and destroy

Question 6

What is another name for neutrophils?

Answer 6

polymorphonuclear leucocytes

Question 7

Why are neutrophils also called polymorphonuclear leucocytes?

Answer 7

Because of their multilobed nucleus

Question 8

What is the most common type of granulocyte?

Answer 8

Neutrophils

Question 9

Describe neutrophils

Answer 9

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.

Question 10

What are neutrophils rapidly recruited to sites of infection by?

Answer 10

activated macrophages

peptide fragments of cleaved complement proteins (

and by some PAMPs

Question 11

Describe macrophages

Answer 11

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.

Question 12

What do eosinophils help to do?

Answer 12

Destroy parasites

Modulate allergic inflammatory responses.

Attack cells covered in complement

Question 13

What do phagocytes do?

Answer 13

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

Question 14

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.

Answer 14

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.

Question 15

What are the granules?

Answer 15

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.

Question 16

What does NADPH oxidase do?

Answer 16

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

Question 17

“Most macrophages survive this chemical and enzymatic barrage, but neutrophils normally do not”. Is this true?

Answer 17

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.

Question 18

What is pus made up from?

Answer 18

Dead neutrophils/pathogens

Question 19

What is the usual colour of pus?

Answer 19

Typically white/cream in colour but can be green/yellow because of release of copper-containing compounds and myeloperoxidase from the dead neutrophils

Question 20

What does the addition of sialic acid to capsule components do?

Answer 20

Addition of sialic acid to capsule components avoids complement attack and subsequent engulfment e.g. Neisseria gonorrhoeae (already discussed)

Question 21

Can gonnorhoea be engulfed?

Answer 21

No. Even when it is, it produces a virulence factor that protects against the respiratory burst

Question 22

“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?

Answer 22

Yes

Question 23

"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?

Answer 23

Yes

Question 24

"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?

Answer 24

Yes

Question 25

What aids the killing frenzy?

Answer 25

Inflammation

Question 26

Is it true that the symptoms if inflammation have been recognised for a long time medically?

Answer 26

Yes

Question 27

What are the symptoms of inflammation?

Answer 27

Pain Redness Heat Swelling

Question 28

Dolor meanin

Answer 28

Pain

Question 29

Rubor meaning

Answer 29

Redness

Question 30

Calor meaning

Answer 30

Heat

Question 31

Turgor meaning

Answer 31

Swelling

Question 32

Describe how inflammation occurs

Answer 32

- 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.

Question 33

What can go wrong with inflammation?

Answer 33

Systemic release of inflammatory cytokines can lead to excessive blood vessel dilation, resulting in sudden lowering of blood pressure (shock).

Question 34

What happens in widespread inflammation?

Answer 34

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

Question 35

"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?

Answer 35

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

Question 36

When double stranded RNA is detected by TLR9, what is activated?

Answer 36

Interferons

Question 37

IS it true that interferons are key cytokines in antiviral activity?

Answer 37

yes

Question 39

Describe the steps involved when double stranded RNA induces interferon production ?

Answer 39

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.

Question 40

IFN-γ (Interferon-gamma) is mainly produced by T cells when they recognize their specific antigen.. Is this true?

Answer 40

Yes

Question 41

How do interferons limit viral replication ?

Answer 41

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

Question 42

Is it true that Interferons can inflame the tongue and cause dysfunction in taste bud cells, restructuring or killing taste buds entirely?

Answer 42

Yes

Question 43

NK (natural killer) cells

Answer 43

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.

Question 44

In summary, natural killer cells detect low presentation of proteins and induce apoptosis

Answer 44

In summary, natural killer cells detect low presentation of proteins and induce apoptosis

Question 45

What happens when natural killer cells induce apoptosis?

Answer 45

Apoptosis results in cell fragmentation and phagocytes will engulf the ‘apoptotic bodies’ that are left behind