MII2 killing pathogens

what is the role of CD4+ T cells

Help activate B cells and macrophages by releasing cytokines.

what is the role of CD8+ T cells

killing infected target cells, macrophage activation

what are the 4 subsets of Th cell

Th1, Th2, Th17, Tfh

what is the purpose of the different Th subsets

specialised for dealing with different infection types

what is the first signal required for Th cell subset differentiation

T cell receptor recognises an Ag presented by MHC

what is the second signal required for Th cell subset differentiation

Ag presenting cell upregulates B7 to signal to the T cell that the Ag is from a microbe

what is the third signal required for Th cell subset differentiation

usually given by cytokines-- tells the T cell the infection type (eg bacteria, virus, parasite etc), and this which subset to differentiate into

which subset T cells migrate to infection sites once differentiated

Th1,2,17

where does Tfh go once differentiated

remains in the lymph node for interaction with B cells

what are activated (antibody producing) B cells called

plasma cells

what are B cell effector functions defined by

the class/isotype of antibody it produces

what are the types of antibodies (reminder)

what are the three things antigens can help block to prevent pathogen infection

1. penetrating epithelial barrier

2. binding of microbe for infecting of cells

3. binding of toxins to cellular receptors

what does the antibody in the SARS Cov-2 vaccine do

prevents entry to cells by acting on the spike protein

what does the antibody in the tetanus vaccine do

blocks the function of the tetanus toxin

What does the classical complement pathway use for pathogen recognition and what is the advantage of this

Uses antibody (IgM/IgG) to identify the pathogen.

The Ab has very high affinity for its Ag, increasing the specificity and efficacy of complement activation.

what are the three main effector functions of the complement

1. opsonisation to enhance phagocytosis

2. stimulating inflammation by recruiting and activating immune cells

3. lysing microbes and cells

describe opsonisation

pathogens are coated with opsonins (such as C3b),

recognition of C3b by phagocyte,

phagocytosis of pathogen

describe how the complement mediates inflammation (what complement molecules are involved (3) and how do they behave)

C3a, C4a, C5a release during complement activation. They act locally similar to inflammatory cytokines. Eg:

- Recruit cells to infection site

- Activate cells

describe how the complement mediates cytolysis

The membrane attack complex (MAC) forms in the membrane of bacteria. Water enters, ions exit, causing the microbe to burst.

This process can also kill host cells.

reminder: where do macrophages reside

in tissues and blood

reminder: where do neutrophils reside

the blood

what are the 4 steps of phagocytosis

1) Phagocyte detects microbe via PRR, complement, or Ab, and extends pseudopodia to engulf microbe.

2) Membrane invaginates forming an inside out vesicle called a phagosome

3) The phagosome fuses with a lysosome to form a phagolysosome. The lysosome contains the toxic molecules that degrade microbes.

4) The chemicals in the phagolysosome activate and digest the microbe.

what is the action of vacuolar ATPases in the phagosome

Pump H+ into phagosome to acidify the environment

what is the action of phagocyte oxidase and cofactor NADPH oxidase in the phagosome

They initiate the respiratory burst, converting O2 into reactive oxygen species

- Eg hydrogen peroxide

what does myeloperoxidase make in the phagosome and which cells express this

neutrophils express myeloperoxidase which makes HOCl (bleach)

name a proteolytic enzyme produced by neutrophils in the phagosome that degrades bacteria

elastase

how can phagosomes starve the pathogen

withhold nutrients

what are defensins

microbicidal proteins

what enzyme mediates production of peroxynitrite radicals in the phagosome

nitric oxide synthase

how do antibodies make phagocytosis more efficient

Ab bind to microbe (opsonisation) with high specificity and affinity.

Phagocyte binds to Ab via Fc Receptor (FcR)

This is a more efficient detection system than PRRs

what immune process takes advantage of neutrophil death (name and describe this process)

Neutrophil extracellular traps (NETs)

Neutrophil dies via a process called NETosis

Nucleus swells and burst extruding DNA like a net.

The DNA has anti-microbial molecules attached (e.g. defensins, proteases)

Traps and kills bacteria, fungi, and viruses (pus)

What cytokines do T cells use to enhance macrophage and neutrophil killing

IFN-y and IL-17

Phagocytes can bind to the Fc region of an Ab bound to a microbe. Is this detection system more or less efficient than via PRRs?

more efficient

what are granulocytes

White blood cells originating from bone marrow:

neutrophils, eosinophils, basophils

How do granulocytes uniquely help in immune responses

they pre-store effector molecules in granules in the cytoplasm, so that they are ready to release when activated.

describe antibody-dependent cell-mediated cytotoxicity (ADCC)

1. Antibodies bind to the target cell or microbe

2. Fc portion of the Ab binds to the Fc receptor on an innate cell

3. The cell is activated if multiple Fc receptor-Ab interactions occur

4. The cell releases its granules at the target

- This is destructive and causes collateral damage.

which granulocyte can use ADCC on extracellular microbes

eosinophils

what is the weep and sweep response

Tissue dumps fluids then fluids are swept out of body (washes pathogens out of body)

what is the benefit of T and B cells differentiating

if they become memory cells they retain their effector functions (eg Th1/IgM etc) for a faster response

what are 2 benefits for a pathogen infecting immune cells

1. immune cells migrate readily around the host

2. easier to manipulate immune pathways from inside the immune cell

where can intracellular PRRs be found

endosomes (including phagosomes) and the cytosol

what PRRs are found in endosomes

Toll-like receptors TLRs

what PRRs are found in the cytosol

NOD-like and RIG-like receptors

how does Legionella avoid phagocytosis

prevents lysosome fusion with the phagosome

it replicates in the phagosome and eventually the cell will burst

How does Listeria avoid phagocytosis

disrupts the phagosome membrane with Listeriolysin O (LLO) to break out

Lives and replicates in the cytosol and moves between cells with host actin

what cytokine fully activates macrophages

IFN-γ

high levels of which type of T cell is best for macrophage activation

Th1

which cells can produce IFN-gamma

NK cells, T cells Th1 and CTLs (cytotoxic)

what is the result of TB evading phagocytosis so well

chronic infection with continual production of IFN-γ and macrophage activation

reminder: what is the immune response to TB bacteria

granuloma formation

which interferons are stimulated by viral infection (2)

Type 1 interferons: IFN-alpha and IFN-beta

what are the 3 functions of type 1 interferons

1. inhibition of viral gene expression

2. induces apoptosis

3. promote T cell and NK cell activation

how do type 1 IFNs inhibit viral gene expression (3)

- block viral transcription and translation

- viral RNA degradation

- autophagy

what is autophagy

The cell recycles its own organic material

how do type 1 IFNs induce apoptosis (2)

- misfolded viral proteins triggers protein response causing apoptosis

- alters cell response to TNF-alpha from pro inflammatory to apoptosis

How do type 1 IFNs promote T cell and NK cell activation (4)

• Sequester lymphocytes in LN

• Increase cytotoxicity of CTL and NK cells

• Promote Th1 differentiation

• Upregulate MHC class 1

what types of infection do NK cells target (3)

bacteria, viruses, protozoa (and tumour)

how do NK cells compare to cytotoxic T cells

they are the innate counterpart -- they are faster but less precise

why might NK cells be essential over cytotoxic T cells

some pathogens can evade cytotoxic T cells by inhibiting the MHC class 1 presentation

what is necessary for full NK cell activation

IFN-gamma

what do NK inhibitory receptors recognise

ligands on healthy cells such as self MHC class I

what do NK activating receptors recognise

ligands on infected or injured cells -- stress signals

give an example of something that an activating receptor would recognise

MHC class I downregulated and/or stress molecule expression

what is the difference between necrosis and apoptosis

necrosis: uncontrolled cell death, cell rupture releases contents, highly inflammatory

apoptosis: programmed, apoptotic cells cleared by phagocytosis, non inflammatory

how do NK cells use Abs to recognise infected cells

if a microbe leaves an antigen on the surface of a cell upon entry, Abs can bind to that antigen, then the NK cell can bind the Fc region and kill the cell

how do Th1 cells help cytotoxic T cells (2)

produce IFN-gamma and cytokines that stimulate CTL differentiation

what method of cytotoxic T cell identifying infected cells makes them more specific than NK cells

the ability to recognise Ag presented by MHC class 1

how do cytotoxic T cells interact with infected/tumour cells

via forming a synapse between the cells to allow precise control over which cell Is killed

do NK and cytoT cells have the same killing mechanisms

yes

what protein do NK and cytoT cells use to breach an infected cell membrane

perforin

what is released into the infected cell via the perforin pores

granzyme

what does granzyme do

induce apoptosis

what is the second mechanism for NK/CTL cell killing (name)

Fas/FasL mediated

describe this mechanism

Target cells express Fas.

CTL/NK cells express FasL (ligand) which activates Fas.

Fas activation induces apoptosis.

which cells recognise MHC class II

CD4+ Th cells

what is cross-presentation

a process that allows specialised dendritic cells to take up extracellular antigens and present them on MHC class I instead of class II

what is the purpose of cross-presentation

be able to activate CD8+ (cytotoxic) T cells

When can Abs detect intracellular pathogens

during movement between cells

which complement molecules are involved in the membrane attack complex (4)

C6-C9

which complement molecules are involved in activating the classical pathway

C1

which complement molecules are involved in activating the alternative pathway

C3

which complement molecules are anaphylatoxins.

and what are anaphylatoxins

C3a, C4a, C5a

they are proinflammatory peptide fragments