Innate Immunity

Question 1

Which cells/components play a role in the innate immune system?

Answer 1

Epithelial cells (provide barrier, secrete defensins and cathelicidins[antibiotics])
Phagocytes (non-specifically engulf pathogens)
Dendritic Cells
Complement
Cytokines
NK cells

Question 2

What are the 2 main structures recognised by the innate immune system?

Answer 2

PAMPs (pathogen associated molecular patterns- structures shared by pathogens and required by them to function/exist)
DAMPs (damage associated molecular patterns- eg ATP, heat shock proteins, uric acid, DNA, heparin)

Question 3

How are PAMPs recognised?

Answer 3

By Pattern Recognition Receptors (PRRs)

Expressed on APCs, not clonal, triggering activates the cell immediately

Question 4

Which cells are generally the first to deal with a pathogen that has penetrated epithelial barrier?

Answer 4

Macrophages (differentiate from monocytes)

Question 5

Which cells are attracted second to the site of pathogen breach (attracted by the macrophages)?

Answer 5

Neutrophils?

Question 6

What is the innate response by macrophages and neutrophils to a pathogen?

Answer 6

Ingest non-specifically via surface receptors
Degrade in a phagosome (fuse with lysosomes antomicobial enzymes and proteins)
Generate toxic products in an oxidative burst (NO, H2O2, OH etc)

Question 7

Which cell of the innate immune system is responsible for pus?

Answer 7

Neutrophils (dead ones)=pus

Question 8

What is the role of Toll-Like Receptors (TLRs) in the innate immune system?

Answer 8

TLRs are cell surface proteins that signal to the cytosol and act via NK-kB on promotor regions to upregulate antimicrobial peptides (B7, IL-1, IL-6, IL-8)
Different types to TLRs recognise different PAMPs

Question 9

Describe the role of TLR4 in shock

Answer 9

TLR4 recognises bacterial lipopolysaccharide from gram negative organisms
Systemic activation induces cytokines and co-stimulatory molecules that are responsible for sepsis

Question 10

What is the connection between TLRs and herpes simplex encephalitis?

Answer 10

Some children with HSV encephalitis have been shown to have TLR3 pathway deficiency
TLR3 is expressed in the CNS and controls the IFN response to dsDNA of HSV1

Question 11

What is the role of TLRs in autoimmunity?

Answer 11

TLR engagement by nucleic acids (eg ANA, dsDNA in lupus) in B cells leads to autoantibody formation

Question 12

What is the role of Mannose Binding Lectin (MBL) in the innate immune system?

Answer 12

An acute phase protein
Binds a wide spectrum of oligosaccharides (the universal antibody)
Acts as an opsonin (facilitate uptake by macrophages)
Activates complement (structurally similar to C1q, cleaves C2 and C4)

Question 13

What is the difference between TLRs and NOD-like receptors (NLRs)?

Answer 13

TLRs are surface receptors, NLRs are cytosolic

Detect PAMPs and DAMPs and activate caspases which activate release of IL-1beta and IL-18

Question 14

What is the major role of IL-1?

Answer 14

Produced by macrophages, monocytes and dendritic cells
Increases expression of adhesion molecules (leukocytes migrating to the site)
Resets hypothalamus thermoregulatory centre (fever)
Stimulates IL-6 production

Question 15

What is the major role of TNF?

Answer 15

Transmembrane protein with local and systemic effects
Activates endothelium
Increases vascular permeability
Shock when released systemically

Question 16

What is the major role of IL-6?

Answer 16

Lymphocyte activation (Bcell and Ab formation)
Fever

Question 17

What is the major role of NALP3 inflammasome (Cryopyrin)?

Answer 17

Produced in response to the detection of PAMPs/DAMPs and results in production of IL-1beta and IL-18

Question 18

What conditions result from NALP3 mutation due to “gain of function” leading to excessive release of IL-1?

Answer 18

Familial cold urticaria syndrome (fever, urticaria, conjunctival injection, arthralgia, leukocytosis , after exposure to the cold)
Muckle-Wells syndrome (fever, headache, rash, arthralgia, progressive sensorineural hearing loss, secondary amyloidosis wwith nephropathy)
Neonatal onset multisystem inflammatory disease (NOMID) (fever, rash, impaired growth, abnormal facies, chronic meningitis, cerebral atrophy, prgressive sensorineural hearing loss, uveitis, lymphdenopathy, splenomegaly)
Treated with Anakinra (IL-1 antagonist)

Question 19

NAPL1 single nucleotide polymorphisms are associated with which autoimmune diseases?

Answer 19

Vitiligo, thyroid, SLE, RA, T1DM

Question 20

What is the role of RIG-I helicase receptors?

Answer 20

Cytoplasmic receptors for viral RNA

Respond by releasing IFN-1 alpha and beta

Question 21

What is the main interaction between the innate and adaptive immune systems?

Answer 21

PAMP recognition leads to uprregulation of co-stimulatory molecules on the APC
CD80/CD86 (B7.1 and B7.2)
engages CD28 on the T cell

Question 22

Which interleukin leads to development of a NK cell from a common lymphoid progenitor?

Answer 22

IL-15

NK cells are bone marrow derived? Non-thymic!

Question 23

What is the role of NK cells in the immune system (x2)?

Answer 23

Kill virally infected cells via Ab-dependant Cell mediated cytotioxicity, ot loss of MHC expression
Kill tumour cells via loss of MHC expression

Question 24

How do NK cells stimulate the adaptive immune system?

Answer 24

Release IFN gamma which stimulates macrophages and favours Th1 differentiation

Question 25

What is the role of NK cells in the pregnant uterus?

Answer 25

Protect the foetus from viral infection

Prevent attack of paternal MHC

Question 26

Describe Ab-dependant Cell mediated cytotoxicity involving IgG

Answer 26

NK cells express a receptor for the Fc region of IgG (FC gammaRIII)
IgG binds to viral antigen expressed on cell surface
NK cell becomes activated and kills via perforin-granzyme or Fas pathway

Question 27

Describe Ab-dependant Cell mediated cytotoxicity involving IgE

Answer 27

Activated eosinophils express the high affinity recpetor for IgE FcepsilonR-I
IgE targets helminths, binds to eosinophil via the Fc
Induces degranulation and release of eosinophilic toxic proteins
Kills the helminth

Question 28

Describe how NK cells differentiate self from virally/tumour affected cells

Answer 28

2 NK cells receptors (activating and inhibitory- MHC)
If MHC (inhibitory) receptor, joins with activating receptor–> attack inhibited
If MHC presenting viral antigen–> lethal hit
If MHC not present, no inhibitory signal–> lethal hit

Question 29

Why are red blood cells not attacked by NK cells?

Answer 29

Lack activating receptor

Question 30

Describe the leukocyte adhesion cascade, and deficiencies in LAD I and LAD II

Answer 30

1) endothelium activation by expozure to TNF, IL-1, C5a, C3a, LTB4, histamine, LPS
2) upregulation of selectins which interact with sialyl-Lewis X on the leukocyte –> rolling (deficiency of sialyl-Lewis selectin ligand in LAD II)
3) integrins and IgSF molecules –> adhesion and then diapedesis (go through endothelium to the tissue) (deficiency of integrins in LAD I)
3)

Question 31

What are the main three cytokines responsible for the acute phase response?

Answer 31

TNF
Il-1
IL-6
act on the liver to release specific proteins to fight infection (MBL, CRP), prevent tissue damage (alpha-1 anti trypsin), promote healing (fibrinogen)

Question 32

What is the role of interferons in the innate immune response?

Answer 32

released in response to viral infection by many cells, after viral detection by TLRs, RIG-1 etc
Creates a general anti-viral state in cells:
- induce resistance to replication
- increase MHC-1 expression and antigen presentation
- activate DCs, Macrophages and NK cells