Innate immune system

Question 1

Innate immune Responses

Answer 1

Limited
Inflammation
Interferons –> anti-viral

Stimulate adaptive immunity

Question 2

Innate receptors

Answer 2

Recognise foreign via common molecular motifs

PAMPs - foreign structures
DAMPs - dying cells

Question 3

What are PAMPs?

Answer 3

Pathogen associated molecular patterns

Highly conserved structures shared by groups of micro-organisms

Question 4

What is the role of PRR?

Answer 4

Pattern recognition receptors

Bind PAMPs
Expressed on APCs
Triggering activates cell

Germline encoded
Limited diversity

Question 5

Types of PRRs

Answer 5

Toll-like receptors
C-type lectin Receptors
Nod-LRs
Rig-LRs
MBL
C1q
CRP

Question 6

Role of Toll-like receptors

Answer 6

Primordial cell surface proteins responsible for host defense

Cell surface = bacterial protein PAMPs
Endosomal = viral - DNA and RNA PAMPs
–> upregulation of cytokines, chemokines and co-stimulatory molecules

Question 7

Role of TLR-4 in disease?

Answer 7

Binds bacterial LPS

Responsible for shock in gram negative sepsis

Question 8

What is IRAK4/MyD88 deficiency?

Answer 8

Genetic disease - autosomal recessive

Loss of signalling distal to TLRs and IL-1, IL-18 and IL-33

–> recurrent invasive pyogenic bacterial infections

Question 9

Role of C-type lectin receptor proteins

Answer 9

Universal Antibody

Acts as opsonin

• -> uptake by macrophages
• -> complement activation

Question 10

Role of NOD-like receptors

Answer 10

Sense PAMPs and DAMPs

Form inflammasomes
Activate caspases –> IL-1beta and IL-18
–> inflammation

Question 11

Role of inflammasomes in gout

Answer 11

Gout = inflammasome mediated disease

Urate crystals ingested by cells –> can’t digest –> burst phagosome –> activation of NALP3 inflammasome –> activates caspase 1 –> IL-1 beta –> acute inflammation

Inflammation decreased by anakinra
Colchincine = uncouples urate crystals from inflammasone activations

Question 12

Role of RIG-1 receptors

Answer 12

Receptors for RNA of viruses

Located in cytoplasm

Release type 1 interferons and inflammatory cytokines

Question 13

Role of plasmacytoid dendritic cells

Answer 13

Respond to viral infection

Release interferons

• -> antiviral state
• -> alter cellular processes to decrease viral replication and cause apoptosis of infected cells
• -> increase NK cell lysis
• -> increased MHC-1 expression

Question 14

Role of phagocytes

Answer 14

Ingest pathogens
Macrophages –> ingest pathogens –> attract neutrophils

Neutrophils and macrophages –> ingest pathogens –> degrade pathogens in phagosome –> oxidative burst

Question 15

What is the oxidative burst?

Answer 15

Generation of toxic products which occurs in phagosome with lyzosome

NO2, O2, H2O2, OH, OCl, OBi

Question 16

What is chronic granulomatous disease?

Answer 16

X linked genetic disease

Loss of gp91 on X chromosome

–> Molecular defect - deficiency of 1 or 4 subunits of NADPH oxidase

–> Loss of respiratory burst in neutrophils necessary for killing intracellular organisms

–> recurrent infection with coagulase negative bacteria and fungi

Question 17

What is the role of dendritic cells?

Answer 17

In tissues as sentinels

Capture antigens and present it with MHC and co-stimulatory molecules

• -> Migrate to LNs and spleen
• -> Initiate immune response - stimulate B and Tcells

Role in T cell tolerance

Question 18

Role of NK cells

Answer 18

Kill virally infected cells

• -> recognise by activation of Ab-Dependant cell-mediated cytotoxicity
• -> recognise by loss of MHC expression by cells

Kill tumour cells
–> recognise by loss of MHC expression

Release IFN-gamma–> activation of adaptive immune system

Question 19

How does Ab-dependant cell-mediated cytotoxicity work for NK cells?

Answer 19

IgG
NK cells express Fc-gammaR-III - receptor for IgG
IgG binds to viral Ag on surface of infected cells
–> activation of NK cell –> kills infected cell via proforin-granzyme or fas pathway

Question 20

How does ADCC work for eosinophils?

Answer 20

Eosinophils express Fc-gammaR-1 receptor for IgE

IgE binds to helminths
Eosinophils bind –> induction of degranulation and release of eosinophil toxic proteins

Question 21

How do NK cells recognize MHC?

Answer 21

Killer inhibitory receptors

Bind MHC
If MHC not present - virus infected or tumour cells –> NK cell activation –> cell death

Question 22

What is the role of MHC Class I?

Answer 22

HLA-A, -B, -C

All cells except RBCs and some neuronal cells

Present intracellular peptides to CD-8 cells - viruses

Allows cytotoxicity by CD-8 cells to eliminate virally infected cells

Question 23

MHC class I processing pathway?

Answer 23

Production of the protein in the cytosol

• -> Proteolytic degradation of proteins by proteasome
• -> Transport of peptides from cytosol to endoplasmic reticulum
• -> Assembly of peptide-MHC complex in endoplasmic reticulum
• -> Transport to cell surface by golgi apparatus
• -> surface expression of peptide-MHC complex

Question 24

What is the role of MHC class II?

Answer 24

HLA-DR, -DP, -DQ

Only on APCs

Present peptides from ingested extracellular antigens to CD-4 cells –> activation of CD-4 cells

Question 25

MHC class II processing pathway?

Answer 25

Uptake of extracellular proteins into endosome

• -> processing of internalized proteins in endosomal-lysomal vesicles
• -> MHC produced in ER and transported to endosome via golgi apparatus
• -> Peptide-MHC complex formation
• -> surface expression of peptide-MHC complex