Innate immunity - in health and disease

Question 1

What is innate immunity?

Answer 1

• First line of defence (initial response to injuries)
• Reacts to microbes and injuries of cells/tissues
• Rapid
• Prevents, controls and can eliminate infections
• Many pathogens have evolved to resist/evade
• Keeps infections in check by activating the adaptive immune system

Question 2

What are the components of the IIS?

Answer 2

• Barriers - physical, chemical, biological
• Effector cells - phagocytes, NK cells, innate lymphoid cells, lymphocytes with limited diversity
• Soluble molecules - effector proteins (complement), inflammatory mediators (cytokines)

Question 3

What are the different barriers we have against pathogens?

Answer 3

• Epithelial surfaces - skin, mucosa of GI/resp tract. Physical barrier to prevent entry
• Chemical barriers - antibacterial enzymes/peptides. Destroy pathogens
• Microbiological barrier - normal flora gives competition

Question 4

How can the barriers fail?

Answer 4

• Loss of barrier integrity predisposes to infection - wounds/burns
• Genetic defects - CF: mucus produced more viscous, inhibits ciliary movements. Causes freq. lung infections

Question 5

What are NK cells?

Answer 5

• recognise infected (eg virus) and stressed cells (eg tumours) and kill them - dont need prior activation like CTL
• express cytotoxic enzymes - perforin (creates pores in cell) and granzymes A/B (lyse cell)
• produce IFN-gamma to activate macrophages

Question 6

How do NK cells and macrophages cooperate with each other?

Answer 6

• Macrophages produce IL-12, which activates NK cells

- NK cells then produce IFN-gamma, activating macrophage to enhance its killing

Question 7

How do NK cells recognise target cells?

Answer 7

• Have inhibitory and activating receptors
• Inhibitory receptors recognise ligands on healthy cells
• All nucleated cells have MHC I, which is recognised by inhibitory receptor, blocking the activating receptors (stops attack of healthy autologous cell)
• Activating receptors recognise infected/ stressed cells
• The outcome of the NK interaction is determined by the integration of the 2 signals

Question 8

What happens with NK and healthy cells?

Answer 8

• Healthy cell has MHC class I
• Inhibitory receptor recognises this and stops the activation
• No cell killing

Question 9

What happens with NK and virus-infected and malignant cells?

Answer 9

• Activating receptors recognise ligands that are induced on unhealthy cells
• Both downregulate the expression of MHC I
• Inhibitory receptors are not ligated by MHC I, signals from activating receptors arent blocked, NK cells attack and kill the cell

Question 10

How do the NK receptors cause their actions?

Answer 10

• Cytoplasmic tails of inhibitory receptors have immunoreceptor tyrosine-based inhibitory motif (ITIM) - engages phosphatases that block the signalling pathways triggered by activating receptors
• Activating receptors have immunoreceptor tyrosine-base activation motif (ITAM)
• ITAMs engage protein TK-mediated events - promotes target cell killing and cytokine secretion by NK cells
• ITAMs may be located in cytosolic portion of adaptor molecules (DAP12)

Question 11

How do NK cells kill the target cells?

Answer 11

• Perforin forms pores in the membrane, allowing delivery of granzymes
• Granzyme A,b,c initiate apoptosis by activating caspases
• Granzyme B can trigger mitochondrial apoptotic pathway

Question 12

What defects can we have in NK cells?

Answer 12

• Part of broader immunodeficiency (Chediak-Higashi)
• Complete absence of circulating NK cells
• Functional NK cell deficiencies (normal numbers)
• HSV - fatal viral infections

Question 13

What are innate lymphoid cells (ILCs)?

Answer 13

• Lymphocyte-like cells - have similar functions but dont express TCRs and have no clonal expansion/ differentiation properties
• Ready to act - produce cytokines
• Faster responses as innate immunity
• 3 different types depending on cytokine activation

Question 14

What are the 3 classes of ILCs?

Answer 14

• ILC1 (Th1-like) = produces IFN-g -> defence against viruses
• ILC2 (Th2-like) = produces IL-5 + IL-13 -> allergic inflammation
• ILC3 (Th17-like) = IL-17 + IL-22 -> intestinal barrier function; lymphoid organogenesis

Question 15

What are lymphocytes with limited diversity?

Answer 15

• Combine features of lymphocytes and innate cells
• Express Ag receptors (TCR, BCR)
• Recognise rather limited number of Ags
• Respond in early stages of immune response
• 4 types: gamma/delta T cells; NK-T cells; B-1 B cells; MZB cells

Question 16

What are gamma delta T cells?

Answer 16

• Most T cells have alpha beta TCR, few have gamma delta TCR
• Less diverse TCRs
• Recognise Ags that arent peptides
• Local protection in epithelia

Question 17

What are NK-T cells?

Answer 17

• Express TCR (less diverse recognition)
• Also express cell surface markers found on NK cells
• Present in epithelia and lymphoid organs
• recognise lipids bound to CD1 (MHC-1 related molecule)

Question 18

What are B-1 B cells?

Answer 18

• peritoneal cavity, mucosal tissue (not lymphoid or BM)
• produce mainly natural low-affinity IgM, directed against polysaccharide and lipid ags
• Fast response to bacteria in the gut

Question 19

What are Marginal zone B cells (MZBs)?

Answer 19

• Found in spleen and lymph nodes
• Produce mainly IgM class abs, directed against polysaccharide
• Rapid responses to polysaccharide-rich blood-borne bacteria

Question 20

What do phagocytes do?

Answer 20

• indentify, ingest and destroy pathogens
• e.g. neutrophils, macrophages and DCs
• protection from pathogens
• disposal of damaged/dying (apoptotic) cells
• processing and presentation of antigens (Ag)
• Chemotaxis to site of infection, attach and engulf the microbe
• lysosome-phagosome fusion - kill them in phagolysosome

Question 21

What phagocyte defects are there?

Answer 21

• Chronic granulomatous disease
• Chediak-Higashi
• Leukocyte adhesion defects (LADs)

Question 22

What is chronic granulomatous disease?

Answer 22

• Mutation in NADPH component
• Defect in oxidative burst
• Usually in phagolysosome, the oxygen will be converted into a superoxide anion -
  reacts with water to make more ROS - killing the microbe
• Cannot make this in CGD, so cant kill phagocytosed microbe -> recurrent infections

Question 23

What is Chediak-Higashi syndrome?

Answer 23

• Caused by rare genetic disease, causing defective lysosomal trafficking regulator (LYST)
• Leads to defective phagosome-lysosome fusion - pathogens cant be killed and so causes recurrent infections
• Also get neutropenia
• giant granules in the cytosol of neutrophils - cant kill microbes

Question 24

What are leukocyte adhesion defects?

Answer 24

• Defect in b2-chain integrins (LFA-1, Mac-1) - decreased no. of integrins on phagocytes
• Defect in selectin ligand
• Defective neutrophil chemotaxis
• Means that neutrophils cannot get from the blood into the tissues

Question 25

What are TLRs?

Answer 25

• Recognise pathogens
• present on phagocytes, mucosal epithelial cells and enodthelial cells
• TLR1,2,4,5 are on cell surface -> detect EC pathogens
• TLR3,7,8,9 inside cells -> detect microbial nucleic acids

Question 26

What happens if there are defects in TLRs?

Answer 26

• Defect in signalling - MyD88 defect leads to bacterial pneumonia
• Polymorphism in TLR genes predisposes to bacterial infections, asthma and autoimmunity

Question 27

What deficiencies are there in complement proteins?

Answer 27

• C2, 4, 1q deficiency -> SLE-like syndrome
• C3 deficiency -> frequent serious infections with pyogenic bacteria
• C5-9 (MAC) deficiency -> disseminated infections with neisseria

Question 28

What deficiencies are there in complement regulatory proteins?

Answer 28

C1 INH deficiency

• Increased cleavage of C4 and C2
• Oedema in skin/mucosa -> abdominal pain, vomiting, diarrhoea, airway obstruction
• hereditary angioedema

DAF, CD59 deficiency

• recurrent intravascular haemolysis (RBC lysis)
• paroxysmal nocturnal haemoglobinuria