ILCs in Inflammatory Disease

Question 1

What are the major roles of ILCs?

Answer 1

Roles in inflammatory diseases and in maintenance of gut microbiota.

Question 2

Describe the asthmatic airway.

Answer 2

Increased inflammation in the bronchial tubes.

Question 3

Describe the asthmatic airway during an asthma attack.

Answer 3

Increased swelling, tightening of the muscles in the airway, excess mucus production.

Question 4

Give the main features of asthma.

Answer 4

Goblet cell hyperplasia, increased mucus production, increased ASM contractability and collagen deposition.

Question 5

Give the cytokines released by lung epithelial cells that act upon ILC2s.

Answer 5

IL-33, IL-25 and TSLP.

Question 6

Give examples of allergens involved in asthma.

Answer 6

Pollen and HDM Der p1 Cys protease.

Question 7

Give the cytokines produced by eosinophils and basophils.

Answer 7

Eosinophils - IL-4 and IL-5

Basophils - IL-4 (activates ILC2s)

Question 8

What does the functionality of mast cells depend on?

Answer 8

Their level of activation.

Question 9

What happens when mast cells are activated by IL-33?

Answer 9

Mast cells activate Tregs to produce IL-10, which suppresses ILC2 activity.

Question 10

How are mast cells fully activated?

Answer 10

By IgE crosslinking to FcεRI and degranulation.

Question 11

What happens when mast cells are fully activated?

Answer 11

Mast cells produce lipid mediators, e.g. prostaglandin-2 - which activate ILC2s.

Question 12

Give evidence for the importance of ILC2s in asthma.

Answer 12

• Rag2 -/- IL-2Ry -/- mice have less airway inflammation in papain/IL-33 induced asthma, due to lack of ILC2s.
• Adoptive transfer of ILC2s into these mice increases inflammation.
• Increased ILC2s associated with severe asthma.
• Increased ILC2-derived cytokines in sputum correlates with poorer respiratory function.
• Experienced ILC2s respond more vigorously to secondary challenge.
• Polymorphisms in IL-13/IL-13R associated to paediatric asthma.

Question 13

What is chronic rhinosinusitis?

Answer 13

Condition where the sinus in the nasal cavity is swollen.

Question 14

What cells are expanded in chronic rhinosinusitis?

Answer 14

Eosinophils and ILC2s - drive the inflammation.

Question 15

How do eosinophils and ILC2s cross activate each other?

Answer 15

IL-4 released by eosnophils reinforces ILC2 action, resulting in increased IL-5 production from ILC2s, which activates eosinophils.

Question 16

Give evidence for the importance of ILC2s in allergic responses.

Answer 16

Peripheral blood ILC2 levels are higher in patients with allergic rhinitis (hayfever), sensitised to HDM or grass pollen.

Question 17

How can ILC2 levels be decreased in allergic rhinitis patients?

Answer 17

Through injection of small amounts of allergens - giving some desensitisation effects.

Question 18

What is COPD?

Answer 18

COPD = Chronic Obstructive Pulmonary Disease

- group of lung conditions, including emphysema and chronic bronchitis.

Question 19

What is the main cause of COPD?

Answer 19

Smoking.

Question 20

How do lung ILC2s respond to cigarette smoke challenge in mouse models?

Answer 20

Respond to IL-12 and IL-18, released by lung epithelial cells, by downregulating GATA3 and upregulating T-bet and IFNy -> switch from ILC2 to ILC1 phenotype.

Question 21

What is plasticity in the ILC2 phenotype due to?

Answer 21

Action of IL-1b on ILC2s.

Question 22

How does the ratio of ILCs relate to COPD disease severity?

Answer 22

Higher ratio of ILC1s than ILC2s in COPD patient blood and lungs correlates with disease severity.

Question 23

What does the ILC2 phenotypic switch occur in response to during COPD?

Answer 23

Cigarette smoke.

Question 24

How does IFNy production contribute to COPD?

Answer 24

Stimulates lung epithelial cells to produce more ILC2-activating cytokines.

Question 25

Give the two major ILC1 populations in the human gut.

Answer 25

- NCR- ILC1s (no NKp44) in the lamina propria. | - NKp44+ ILC1s (intraepithelial ILCs)

Question 26

What cell population is expanded in Crohn's disease?

Answer 26

ILC1s - higher numbers associated with increased disease severity.

Question 27

Why are ILC3s also significantly reduced in IBD patients?

Answer 27

ILC3s differentiate to give ILC1s in response to IL-12, released by DCs.

Question 28

Towards which subtype does ILC plasticity tend to be?

Answer 28

Towards ILC1s.

Question 29

Describe the ILC plasticities seen in IBD patients.

Answer 29

ILC3s -> ILC1s | ILC2s -> ILC1s

Question 30

Describe the role of ILCs in liver damage and hepatic fibrosis.

Answer 30

Liver damage leads to IL-33 release, which results in accumulation of ILC2s in the liver.

Question 31

Give evidence for the role of ILC2s in hepatic fibrosis.

Answer 31

- chronic schistomiasis infection is used to induce liver damage in mice. - when mice are given thy1.2 ab that depletes ILCs, there is decreased collagen deposition and therefore decreased liver damage. - addition of ILC2s by adoptive transfer showed standard disease progression.

Question 32

Give examples of when ILCs are involved in inflammation of the skin.

Answer 32

ILC2s - associated with eczema. | ILC3s - associated with psoriasis.

Question 33

Describe the role of ILCs in skin repair.

Answer 33

- Epidermal Notch-1 signalling recruits ILC3s to damaged skin. - TNF helps localise the ILC3s. - IL-17F produced by ILC3s helps to recruit macrophages. - IL-33 expression and the ILC2 response are increased after cutaneous wounding.

Question 34

Give evidence for the role of ILC2s in wound repair.

Answer 34

Mice given injection of IL-33 have increased ILC2s at the wound site, which produce IL-13 and IL-5 to enhance wound closure and re-epithelisation. Mice lacking ILCs have inefficient wound repair.

Question 35

Describe the role of ILC2s in influenza infection.

Answer 35

During influenza infection, there is lots of airway epithelial cell death -> repair stimulated by amphiregulin, released by ILC2s.