Lecture 16 - Mucosal Immunity - specialised immune regulation at barrier sites

Question 1

Antigenic load of the gut: what does that mean?

Answer 1

A balance is needed between immunity and tolerance in the gut - pathogens vs commensal bacteria

Question 2

T-cell control in the intestinal immune system

Answer 2

T-reg numbers highest in intestine - the number increases after birth

High proportion of T-regs are induced by specific commensal bacteria (Clostridum family)

Question 3

Why are Tregs required in the gut?

Answer 3

Preventing immune responses to commensal bacteria

Question 4

Dendritic cell control in the intestinal immune system

Answer 4

Specialised to promote immune tolerance by generating Tregs for commensal bacteria

Question 5

Macrophage control in the intestinal immune system

Answer 5

Sample bacteria - become hyporesponsive to bacterial stimulation

Maintain local populations of Tregs in the tissue lamina propria

Question 6

How do intestinal bacteria cause regulatory effects on immune cells?

Answer 6

Generation of short-chain fatty acids, brought from fibre

• Act on t-cells - generate Tregs
• Act on DCs - promote Treg generation
• Act on macrophages - induce hypo-responsiveness to bacteria

Question 7

What happens when symbiosis between gut microbiota and immune system breaks down?

Answer 7

Inflammatory bowel disease:
* Ulcerative collitis
* Crohn’s disease

Question 8

Inflammatory bowel disease: what is it?

Answer 8

Dysregulated immune response directed against the intestinal microbiota, in genetically susceptible individuals

Question 9

Crohn’s disease: what part of the body does it affect and when does it appear?

Answer 9

May affect any part of the GI tract but mainly affects the ileum and colon

20-30 years old

Question 10

Ulcerative collitis: what part of the body does it affect, when does it appear, and what cytokines are noted with it?

Answer 10

Affects only the colon

30-40 years old

IL-17 specifically as well as others

Question 11

IBD: what is it, what occur when you have it it, what immune cells are involved with it, what cytokines are involved with it, and what key features are needed for it to occur?

Answer 11

Inflammatory bowel disease

Enhanced t-cell responses against commensal bacteria

Innate - Macrophages and DCs
Adaptive - CD4+ (Th1/17) cells

IL-6, IL-1β, TNF-α, IL-23

• Genetic susceptibility
• Environmental factors
• Immune response
• Luminal microbial antigens and adjuvants

Question 12

IL-12 and IL-23

Answer 12

Specific to myeloid cells but are secreted to affect lymphoid lineages

Question 13

Lung microbiota

Answer 13

Heavily exposed - inflammatory responses must be turned off at a certain point

Question 14

How do the lungs reduce inflammation

Answer 14

• Clearance of self-cells
• Turnover of ECM products

Question 15

Alveolar macrophages: where do they reside, what receptors do they express, and ?

Answer 15

Sit in airways on environment side of epithelial barrier - direct exposure to inhaled particles, allergens, and pathogens

CD200R, TGFβR, and IL-10R

Expression of TREM2

Question 16

Alveolar macrophages: how is their population maintained?

Answer 16

Usually tissue resident and self renewing in earlier years

At older years replenishment from blood monocytes must occur - this must be well-controlled

Question 17

Monocytes play a critical role in respiratory infections

Answer 17

Rewatch leccy

Question 18

Macrophages: what are the types, what do they do, and what pathways are they derived from?

Answer 18

M1 (classically activated) - proinflammatory
M2 (alternatively activated) - immunosuppressive

Question 19

M1 macrophages: what are they, what pathway are they activated by, what ligands are they activated by, and what do they do?

Answer 19

Proinflammatory macrophages that are highly and rapidly responsive to microbes which cause acuteinflammation and produces proinflammatory cytokines

Classical pathway

LPS and INF-γ

• Type I inflammation
• Killing of intracellular pathogens
• Tumour resistance
• Tissue destruction

Question 20

M2 macrophages: what are they, what pathway are they activated by, what do they do, and what occurs when they are dysregulated?

Answer 20

Immunosuppressive macrophages that promote wound repair, healing and remodelling, angiogenesis

Alternative pathway

TGF-β, IL-4, IL-13, and glucocorticoids

• Type II inflammation
• Parasite encapsulation
• Tissue remodelling and angiogenesis
• Tissue promotion
• Activate local stem cells and progenitor cells
• Breakdown and synthesise extracellular matrix components
• Produce mediators that stimulate fibroblasts to differentiate into myofibroblasts
• Phagocytose cellular debris

Type II inflammation and fibrosis

Question 21

Relm⍺: Resistin like molecule ⍺, hallmark signature protein for alternatively activated macrophages. Induced by type 2 cytokines and promotes tissue repair.

Answer 21

Leccy/read

Question 22

Uterine macrophages: what are they, what receptors do they express, what do they do, and what cytokines are they activated by?

Answer 22

M2 macrophages that are present in abundance in the uterus that aim repair the uterus - menstrual cycle

• Expression markers of alternative activation e.g. scavenger receptors CD206, CD163
• High levels of TGFβ receptor

Express genes involved in tissue remodelling and repair pathways e.g. collagen deposition, apoptotic cell clearance, angiogenesis, fibroblast activation

Macrophages in the uterus are highly responsive to the type 2 cytokine IL-4 and express genes involved in tissue remodelling and repair: conserved across species