Lecture 16 - Mucosal Immunity - specialised immune regulation at barrier sites Flashcards
Antigenic load of the gut: what does that mean?
A balance is needed between immunity and tolerance in the gut - pathogens vs commensal bacteria
T-cell control in the intestinal immune system
T-reg numbers highest in intestine - the number increases after birth
High proportion of T-regs are induced by specific commensal bacteria (Clostridum family)
Why are Tregs required in the gut?
Preventing immune responses to commensal bacteria
Dendritic cell control in the intestinal immune system
Specialised to promote immune tolerance by generating Tregs for commensal bacteria
Macrophage control in the intestinal immune system
Sample bacteria - become hyporesponsive to bacterial stimulation
Maintain local populations of Tregs in the tissue lamina propria
How do intestinal bacteria cause regulatory effects on immune cells?
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
What happens when symbiosis between gut microbiota and immune system breaks down?
Inflammatory bowel disease:
* Ulcerative collitis
* Crohn’s disease
Inflammatory bowel disease: what is it?
Dysregulated immune response directed against the intestinal microbiota, in genetically susceptible individuals
Crohn’s disease: what part of the body does it affect and when does it appear?
May affect any part of the GI tract but mainly affects the ileum and colon
20-30 years old
Ulcerative collitis: what part of the body does it affect, when does it appear, and what cytokines are noted with it?
Affects only the colon
30-40 years old
IL-17 specifically as well as others
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?
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
IL-12 and IL-23
Specific to myeloid cells but are secreted to affect lymphoid lineages
Lung microbiota
Heavily exposed - inflammatory responses must be turned off at a certain point
How do the lungs reduce inflammation
- Clearance of self-cells
- Turnover of ECM products
Alveolar macrophages: where do they reside, what receptors do they express, and ?
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
Alveolar macrophages: how is their population maintained?
Usually tissue resident and self renewing in earlier years
At older years replenishment from blood monocytes must occur - this must be well-controlled
Monocytes play a critical role in respiratory infections
Rewatch leccy
Macrophages: what are the types, what do they do, and what pathways are they derived from?
M1 (classically activated) - proinflammatory
M2 (alternatively activated) - immunosuppressive
M1 macrophages: what are they, what pathway are they activated by, what ligands are they activated by, and what do they do?
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
M2 macrophages: what are they, what pathway are they activated by, what do they do, and what occurs when they are dysregulated?
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
Relm⍺: Resistin like molecule ⍺, hallmark signature protein for alternatively activated macrophages. Induced by type 2 cytokines and promotes tissue repair.
Leccy/read
Uterine macrophages: what are they, what receptors do they express, what do they do, and what cytokines are they activated by?
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
