HTHSCI 1DT3 Lecture Notes - Lecture 21: Transforming Growth Factor Beta, Autophagy, Autoantibody
23 Jun 2018
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Barrier function + loss of tolerance
Gut in constant state of immune activation, example is activated lymphocytes in the lamina
propria, and higher than usual level of pro-inflammatory cytokines e.g. IFN-gamma
This is kept in check by immune suppression and the mucosal barrier
Components of GI defense: saliva (anti-microbial peptides and enzymes), acid, proteases,
peristalsis, gut flora, EPITHELIAL BARRIER, BILE, MUCOUS AND MUCUS PRODUCTS (DEFENSINS),
WATER & ELECTROLYTE SECRETION
Gut microbiota: colonises 24 hours after birth; weighs 1-2kg; contains 1014 different organisms,
an individual’s flora is immunologically distinct
Damage to the gut flora by antibiotics causes c.difficile to be able to gain a foothold
Breakdown of mucosal integrity leads to uncontrolled inflammation, even in a normal immune
system (shown by transgenic mice models with patchy disruption of E-cadherin expression
which causes focal increases in mucosal permeability)
Organisation of the mucosal immune system
GALT: including Peyer’s patches, tonsils, adenoids and appendix:
- M cells are interspaced between enterocytes and in close relation to subepithelial lymphocytes and
DCs, whom they present antigen to
- Activated DCs migrate to mesenteric lymphoid tissue activated drain back to mucosa
inflammation + pathogen eradication
- N.B. epithelial cells can also act as non-professional APCs, presenting antigens and activating
lymphocytes by non-classical pathways; they produce a variety of chemokines
IEL:
- between enteroyctes
- are large granular cytotoxic CD8 cells
- have a gamma-delta TCR
- activated by IL-2 and IFN-gamma, may have an alternative activation pathway too
Lamina propria lymphocytes:
- are the effector T cells of the gut immune system, mostly CD4 (helper) cells
- activate cellular immunity (Th1 - intracellular pathogens – viruses, TB, leishmania) via IFN-gamma and
humoral immunity (Th2 – allergens, parasites, bacteria, fungi) via IL-4
- and TH3 (IL-10, regulatory) + Th17 (associated with autoimmunity, cancer and defence against
extracellular bacteria)
- have alpha-beta TCRs
- may be activated by NK cells, mast cells, macrophages
find more resources at oneclass.com
find more resources at oneclass.com
Adaptive Immune responses in IBD
This diagram shows how in IBD, activation of CD4+ regulatory cells by CD4+ T cells activated by DCs and
epithelial cells is blocked
Crohns disease
A Th1-mediated disease
Granulomata are associated with cellular-mediated immunity
CD patient have increased IL-6, -8, -12, -18 and IFN-gamma and TNF-alpha
It may regress in AIDS (where cellular immunity impaired)
Antibodies targeting Th1 cytokines may improve outcome
UC
Used to be thought of as a Th2 disease
Due to increased IgG1 and IgG1:IgG2 ratio, and elevated Il-15
However it is higher elevation of some of the Th1 cytokines listed above under Crohns (IL-6, IL-8,
TNF-alpha, IFN-gamma) AND IL-16
Whilst inactive APCs secrete TGF-beta causing FoxP3 expression and naïve T cell differentiation
into a regulatory T cell; it is thought APCs secreting IL-6 WITH TGF-beta may cause activation of
naïve T cell into Th17 cells, causing inflammation via Retinoid-O receptor-gamma and STAT3:
Maybe Crohns and UC are both Th17 NOT Th1 diseases
Evidence for this idea includes:
Duerr 2000 found IL23R mutations to associate with both UC and CD
in H.hepaticus mouse model IL-23 is essential for inflammation (causes Th17)
in IL-10 KO IL-23 is necessary for chronic inflammation whilst IL-12 isn’t –Yen, 2006
both Th1 and TH17 cells are found in CD patients
find more resources at oneclass.com
find more resources at oneclass.com
Document Summary
Gut in constant state of immune activation, example is activated lymphocytes in the lamina propria, and higher than usual level of pro-inflammatory cytokines e. g. ifn-gamma. This is kept in check by immune suppression and the mucosal barrier. Components of gi defense: saliva (anti-microbial peptides and enzymes), acid, proteases, peristalsis, gut flora, epithelial barrier, bile, mucous and mucus products (defensins), Gut microbiota: colonises 24 hours after birth; weighs 1-2kg; contains 10 14 different organisms, an individual"s flora is immunologically distinct. Damage to the gut flora by antibiotics causes c. difficile to be able to gain a foothold. Breakdown of mucosal integrity leads to uncontrolled inflammation, even in a normal immune system (shown by transgenic mice models with patchy disruption of e-cadherin expression which causes focal increases in mucosal permeability) Galt: including peyer"s patches, tonsils, adenoids and appendix: M cells are interspaced between enterocytes and in close relation to subepithelial lymphocytes and.
