balance and regulation in the GIT

the mucosal immune system

• which immune cells are present

• what antibody is constantly secreted

  • by what cells

  • what cells produce defensins

  • what cells produce serotonin

• what lymphoid tissue is present

  • whats in them

• B T cells, CD4, CD8, intraepithelial DCs, macrophages

• IgA

  • plasma cells

  • paneth cells

  • mast cells

• peyers patches - ileum

  • clusters of BT cells, follicular DCs, macrophages

  • form germinal centres

what are the three layers of before the epithelium

• microbiota

• outer mucous layer

• inner mucous layer

whats in each layer

• microbiota

• outer mucous layer

• inner mucous layer

• microbiota

  • non pathogenic bacteria

  • constantly proliferating and passing through the GIT

• outer mucous layer

  • non-sterile layer

  • degrading mucous, microbes using mucin carbs

• inner mucous layer

  • sterile

  • contains IgA, defensins

where in the GIT is a-defensins seen

• where is b-defensins

Paneth cells produce defensins, predominantly α-defensin in the small bowel
and β-defensin in the colon

microbiota benefits

• what vitamins can they produce

  • what is this vit needed for

• what can they breakdown 2

• how do they protect us from harmful bacteria

• vit K

  • needed for clotting factor synthesis

• break down non-digestible carbs (into short chain fatty acids - acetate, butyrate) and degrade toxins into harmless components

• outcompete pathogenic species

what does SCFA producing bacteria stand for

• high levels of them mean a lower risk of what metabolic disease

short chain fatty acid producing bacteria

• lower risk diet obesity and insulin resistance

• they are absorbed and reach the liver and peripheral organs for gluconeogenesis and lipogenesis

• what can influence microbiota

• by what age has a child established adult like microbiota

• medication, diet, lifestyle, disease

• by the age of 3 symbiosis happens

how do these cells keep the GIT in an anti-inflammatory state

• Th17 cytokines 2

  • what cells do they act on

• Tregs

  • control ppn of what

• intraepithelial leukocytes

  • how do they target virally damaged cells

  • what IL is released

• TLR downregulation

  • why

• Th17 produce IL22/17 that act on endothelial cells by inducing defensin expression

• Tregs present in large amounts to control the ppn of effector cells

  • th2 cells are high in abundance

  • th1 lvls kept low (increase is seen in IBD)

• mainly CD8+ that survey and remove damaged/infected cells

  • virally infected cells are detected by MHCI

  • once detected CD8 releases IL15 which targets them for killing

• TLR downregulation

  • tlrs are downregulated on the apical surface of epithelium and are present in cytosol/basal layer

  • NOD can trigger inflammatory cytokine release and autophagy to remove bacteria

IS gut sampling

• what two immune cells are capable of phagocytosis

  • they are also adapted to not produce what type of cytokine, why

• dentritic cells and macrophages

  • they can phagocytose and not produce inflammatory cytokines

  • keeps the GIT in an anti inflammatory state

• DCs in peyers patches produce which IL in response to antigen uptake

  • what does this promote 2

• what can antibodies on FC receptors do to antigens they sample in the gut lumen (DCs can also do this)

• what type of cells are phagocytosed by DCs

• IL10

  • promotes Treg activation and IgA production

• they can transcytose antigens to DCs in lamina propria, DCs sample gut lumen entre cells

• apoptotic cells infected with bacteria

whats the difference in response between when bacteria is detected by sampling and when it enters through epithelium

• when samples = anti inflammatory defence response

• when enters on its own = inflammatory response

sampled bacteria response - anti inflammatory

• why do epithelial cells secrete stromal lymphopoietin TSLP and TGF-B

• DCs respond poorly to TLRs and express IL10 for what antibody release and T cell production

• maintain alternative macrophage phenotype

• to express IgA by B cells, Treg→Th1, Th17

bacteria entering through epithelia - inflammation

• what immune cell enters

• how do they stimulate Th1/17 responses

• DCs

• DCs are activated, make co-stimulatory molecules, inflammatory response

how does Clostridium difficile infect the GIT

• what type of antibiotics cause this

• how does the pathogen cause harm, what is produced

• what leaks into the GIT

opportunistic infection - microbiota depletion (dysbiosis)

• broad spectrum antibiotics kill off commensa

• once colonised they produce toxins

• neutrophils and RBCs

what procedure helps replenish natural microbiota after clostridium difficile

• what has to be regulated before doing it

foecal microbiota transplantation

• donor stool has to be a close relative

• screened for infectious disease

• produced into a bowel prep and given through an NG tube, enema, colonoscope

• same BMI

what two diseases come under inflammatory bowel disease

• ulcerative colitis

• crohns disease

ulcerative colitis

• what part of the GIT does this affect

• what is the main characteristic of this disease

• symptoms

• what other symptoms can patients experience outside the GIT

• inflammation of the colon and rectum

• ulcers develop on the colon mucosa lining

• recurring diarrhoea, abdominal pain, frequent bowel emptying, loss of apetite/weight, fatigue

• painful joints, mouth ulcers, red and swollen skin

crohns disease

• how is this different to UC

• where can it affect in the GIT

• symptoms

• why can blockages occur (link to strictures)

• CD affects all layers of the GIT (epithelium, lamina propria +)

• anywhere in the GIT, commonly ileum or colon terminals (mout-anus)

• rectal bleeding, abdominal pain, diarrhoea, tiredness, fatigue, feeling feverish, mouth ulcers, loss of apetite/weight, anaemia

• patients can have pain when eating due to strictures (narrow), the body attempts to repair this with scar tissue and that can lead to blockages

comparing crohns and ulcerative colitis

• where in the GIT can this occur

• how many layers of the bowel can this affect

• are there non caseating granulomas

• mucosa appearance

CROHNS

• Can occur anywhere in the GI tract

• Affects all 4 layers of the bowel (mucosa, submucosa, muscularis externa, adventitia)

• Inflammation is patchy - Skip lesions

• Non-caseating granulomas are present

• Mucosa can appear cobblestone like

UC

• Affects only the colon

• Continuous inflammation along the length without gaps.

• Only the mucosal layer is affected

• No granulomas but can see pseudopolyps in the mucous

how IBD develops

• what are the two main factors

  • explain how intestinal microbiota can cause iBD

• environmental triggers (commensal bacteria, pathogens, antibiotics, stress) + genetic disposition (disrupted barrier function, dysregulated immune response)

  • gut microbiota can trigger changes which induce IBD

  • excessive activation of the GI immune system towards intestinal bacteria can cause IBD

• crohns only

  • what signalling is activated

  • immune cell response

• both crohns and ulcerative colitis

  • what T helper cell is activated

  • what signalling is involved

• ulcerative colitis

  • what type of immune response is triggered

• crohns only

  • NOD2 signalling

  • autophagy chemokines

  • T cell proliferation

• both crohns and ulcerative colitis

  • Th1/17 activation

  • TLR TNF signalling

• ulcerative colitis

  • anti-inflammatory signalling

• name the functional role for each gene

• explain how this links to crohns disease

explain the main difference entre irritable bowel syndrome and inflammatory bowel disease

• IBS - experiencing symptoms of pain and irritation

• relieved by defecation

• IBD - autoimmune disease

• more blood markers

explain risk factors IBD

• mucous composition

• defensin

• NOD2 recognition

• permeability entre epithelia

• an altered mucous composition due to mucin genes

• decreased defensin expression from paneth cells

• defective NOD2 protein decreases autophagy

• weakened junctions between epithelial cells

immunology

• what response is triggered when bacteria is detected and enters

• macrophages phagocytose and secrete which interleukins

• dendritic cells recruit which two T cells

  • what are their functions

• what other type of immune cells enter, GCs

• inflammatory response

• pro inflammatory cytokines (IL6/1B/TNFa) and IL12

• Th 1 and 17

  • Th1 - promote inflammation and macrophage activation (M1)

  • Th17 increase inflammation

• granulocytes enter where there is tissue damage (eosinophils and neutrophils)

crohns disease treatment

• what is the main goal for these medications

• name 3 steroids/immunosuppressants P,A,M

• what type of medication are biologicals mab

• if medications dont work what is an alternative method

• focus on reducing inflammation to relieve symptoms and trigger remission

• prednisolone, azathioprine, mercaptopurine

• monoclonal antibodies

• surgery to remove inflamed sections of the GIT

how do these work

• steroids/immunosuppressants

  • prednisolone

  • azathioprine

  • mercaptopurine

• biologicals

  • adalimumab, infliximab

  • vedolizumab

  • ustekinumab

• steroids/immunosuppressants

  • prednisolone - glucocorticoid reduce inflammatory cytokines and T cell proliferation

  • azathioprine - reduce T and B cell proliferation and stimulate T cell apoptosis

  • mercaptopurine - antimetabolite to reduce T cell proliferation

• biologicals

  • adalimumab, infliximab - bind to TNFa and inhibit

  • vedolizumab - binds to adhesion molecule a4b7 integrin and reduces leukocyte recruitment

  • ustekinumab - binds to p40 subunit present in IL12,23

oral tolerance

• what is the function of M cells in the GIT

• how is the immune system taught the difference between pathogenic and non pathogenic molecules

  • what IL do DCs produce to result in no innate immune activation (Tregs)

• what does high antigen presentation rate by DCs do to effector T cells

• they take up soluble proteins and macromolecules

• DCs present the antigen alongside IL10 to trigger no innate immune response

• anergy - ineffective response

coeliac disease

• what is this

• patients have HLA DQ2/8, this allows their DCs to do what

• symptoms

• what is a key histological indication of CD (villi affected)

  • what does this lead to

• name markers present in serology

  • IgA against what enzymes/molecules

• immune mediated inflammatory disease directed towards gluten

• DCs present gluten antigen

• diarrhoea, malabsorption, weight loss, anaemia, irritability, muscular wastage

• VILLOUS ATROPHY - loss of villi and mature epithelium causing reduced absorption

  • anti-TTG tissue transglutaminase

  • can also test for anti-gliadin, anti-endomysial

immunology for coeliac disease

(oral trigger leads to the breakdown of oral tolerance and gluten enters the epithelium)

• what does tissue transglutaminase TTG breakdown (into..)

• DCs present antigen and promote which Th cell

• these cells promote what and activate which other immune cells

• how does this immune cell lead to the secretion of anti TTG antibodies

• IELs target what

• what do epithelial cells upregulate in response to stress by gladin peptides

• gluten into antigenic peptides = gladin

• Th1 cells

• they promote inflammation and support B cell activation

• B cells with receptors to TTG, take up the complex and present gladin and TTG components

  • the T cell recognises the gladin to stimulate B cell to secrete anti TTG antibodies

• they target stressed cells and kill them

• epithelial cells become stressed by gladin peptides and upregulate MICA, MICB and secrete cytokines