Mucosal Immunology Flashcards by Sasha Murdoch

What is the name of the specific immune follicles in the Large intestine?

Lymphoid follicles

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WHat is the name of the specific area related to immunity in the small intestine?

Peyer’s Patch

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What is concentrated in muscosal sites?

Specialised lymphoid tissue

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Why is the immune system highly vulnerable to infection

Due to the fragility and permeability of the tract. Any food we ingest could be contaminated and require an immune response to remove the antigen

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What 5 types of cells are found in the monolayer separating the microbiota from the lamina propria

Enteroabsorptive cell
goblet cells 
neuroendocrine cells
paneth cells 
M cells

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What is the benefit of the villi and crypts

THey provide a large surface area for antigens to interact

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What is the purpose of the Paneth cells

They are defensins

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What occurs in the Peyer’s Patches?

Antigen sampling and immune activation

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What types of cells is the large intestine mostly made up of?

Crypts (not villi), enterocytes and lots of goblet cells and mucus

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Which has the higher bacterial load? the small or large intestine

Large intestine

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Why do enterocytes have a much more important contribution to antimicrobial peptide production in the large intestine?

There are no Paneth cells in the large intestine

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Where do natural killer T cells have a more significant role to play?

In the colon

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What are the main secretors of antimicrobial peptides

The Paneth Cells

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What 3 types of cells capture, initiate the local immune response and carry out effector functions to clear any infection?

Intestinal epithelial associated - innate immunity, antigen capture and effector function
Peyer’s patches and lymphoid follicles - antigen capture and initiation
Lamina propria - effector cells (remove the danger and repair any damage)

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How do dendritic cells capture antigens across the epithelium?

They can extend their processes to capture antigens from the lumen of the gut

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What are the direct antigen sampling organisms of the gut?

The Peyer’s patches

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Describe the structure of Peyers patchs

covered by an epithelial layer containing specialised cells (M cells) which have characteristic membrane ruffles

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What is situated directly below an M Cell?

Dendritic cells

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Describe the steps of the M cells

Uptake of antigen by endocytosis and phagocytosis
Transporation of antigen across the M cells in vesicles released at the basal surface
Antigen is bound to dendritic cells, activating T cells

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What is the major effector molecule in the gut called?

IgA

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What type of cells enter the Peyer’s patches form blood vessels?

T cells

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What happens to the T cells in the Peyer’s patch when an antigen is transported across M cells?

They become activated by dendritic cells

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What is the make up of the humoral intstinal response?

80% IgA
15% IgM
5% IgG

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As peristalsis occurs, what happens to IgA

It is moving and being produced continuously

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How does IgA move accross the membrane from the lamina propria to the lumen?

Endocytosis then transcytosis

What is the function of IgA cells

They bind and neutralise pathogens and toxins to prevent damage to the epithelial cells

What 3 ways can IgA work>

Bind to the antigen in the gut or on the mucus layer Neutralise antigens in endosomes Export toxxins and pathogens from the lamina propria whilst being secreted

What molecule takes over this role in patients who are IgA deficient?

IgM

How frequently are intraepithelial lymphocytes found?

1 in every 10 epithelial cells

What anchors intraepithelial lymphocytes in the epithelium

Expression of Alpha E: Beta 7 integrin

What is the main function of intraepithelial lymphocytes?

To kill infected epithelial cells by initiating programmed cell death

What are the 2 types of intraepithelial lymphocytes?

Virus speciic recognition - TCR/CD8 cells | Stress specific recognition - NK cells

How do TCR/CD8 cells kill?

Via FAS=FASLigand

How do NK cells kill?

Via perforin/granzyme system

Where do specialised T cells in the gut sit?

Next to the epithelial cells: membrane:membrane proximity

Why do they sit so close?

So that they can target a specific cell and minimise the damage to the surrounding cells

Describe 4 proposed mechanisms of mucosal hyporesponsiveness

Anergy or deletion of antigen specific T Cells Generation of regulatory T cells particularly CD4+ TGF Beta producing Th3 cells Both immunosuppressive and induces switching of B cells to IgA production Commensal organisms help regulate local hyporesponsiveness

How is a balance maintained between protective immunity and homeostasis?

Developed sophisticated means of discriminating between pathogen and innocuous antigens Default response to oral administation of portein state of specific peripheral unresponsiveness - oral tolerance T cell and IgE mediated reponses are inhibitored more than serum IgG responses both locally and systemically because these cause aggressive immune responses

In what state does mucosal dendritic cell maturation inhibited

In the presence of commensal bacteria,

How do mucosal dendritic cells become active?

Invasive microorganisms penetrate epithelium

Activated dendritic cells express what?

Strong co-stimulatory ligands

What do immature dendritic cells give?

Weak co-stimulatory signals and induce CD4 T cells to differentiate into regulatory TH3 or Treg cells

What do strong co-stimulatory ligands induce?

CD4 T cells to differentiate into effoector TH1 and TH2 cells

Name the 3 distinct features of mucosal immune system

Anatomical, effector mechanisms Immunoregulatory environment

Describe some of the anatomical features

Intimate relationship between mucosal epithelia and lymphoid tissue Organised lymphoid structures unique to mucosal sites Specialised antigen uptake mechanisms

Describe some of the effector mechanisms

Activated / memory T cell predominate | Natural effector / regulatory T cells

Describe some of the immunoregulatory environment

Active down regulation of immune response | Inhibitory macrophages and tolerising dendritic cells

Why do rural children (living with high intestinal parasites loads) get less alllergy

They have exposure of the developing immune response to certain environmental microorganisms

Describe the speed of innate mechanisms eliminating most intestinal infections

Rapid

How does activation of mucosal immune responses occur?

Activation through ligation of pattern recognition receptors (PRR)

Why does everyone make slightly different immune responses?

Because of variations in our genetics

What determines the outcome of infection by intestinal pathogens?

A complex interplay between the microorganism and the host immune response

Name a classic example of a disease in which the outcome varies greatly?

Leprosy

Describe coeliac disease

Geneticlaly linked, autoimmune disorder, causes damage to the small intestine leading to malnurtition as you can no longer absorb

What type of viruses are thought to be a trigger?

Enteric viruses

What happens if you do not have HLADQ2/ HLADQ8

You are genetically susceptible and there must be a T cell component

Describe the changes that occur to the small intestine in Coeliac's disease

Flattened epithelial cells Small intestine has scalloping Small intestine with villous atrophy instead of normal finger like projections Epithelial cells get more and more ragid Packed full of cells (cellular infilitrate) Hugely reduced surface area = hugely reduced absorption

What does the MARSH score tell us?

The level of celiac disease (0,1,2,3a,3b,3c) 0 = normal 3c = total atrophy

As damage recedes, the ragged, lymphocyte infiltrated enterocytes are replaced by what type of cells?

Normal columnar ones | This assures normal transport from the lumen into the body

What happens if epithelial cells express a stress marker?

The intraepithelial lymphocyte cells will kill the epithelial cells

What initiates the stress response in the cells causing lymphocytes

Gluten peptides

What is the function of transglutaminase and where is it found?

To modify gluten peptides | found in all epithelial cells

What does the modfied peptide bind to?

MHC class 2 molecules

What does the bound peptide then go on to activate?

Gluten-specific CD4 T cells

What do the gluten specific T cells then do?

Target epithelial cells which have fluten peptide in them as it think that the gluten is a virus

What type of immune response is a gluten intolerance?

Innapropriate

What do we do for everybody complaining of gluten intolerance

Antibody test (screening test to see hwo needs to further tests)

What do we do for people who are positive for the anitbody test?

Biopsy them

How do we diagnose children?

Through serology and genetics.

What happens if a patient has not eaten gluten?

There will be a false negative. THe patient will then have to go back on to gluten for 6 weeks before being tested again

What is the main cause of persistant symptoms?

Lack of compliance

Who are more likely to have Caeliacs disease?

Patients who are IgA deficient

The proper development and function of the intestinal immyne systemic is dependent on what?

Specific microbiota which have evolutinonary co-evolved

What does Inflammatory bowel disease prevent?

The invasion of harmful pathogens while remaining tolerant to innocuous food substances and commensal micro-organisms

What might lead to inflammatory bowel disease?

An altered function and imbalance of the relationship between the immyne system and tolerance to innocuous food substances

Where is the site of Ulcerative Colitis?

Colon

What inflammation occurs in Ulcerative Colitis?

Mucosal (superficial)

What does smoking do in Ulcerative Colitis do?

Protects

What cytokine profile is involved in xUlcerative Colitis?

Th2 IL-5/13

What genetic factors are involved in Ulcerative Colitis?

HLADR2

Where does Crohn's disease occur?

Any part of the GI tract

What inflammation occurs in Crohns disease

Transumral / granulomatous

What cytokins are you present in CD profile?

Th1, IL23, gamma IFNG

Granulommas are always associated with what type of responses?

Th1 responses

Describe the inflammation in Crohn's disease

Focal and discontinuous inflamation with deep and eroding fissures +/- granulomas

What factors contribute to Crohn's disease

Multiple genetic deficiency and immunologic mechanisms

What is the gene which has been identified in Crohn's disease?

NOD2

Where does ulcerative colitis occur?

The rectum and colon

What way does ulcerative colitis move?

Proximally and contiguously (touching eachother)

What occurs in the surface mucosa?

Inflammation and ulceration

Where do all of these diseases occur?

Urbanised westernised societies

Both conditions produce large amounts of what?

Inflammatory cytokines | IL-1, IL-6 and TNF alpha

How can we treat these types of disorders?

Non specific anti-inflammatory and immunosuppressive drugs, steroids, azathiprine, cyclosporin, methotrexate

What type of reaction is a food allergy ?

Type 1 hypersensitivity reaction

How is a reaction initiated?

By cross linking of allergen specific IgE on the surface of mast cells with the specific allergen