Mucosal Immunology Flashcards
What is the name of the specific immune follicles in the Large intestine?
Lymphoid follicles
WHat is the name of the specific area related to immunity in the small intestine?
Peyer’s Patch
What is concentrated in muscosal sites?
Specialised lymphoid tissue
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
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
What is the benefit of the villi and crypts
THey provide a large surface area for antigens to interact
What is the purpose of the Paneth cells
They are defensins
What occurs in the Peyer’s Patches?
Antigen sampling and immune activation
What types of cells is the large intestine mostly made up of?
Crypts (not villi), enterocytes and lots of goblet cells and mucus
Which has the higher bacterial load? the small or large intestine
Large intestine
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
Where do natural killer T cells have a more significant role to play?
In the colon
What are the main secretors of antimicrobial peptides
The Paneth Cells
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)
How do dendritic cells capture antigens across the epithelium?
They can extend their processes to capture antigens from the lumen of the gut
What are the direct antigen sampling organisms of the gut?
The Peyer’s patches
Describe the structure of Peyers patchs
covered by an epithelial layer containing specialised cells (M cells) which have characteristic membrane ruffles
What is situated directly below an M Cell?
Dendritic cells
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
What is the major effector molecule in the gut called?
IgA
What type of cells enter the Peyer’s patches form blood vessels?
T cells
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
What is the make up of the humoral intstinal response?
80% IgA
15% IgM
5% IgG
As peristalsis occurs, what happens to IgA
It is moving and being produced continuously
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
