Mucosal Immunity Flashcards
What are the 2 ways of transporting substances across the mucosa?
Transcellular - across the cell
Paracellular - between the cells
What are the distinctive features of the gut mucosal immune system?
- Intimate relationship between mucosal epithelia and lymphoid tissue
- Organised lymphoid structures unique to mucosal sites
- Specialised antigen uptake mechanisms
- Activated/memory T cell predominate “natural” effector /regulatory T cells
- Active down regulation of immune response
- Inhibitory macrophages and tolerising dendritic cells
Why is the gut a common site of HIV infection?
Because there are so many activated T cells
What are peyer’s patches?
essentially the small intestine lymph node
What is the purpose of the germinal centres in the peyer’s patches?
Makes a lot of immunoglobulin to make a lot of antibodies from the gut
What are the peyer’s patches covered by?
epithelial cells called M cells which have a characterisitic membrane ruffles - microvilli are present on these cells
What is the function of the M cells?
The M cells take up antigens by endocytosis and phagocytosis. The antigen is then transported across the M cell in vesicles and released at the basal surface
The antigen is bound by dendritic cells which activate T cells
Within the rest of the mucosa what are the 2 parts of the mucosal immune system?
cells of the lamina propria
the immune cells of the epithelial layer (intraepithelial lymphocytes IEL) - these are CD8+ T cells
What are the proportions of antibodies within the gut?
IgA - 80% which is dimeric
IgM 15%
IgG 5%
What are the types of immune cells found within the epithelial?
90% T cells with 80% CD8+ (kill cells)
they are in the activated state and have a restricted antigen receptr repertoire
the AE:B7 anchors thee cell to the epithelium
there are 2 types which have different recognition mechanisms
What is important about immunological suppression within the gut?
The gut’s default is to not react you have to push it quite hard, there is also something called oral tolerance where the immune system response is switched off to particular antigen
The main responses which are inhibited are T cell and IgE mediated responses - more than IgG
Dysregulation of the immune response through HIV infection is due to…
Damaging the T cells and spreading the infection through the different immune cells, When dendritic cells bind to the CD4+ cells they pass the HIV
Examples of primary immunodeficiency which cause mucosal immunity problems
Selective IgA deficiency CVID X linked Agammaglobulinaemia CGD SCID
What are the characteristics of selective IgA deficiency?
1:600 people
2/3 asyptomatic
symptomatic remainder get recurrent sinopulmonary infections
Coeliac disease 10x more likely
What is the immunopathology coeliac disease?
T cell/intraepithelial lymphocyte mediated
Gamma interferon from Gluten specific T cell activate epithelial cells which produce IL-15 which induces proliferation and activation of IEL
Both T cells and IEL can then kill epithelial cells
What is the food trigger of coeliac disease?
The gluten in wheat/rye/barley acts as the auto antigen which triggers the immune response and the symptoms associated with the disease
What is the tigger for getting coeliac disease?
it is genetically linked but people aren’t born with it the trigger is unknown but speculated to be enteric viruses
What is the effect of coeliac disease on the villi?
It causes atrophy of the small intestine villous cells and when they regrow the cells don’t have microvilli anymore - once you stop eating gluten then normaly it goes back to normal
How do you diagnose coeliac disease?
serology is a screening test IgA anti-tissue transglutaminase autoantibodies when these are seen it means that there is someone with coeliac disease who is eating gluten - means the patient needs to be consuming gluten for 6 weeks 2 meals a day with gluten
Biopsy - is the diagnostic test for adults but serology decides who should be biopsied
What is the other use of the IgA anti-TTG test?
Is used to monitor diet compliance
What do Crohn’s disease and Ulcerative colitis react to?
They are inappropriate reaction to bacteria within the gut
How does ulcerative colitis present?
It starts in the rectum and moves proximally, the line of inflammation can be seen - inflammation and ulceration just in the surface mucosa
There is distortion of the crypts with infiltration of monocytes/ neutrophils and plasma cells
Extra-intestinal manifestations can develop - arthritis/ureitis and skin lesions
What connects the immune cells within the mucosa of the gut?
the afferent lymphatic drains the lamina propria and intraepithelial cells as well as the Peyer’s patches and lymphoid follicles all to the mesenteric lymph node
Other than antigens coming across the epithelial layer what is the way dendritic cells can be activated
Dendritic cells can extend processes across the epithelial layer to capture antigens from the lumen of the gut
What is the process of T cells becoming involved in immune response of the gut mucosal immune system?
The T cells enter the Peyer’s patches from the blood vessels - directed by the homing receptors CCR7 and L-selectin
T cells in the Peyer’s patches encounter antigen transported across M cells and become activated by Dendritic cells
They then drain via the mesenteric lymph nodes to the thoracic duct and return to the gut via the bloodstream
The activated T cell expressing alpha4:B7 integrin and CCR9 go to the lamina propria and epithelium of the small intestine
What attracts the effector T cells to the lamina propria and epithelium of the small intestine?
They bind to MAdCAM-1 on the endothelium and are pulled across into the mucosa
Gut epithelial cells express chemokines which are specific for gut-homing T cells
What is the action of IgA within mucosal immunity?
- IgA binds to a receptor on the basolateral face of the epithelial cell
the IgA then passes through the epithelial cell in a vesicle - IgA dimer is released from the apical face of the epithelial cell
- The secreted IgA on the gut surface can bind and neutralize pathogens and toxins
- IgA is able to bind and neutralize antigens which are internalized in endosomes in the epithelial cells
- While the IgA is secreted it can remove toxins and antigens from the lamina propria
What is the physiological function of the IELs?
If a virus infects the mucosal epithelial cell it will express the viral peptide to the CD8 IEL via MHC class I this activated IEL kills infected epithelial cell by perforin/ granzyme and Fas-dependent pathways
How do IELs respond when epithelial cells undergo stress?
The epithelial cells express MIC-A and MIC-B, NKG2D on IELs bind to MIC-A,B and activate IEL. CD8 A:A homodimers also bind to TL
The activated IEL kills the stressed cell through the perforiin/granzyme pathway
The mechanisms of mucosal hyporesponsiveness are thought to be
- commensal organism regulated - PPAR gamma
- anergy or deletion of antigen specific cells
- generating regulatory T cells particularly CD4+ TGF B which produce Th3 cells - this is immunosuppresive and induces B cells to switch to IgA production
What is the response initiated by the TLRs (toll-like receptors) when they recognise a bacteria?
Active TLRs initiate a cascade which activate IKK
IKK phosphorylates IkB - it is then degrades. NFkB translocates to the nucleus and activates gene transcription (to cause B cell proliferation)
How do commensal bacteria stop the process of inflammation once the TLRs have been triggered?
Some block gene transcription by activating PPARy which removes NFkB from the nucleus
Some block degration of phosphorylated IkB which prevents NFkB translocation to the nucleus
What is the effect of commensal bacteria on the dendritic cells?
- PGE2, TGF-B and TSLP inhibits dendritic cell maturation - immature dendritic cells give weak co-stimulatory signals and induce CD4 T cells to differentiate into regulatory Th3 or Treg cells
What is the effect of invasive microorganisms on dendritic cells?
The organisms activate the dendritic cells, once activated they express stron co-stimulatory ligands and induce CD4 T cells to differentiate into effector Th1 and Th2 cells
What is the mucosal response to infection and regulation of the immune response?
- the innate mechanisms rapidly eliminate most intestinal infections
- Ligation of PRRs activates the response, the NFkB pathway is then triggered by intracellular sensors
- Gene transcription and production of cytokines, chemokines and defensins
- then activation of underlying immune response
What are the characteristics of CVID (common variable immunodeficiency)?
1: 50,000 people
- sinopulmonary and GI infections
- there is failure to differentiate into Ig secreting cells
- There is low IgG
- There is sometimes IgA & IgM, if these are low then there are GI infections
- defective antigen specific immune response
What are the characteristics of X-linked agammaglobulinaemia (XLA)?
- presents in boys at 6 months
- need to check B cells (more then FBC)
- sinopulmonary and GI infections
- devastating systemic manifestations of chronic enteroviral infections
- no B cells in the system
What are the characteristics of Chronic Granulomatus disease (CGD)?
1: 100,000 people
- staphlococcus aureus/ inflammatory granulomas
- pneumonia, liver abcess, perianal abcess and skin abcess
- failure of phagocyte repiratory to burst
What are the characteristics of SCID?
- Profound defect in T and B cell immunity
- oral candidasis
- chronic diarrhoea
- interstitial pneumonitis
- GI - CMV/ rotavirus/ EBV
- presents within the 1st month sometimes week of life
What is the mechanism of the coeliac disease response?
There is transamidation of the glidan peptide, this activates the glidan specific T cell, causing activation of plasma cells and other lymphocytes.
Cytokines are released by activated lymphocytes and damage the intestinal epithelium
How is coeliac disease treated?
A gluten free diet
What is Crohn’s disease?
focal and discontinuous inflammation with deep and eroding fissures =/- granulomas
- can affect any part of the GI tract from the mouth to the anus- commonly distal ileum and colon
- mediated by Th1 CD4+ T cells/ gamma interferon/IL-12/ TNF alpha
What are the treatments of ulcerative colitis and Crohn’s disease?
non-specific anti-inflammatorys and immunosupressive drugs
steroids/azathioprine/cyclosporin/methotrexate
anti-TNF
