Mucosal Immunity Flashcards
What is the function of mucosal surfaces?
- Gas exchange
- Food adsorption
- Sensory activities
- Reproduction
- Portal of entry for non pathogenic antigens
(main site of infection)
How does an immune response occur in a lymph node?
Dendritic cells enter the paracortical area and look for T cells.
If there is the correct match of dendritic cells, T cells and antigens then an immune response occurs
What occurs at specialised lymphoid tissue?
site of antigen sampling in the gut
Where do effector mechanisms happen?
lamina propria
What is a Peyer Patch?
- covered by an epithelial layer which contains specialised M cells (covered in microvilli)
- dentritic cells in the peyers patch sample antigens from the M cells
How are T cells activated in the gut?
M cells take up antigens by phagocytosis and endocytosis
Antigens are transpored across the M cells in vesicles and released at the basal surface
Antigen is bound to dentritic cells, which activates T cells
What are other the ways (apart from from the epithelium) that dendritic cells can sample antigens?
lamina propria
- can extend processes through the epithelium and capture antigens from the lumen of the gut
What are the immune cells of the lamina propria?
CD4 T cell Dendritic cell Macrophage Mast cell Plasma cell IgA a4B7 integrin
What are the immune cells of the epithelium?
a4B7 integrin
Dendritic cell
CD8 T cell
In what form is IgA in the gut?
Monomeric
How are T cells contained in the gut?
- T cells enter peyers patches from blood vessels (directed by homing receptors CCR7 and L selectin)
- T cells in the Peyers patch encounter antigen transported across M cells and become activated by dendritic cells
- Activated T cells drain via mesenteric lymph nodes to the thoracic duct and return to the gut via the bloodstream
- Activated T cells expressing a4:B7 integrin and CCR9 home to the lamina propriety and intestinal epithelium of the small intestine
- Gut homing effector T cells bind MAdCAM-1 on endothelium
- Gut epithelial cells express chemokines specidfic for gut-homing T cells
How is IgA re?leased from an epithelial cell
- IgA binds to receptor on basolateral face of epithelial cell
- endocytosis occurs
- transcytosis to apical face of epithelial cell
- release of IgA dimer
Which part of IgA needs protected?
hinge region
What can replace IgA if someone has an IgA deficiency?
IgM
What does IgA prevent?
damage from epithelial cells
What are intraepithelial lymphocytes?
What are they responsible for?
–90% T cells with 80% CD8+
–Activated appearance containing full killing machinery
–Restricted antigen receptor repertoire
–Expression of aE:b7 integrin - anchors them in the epithelium
–2 types with different recognition mechanisms
Major cause of the immunopathology of coeliac disease
Where do intraepithelial cells lie?
within the epithelial gut lining
What happens when a virus infects a mucosal epithelium cell?
- infected cell displays viral peptide to CD8 IEL via MHC class 1
- activated IEL kills infected epithelial cell by perforin/granzyme and Fas-dependant pathway
What are the features of activated IELs?
Detect the infection and they directly kill only the cell that is infected – do it for virus and stress
Protects the cells around it
What occurs when there are lots of killed epithelium cells?
flattened epithelium
i.e. coeliac disease
What does mucosal hyperresponsiveness cause?
Crohn’s disease
What is the mechanisms of mucosal hyperresponsiveness?
- Responses needing controlled in the gut: T cells and IgE (as they cause damage)
- Commensal organisms help regulate local hyporesponsiveness- PPAR gamma
- Anergy or deletion of antigen specific T cells- no costimulation
- Generation of regulatory T cells particularly CD4+ TGF b producing Th3 cells- weak costimulation: Both Immunosuppressive and induces switching of B cells to IgA production
What is the normal dendritic cell response to commensal bacteria?
- production of PGE2, TGF-B and TSLP which 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 dendritic cell repsonse to invasive microorganisms?
- invasive microorganisms penetrate epithelium to activate dendritic cells
- activated dendritic cells express strong co-stimulatory ligands and induce CD4 T cells to differentiate into effector Th1 and Th2 cells
What is the mucosal response to infection?
- Innate mechanisms eliminate most intestinal infections rapidly
- Activation through ligation of pattern recognition receptors
- Intracellular sensors in epithelial cells, PRR, activate the NFkB pathway
- Gene transcription and production of cytokines, chemokines and defensins
- Activation of underlying immune response
How are inflammatory cytokines, chemokines and other mediators expressed on the epithelial cell?
TLRs, NDO1 and NDO2 activate NFkB which induces the epithelial cell to express them
What is the role of Th2 in the gut?
- protective = releases lots of cytokines
- releases IL3 (induces epithelial cell repair) and IL5 (recruits and activates eosinophils)
- produces IgE (through B cells)
What is the role of Th1 in the gut?
- host damage
- activate macrophages and B cells (to produce IgG2a)
What happens when the mucosal immunity becomes deregulated?
Infected dendritic cells shuttle virus from the site of exposure to the regional lymph nodes where they concentrate virus particles and infect CD4+ T cells
What is SCID?
defect in T and B cell immunity - presents earlier in life than others as there is no IgG to protect them
What is Selective IgA deficiency?
asymptomatic remainder recurrent sinopulmonary infections
What is CVID?
recurrent sinopulmonary and GI infections
-failure to differentiate into Ig secreting cells
–Low IgG, IgA, IgM and IgE
–Defective antigen specific antibody response
What is XLA?
Sinopulmonary and GI infections + devastating systemic manifestations of chronic enteroviral infections (xlinked so boys)
–No B cells/ agammaglobulinaemia
What is CGD?
children that present with: Staphlococcus aureus/inflammatory granulomas
- mostly boys
- failure of phagocyte respiratory burst
What is a food allergy?
Type I hypersensitivity reaction initiated by crosslinking of allergen specific IgE on the surface of mast cells with the specific allergen.
Memory response - immune system must be primed
What is Coeliac disease mediated by?
T cells
Describe the immunology of Coeliac disease?
T cell/IEL 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
How is Coeliac disease diagnosed?
biopsy - not for children though
Describe Crohn’s disease?
Focal and discontinous inflammation with deep and eroding fissures +/- granulomas
Mediated by Th1 CD4+ T cells/gamma interferon/IL-12/ TNF alpha
Multiple genetic deficiency and immunologic mechanisms- multifactorial- HLA
Gene identified NOD2 (10-15%)- intracellular PRR- muramyl dipeptide of bacterial peptidoglycan
What is the most common social background to develop ulcerative colitis?
children of immigrants
Describe Ulcerative Colitis?
Produces large amounts of inflammatory cytokines IL-1, IL-6 and TNF alpha
Restricted to rectum and colon
