Mucosal Immunity Basic Science Flashcards
Balance between tolerance and response in mucosal immunity?
Must respond to pathogens but tolerate dietary antigens and commensal bacteria
How does transport occur across cells and between cells?
Paracellular - between cells via tight junctions
Transcellular - across cells
Describe the structure of a lymph node
Afferent lymphatic vessels carry lymph towards the lymph node and efferent vessels carry lymph away
Secondary lymphoid follicles have germinal centres
The T cells are mostly contained within the paracortical areas and the B cells within the primary lymphoid follicles
What effector mechanism are unique to the GUT mucosal immune system?
Activated/memory T cell predominate
Immunoregulation in the gut mucosal immune system?
There is active down regulation of the immune response in the gut mucosal immune system; also, there are inhibitory macrophages and tolerising dendritic cells
Where are intestinal lymphocytes found in the gut mucosal immune system?
There are scattered lymphoid cells in the villi epithelium, which carry out effector functions
Unique to the small intestine, there are organised tissues (Peyer’s patches) where immune responses are induced; in the large intestine, there are more isolated lymphoid follicles
Structure of Peyer’s patches in the small intestine?
Covered by an epithelial layer containing specialised M cells, which have characteristic membrane ruffles (microruffles) to increase the surface area
The dendritic cells are located next to the epithelium, with the T cells below
There are also follicles, with germinal centrea
Function of M cells in peyer’s patches?
M cells face the lumen of the GI tract and capture antigens, bringing them into the patch
Process by which M cells capturing antigens leads to T cell activation?
M cells uptake the antigen by endocytosis and phagocytosis
- Antigen is transported across the M cells in vesicles an released at the basal surface
- Antigen is bound by dendritic cells, which activate T cells
Describe dendritic cells which are in contact with the GI tract lumen
In the lamina propria, there are discrete dendritic cells that can extend processes between epithelial cells to capture antigens in the gut
Two distinct compartment of the mucosal immune system?
Immune cells of the epithelial layer, e.g: intraepithelial T cells
Immune cells of the lamina propria
Describe the process of homing
Homing receptors on immune cells direct them to different sites; different parts of the body have different molecular addresses; but there is some overlap
How do T cells “home” to the lamina propria and intestinal epithelium of the small intestine?
- T cells enter Peyer’s patches from the blood vessels, directed by the homing receptor (CCR7 and L-selectin)
- T cells in the Peyer’s patch encounter an antigen, transported across the M cells and presented by a dendritic cell
- Activated T cells drain via mesenteric lymph nodes to the thoracic duct and return to the gut, via the bloodstream
- Activated T cell has a homing receptor which allows it to home to the lamina propria and intestinal epithelium
Using what molecules does the T cell bind to the endothelium of the blood vessel, to reach the lamina propria?
Gut-homing effector T cells bind MAdCAM-1 on to the endothelium
Gut epithelial cells express chemokines specific for gut-homing T cells
Where else is MAdCAM-1 found?
Vasculature of other mucosal sites; thus, lymphocytes primed in the gut can migrate to other mucosal sites (unified mucosal immune system)
Why is MAdCAM-1 important in HIV research?
Immune response in the uro-genital tract can migrate to the GI tract, due to MAdCAM-1; this is vaccine development target
Which antibodies are involved with the humoral intestinal response?
This is different from the systemic humoral immune response:
80% IgA (1 and 2) - IgA2 is harder to digest so there is less; it is present in its dimeric form, with IgA1: IgA2 being 3:2 (in the periphery, it is 10:1 but the IgA is present in its monomeric form)
15% IgM
5% IgG
How does IgA enter the lumen of the IgA tract?
- The IgA becomes bound to a poly-Ig receptor on the basolateral surface of the epithelial cell
- Endocytosis occurs
- Transcytosis of the vesicle to the apical face of the epithelial cell
- The IgA dimer + secretory component is released at the apical face of the epithelial cell, into the lumen
Function of secretory IgA in lumen?
- On the gut surface, can bind and neutralise pathogens and toxins
- IgA is able to bind and neutralise antigens internalised in endosomes
- IgA can export toxins and pathogens, from the lamina propria, while being secreted
Describe the intranepithelial lymphocytes in the gut
Most are T cells, with most of these being CD8+ T cells
Kill cells by triggering apoptosis but have a restricted antigen-receptor repertoire
How are intraepithelial T cells anchored in the gut?
Expression of αΕ:β7 integrin anchors them in the epithelium
How do the intraepithelial T cells respond to viruses?
Virus infects mucosal epithelium cell
Infected cell displays viral peptide to CD8+ iIEL, via MHC class I
Activated IEL kills infected epithelial cell by perforin/granzyme and fas-dependent pathways
How do damaged T cells stimulate an intraepithelial T cell response?
- Epithelial cells undergo stress as a result of infection, damage, or toxic peptides and express MIC-A and MIC-B
- Activation of intraepithelial cells; the cells will bind to the stressed cell and kill it via the perforin/granzyme pathway
What are the mechanisms by which the mucosa is thought to be hyporesponsive?
Commensal organisms help regulate local hyporesponsiveness - PPAR gamma
Anergy or deletion of antigen specific T cells - no co-stimulation required
Generation of regulatory T cells, part. CD4+ TGF β producing Th3 cells - weak co-stimulation
How is hyporesponsiveness of the mucosa mediated by PPAR gamma?
- Pathogen recognition initiates a cascade of signals that activate IKK
- IKK phosphorylates IKB, targeting it to be degraded; NFKB translocates to the nucleus to activate gene transcription
- Some commensal bacteria block gene transcription by activating PPAR gamma, which removes NFKB from the nucleus
- Some commensal bacteria can block degradation of phosphorylated IKB, preventing NFKB translocation to the nucleus