Mucosal Immunity Basic Science

Question 1

Balance between tolerance and response in mucosal immunity?

Answer 1

Must respond to pathogens but tolerate dietary antigens and commensal bacteria

Question 2

How does transport occur across cells and between cells?

Answer 2

Paracellular - between cells via tight junctions

Transcellular - across cells

Question 3

Describe the structure of a lymph node

Answer 3

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

Question 4

What effector mechanism are unique to the GUT mucosal immune system?

Answer 4

Activated/memory T cell predominate

Question 5

Immunoregulation in the gut mucosal immune system?

Answer 5

There is active down regulation of the immune response in the gut mucosal immune system; also, there are inhibitory macrophages and tolerising dendritic cells

Question 6

Where are intestinal lymphocytes found in the gut mucosal immune system?

Answer 6

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

Question 7

Structure of Peyer’s patches in the small intestine?

Answer 7

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

Question 8

Function of M cells in peyer’s patches?

Answer 8

M cells face the lumen of the GI tract and capture antigens, bringing them into the patch

Question 9

Process by which M cells capturing antigens leads to T cell activation?

Answer 9

M cells uptake the antigen by endocytosis and phagocytosis

2. Antigen is transported across the M cells in vesicles an released at the basal surface
3. Antigen is bound by dendritic cells, which activate T cells

Question 10

Describe dendritic cells which are in contact with the GI tract lumen

Answer 10

In the lamina propria, there are discrete dendritic cells that can extend processes between epithelial cells to capture antigens in the gut

Question 11

Two distinct compartment of the mucosal immune system?

Answer 11

Immune cells of the epithelial layer, e.g: intraepithelial T cells

Immune cells of the lamina propria

Question 12

Describe the process of homing

Answer 12

Homing receptors on immune cells direct them to different sites; different parts of the body have different molecular addresses; but there is some overlap

Question 13

How do T cells “home” to the lamina propria and intestinal epithelium of the small intestine?

Answer 13

1. T cells enter Peyer’s patches from the blood vessels, directed by the homing receptor (CCR7 and L-selectin)
2. T cells in the Peyer’s patch encounter an antigen, transported across the M cells and presented by a dendritic cell
3. Activated T cells drain via mesenteric lymph nodes to the thoracic duct and return to the gut, via the bloodstream
4. Activated T cell has a homing receptor which allows it to home to the lamina propria and intestinal epithelium

Question 14

Using what molecules does the T cell bind to the endothelium of the blood vessel, to reach the lamina propria?

Answer 14

Gut-homing effector T cells bind MAdCAM-1 on to the endothelium

Gut epithelial cells express chemokines specific for gut-homing T cells

Question 15

Where else is MAdCAM-1 found?

Answer 15

Vasculature of other mucosal sites; thus, lymphocytes primed in the gut can migrate to other mucosal sites (unified mucosal immune system)

Question 16

Why is MAdCAM-1 important in HIV research?

Answer 16

Immune response in the uro-genital tract can migrate to the GI tract, due to MAdCAM-1; this is vaccine development target

Question 17

Which antibodies are involved with the humoral intestinal response?

Answer 17

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

Question 18

How does IgA enter the lumen of the IgA tract?

Answer 18

1. The IgA becomes bound to a poly-Ig receptor on the basolateral surface of the epithelial cell
2. Endocytosis occurs
3. Transcytosis of the vesicle to the apical face of the epithelial cell
4. The IgA dimer + secretory component is released at the apical face of the epithelial cell, into the lumen

Question 19

Function of secretory IgA in lumen?

Answer 19

1. On the gut surface, can bind and neutralise pathogens and toxins
2. IgA is able to bind and neutralise antigens internalised in endosomes
3. IgA can export toxins and pathogens, from the lamina propria, while being secreted

Question 20

Describe the intranepithelial lymphocytes in the gut

Answer 20

Most are T cells, with most of these being CD8+ T cells

Kill cells by triggering apoptosis but have a restricted antigen-receptor repertoire

Question 21

How are intraepithelial T cells anchored in the gut?

Answer 21

Expression of αΕ:β7 integrin anchors them in the epithelium

Question 22

How do the intraepithelial T cells respond to viruses?

Answer 22

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

Question 23

How do damaged T cells stimulate an intraepithelial T cell response?

Answer 23

1. Epithelial cells undergo stress as a result of infection, damage, or toxic peptides and express MIC-A and MIC-B
2. Activation of intraepithelial cells; the cells will bind to the stressed cell and kill it via the perforin/granzyme pathway

Question 24

What are the mechanisms by which the mucosa is thought to be hyporesponsive?

Answer 24

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

Question 25

How is hyporesponsiveness of the mucosa mediated by PPAR gamma?

Answer 25

1. Pathogen recognition initiates a cascade of signals that activate IKK 2. IKK phosphorylates IKB, targeting it to be degraded; NFKB translocates to the nucleus to activate gene transcription 3. Some commensal bacteria block gene transcription by activating PPAR gamma, which removes NFKB from the nucleus 4. Some commensal bacteria can block degradation of phosphorylated IKB, preventing NFKB translocation to the nucleus