Mucosal immunology of the GI tract

Question 1

What is the GALT?

Answer 1

The gut associated lymphoid tissue.
This includes the adenoids, the tonsils, the appendix, the peyer’s patches in the small intestine and the large intestine.

Question 2

What does the small intestine have that the large intestine does not have?

Answer 2

Villi
Paneth cells (to secrete defensins)
Peyer’s patches for antigen sampling and immune activation

Question 3

Where are immune cells found in the small intestine?

Answer 3

They can be found in organised tissue - Peyer’s patches

And throughout the lamina propria

Question 4

What immune cells are found in the small intestine?

Answer 4

macrophages
dendritic cells
intra-epithelial lymphocytes
lamina propria effector T cells
IgA secreting plasma cells

Question 5

What are the roles of the immune cells found in the intestines?

Answer 5

Capture antigens
Initiate a local immune response
Carry out effector functions to clear any infection

Question 6

What sort of immune cells are found in the epithelium, and what is their function there?

Answer 6

Innate immune cells. These capture antigens and have an effector function.

Question 7

What is the function of the immune cells found in Peyer’s patches and lymphoid follicles?

Answer 7

Antigen capture and initiation

Question 8

What sort of immune cells are found in the lamina propria?

Answer 8

Effector cells

Question 9

Where can antigen capture occur?

Answer 9

Both in Peyer’s patches and directly across the epithelium. Dendritic cells can extend processes across the epithelial layer to capture antigens from the lumen of the gut.

Question 10

What specialised cells are found in the epithelium which covers Peyer’s patches?
What do these cells do?

Answer 10

M cells (m stands for microfold) which have characteristic membrane ruffles. 
The M cells take up antigens by endocytosis and phagocytosis. 
The antigen is transported across the M cells in vesicles and released at the basal surface. The antigen is then bound by dendritic cells, which activate T cells.

Question 11

Describe some key features of organised lymphoid tissue in the gut.

Answer 11

It has a role in the initiation of the immune response.
There are a large number of B cell follicles.
It is directly exposed to microorganisms and particles within the gut (by M cells).
Isolated lymphoid follicles only contain B cells.
Both isolated lymphoid follicles and peyer’s patches drain to mesenteric lymph nodes where the intestinal immune response is initiated.

Question 12

What are defensins?

Answer 12

Antimicrobial peptides that change the charge on pathogens and kill them

Question 13

Which intestine carries a higher bacterial load?

Answer 13

The large intestine

Question 14

Describe how circulating leukocytes become activated in the gut.

Answer 14

The cells are circulating around the body and passing through all of the lymph nodes. When the cells pass through the gut, they express the CCR7 receptor (a chemokine receptor) and the L-selectin receptor. If they are activated as they circulate through the mesenteric lymph node, they lose the CCR7 receptor and become determined cells, rather than undetermined cells. They can no longer recirculate.

Question 15

What happens to activated T and B cells?

Answer 15

They drain via mesenteric lymph nodes to the thoracic duct and return to the gut via the bloodstream. They express the adhesion molecule alpha4beta7, which attaches to MAdCAM-1 which is on the gut endothelium. The cells also express CCR9 which is attracted to CCL25 on small intestinal epithelium.

Question 16

Which Igs do B cells mostly express?

Answer 16

IgA- 80 %

Question 17

What other immunoglobulins do the B cells express? How much of each?

Answer 17

IgA- 80%
IgM- 15%
IgG- 5%
The reversal of the systemic humoral response

Question 18

Where does IgA primarily exist in the gut?

Answer 18

In the mucous layer of the gut

Question 19

What forms can IgA exist in?

Answer 19

As a monomer or a dimer

Question 20

What is a J chain?

Answer 20

A joiner chain of two IgA molecules which form a dimer

Question 21

What happens to an IgA after it has been produced by an IgA secreting cell?

Answer 21

A dimer binds to the poylmeric immunoglobulin receptor on the basal side of the epithelial cell. Once IgA has inhabited the receptor, the IgA and the receptor are endocytosed across the epithelial cell, and the IgA is released at the lumenar surface of the gut.
The secretory component is the part of the receptor which stays attached to the IgA dimer. It is incredibly important for the half life of the IgA as it covers the vulnerable hinge point of the IgA and prevents it from being digested.

Question 22

What does IgA do in the lumen?

Answer 22

It can bind and neutralize pathogens in the mucous layer in the gut and peristalsis removes them.
It can also bind and neutralise antigens internalized in endosomes.
It can also export toxins and pathogens from the lamina propria.

Question 23

What makes up most of the intraepithelial lymphocytes?

What appearance do they have?

Answer 23

90% T cells with80% being CD8+

They have an activated appearance, which means they are preactivated cells and contain full killing machinery.

Question 24

What anchors the T cells in the epithelium?

Answer 24

The expression of alphaE:beta7 integrin

Question 25

What are the two types of recognition mechanisms in the epithelium?

Answer 25

Virus specific recognition - TCR/CD8 cells. These kill va FAS receptor and ligand and initiate apoptosis
Stress specific recognition- stressed or damaged cells are recognised by NK cells.

Question 26

Where specifically in the epithelium do the intraepithelial lymphocytes sit?

Answer 26

They sit between the epithelial cells, to control any damage on particular epithelial cells and to maintain membrane integrity.

Question 27

How do the T cells kill pathogens?

Answer 27

By the direct release of perforins/granzymes on the cell they have targeted.

Question 28

What are some proposed mechanisms for mucosal hyporesponsiveness?

Answer 28

Anergy or deletion of antigen specific T cells
Generation of regulatory T cells particularly CD4+ TGFbeta producing Th3 cells which control/dampen down the immune response
It is both immunosuppressive and induces switching of B cells to IgA production. IgA does not recruit neutrophils or cause an inflammatory response.
Commensal organisms also help regulate hyporesponsiveness.

Question 29

How is the balance between protective immunity and homeostasis maintained?

Answer 29

A sophisticated means of discriminating between pathogen and innocuous substances has been developed. Inhibitory macrophages and tolerising dendritic cells prevent a response to an innocuous substance.
The default response to oral administration of proteins is that of a specific peripheral unresponsiveness- i.e oral tolerance
T cell and IgE mediated responses are inhibited more than IgG responses both locally and systemically

Question 30

What is the hygeine hypothesis?

Answer 30

Exposure of the developing immune response to certain environmental microorganisms leads to a drie in the production of TGFbeta and IL-10 regulatory T cells.
Rural children and children in environments of high intestinal parasite get lots less allergy.