lecture 7

Question 1

the mucosal system

Answer 1

The mucosal system is an important compartment of the immune system which protects internal surfaces

Up till now we have discussed adaptive immunity in the lymph nodes which is stimulated following infection
via the skin
in internal organs
or systemic in the blood stream

The mucosal system is an even larger immunological compartment and protects surfaces where most pathogens invade

Question 2

organs inovlved in the mucosal system

Answer 2

The mucosal immune system includes lymphoid organs associated with intestine, respiratory tract and urogenital tract and associated glands

Question 3

how is the mucosal surfaces protected by the organs around it?

Answer 3

The mucosal system is protected by commensal microorganisms (microbiota) which are beneficial to their host- the colon is most heavily colonised

vaginal births - combination of fluids will seed the gut flora of that individual. children through cesarian could be more susceptible to alergies or diseases. because they dont get into contact with microflora

Question 4

distinctive features of the mucosal immune system

Answer 4

anatomical features that distinguish it from the systemic immune system
effector mechanisms that are unique to the gut
immunoregulatory environment with unique characteristics

TABLE IN L7 S5

Question 5

what is GALT

Answer 5

The organised tissues which make up GALT are the sites of T and B cell antigen presentation facilitated by M cells

Question 6

how is an immune response triggered

Answer 6

Antigens at intestinal surfaces must be transported across an epithelial cell layer to stimulate the mucosal immune response- the M cells do this

• M cells take up antigen by endocytosis and phagocytosis
• antigen is transported across the M cells in vesicles and released at the basal surface
• antigen is bound by dendritic cells which activate T cells

Question 7

mucosal immune system compartments and cells

Answer 7

The mucosal immune system contains large numbers of immune cells even in the absence of disease and forms two distinct compartments –> the epithelium and the lamina propria.

Question 8

Cellular composition of the two compartments of the mucosal immune system

Answer 8

The lamina propria contains a mixture of IgA secreting plasma cells, memory T cells, conventional CD4+ and CD8+ cells, dendritic cells, macrophages and mast cells.

The major cell type in the epithelium is a CD8+ T cell which expresses an integrin which is able to bind E-cadherin, an epithelial adhesion molecule.

Question 9

How do naïve T cells become effector T cells in the intestinal immune system?

Answer 9

DIAGRAM IN L7 S10

Question 10

how do pathogens get across the membrane?

Answer 10

Unique populations of dendritic cells in the mucosal immune system capture antigen transported across the epithelium by a variety of mechanisms

• non sepcific transport across epithelium
• FcRn dependent transport
• apoptosis dependent transfer
• antigen capture

Question 11

Immune response in the lamina propria and the antigen experienced T cells

Answer 11

The lamina propria contains antigen-experienced T cells which have been activated by dendritic cells.

• The T cell population is in the proportion CD4:CD8 3:1
• CD4+ T cells secrete large amounts of cytokines including IL-17, the colon is the only place in the healthy body, where TH17 cells are found, but TH1 and TH2 also found
• These T cells would in other places cause inflammation- but balanced by Treg cells which secrete IL-10
• During infection effector activity increases owing to either more effector cells recruited or diminished activity of Treg cells

It also contains unusual populations of innate-type lymphocytes producing IL-22 which are somewhat like NK cells

Question 12

unique cells in the epithelium

Answer 12

The epithelium is a unique compartment of the immune system which contains intraepithelial lymphocytes
they are CD8+ T cells
they lie within the epithelial layer between epithelial cells

Question 13

Properties of intraepithelial lymphocytes

Answer 13

The intraepithelial lymphocytes have an activated phenotype in the absence of infection- there are two types (a) and (b).

The intraepithelial lymphocytes express CD8 and contain perforin and granzymes (a).

The TCRs on the intraepithelial lymphocytes display restricted VDJ usage (b).

The intraepithelial lymphocytes express an endothelium binding integrin.

Their importance is to recognise changes in gut epithelial cells as a result of damage or stress of infection.

Question 14

how can Effector T cells (type a) kill virus infected targets?

Answer 14

Effector T cells (type a) can kill virus infected targets by typical Class I MHC recognition

• virus infects mucosal epithelium cell
• infected cell displays viral peptide to CD8 IEL via MHC class I
• activated IEL kills infected epithelial cell by perforin/granzyme and Fas-dependent pathways

Question 15

stressed intestinal cells

Answer 15

Stressed intestinal cells express the non classical MHC molecules MIC-A and B and produce IL-15. Type b IELs are activated by IL-15 and recognise MIC-A,B with a specific receptor NKG2D

DIAGRAM IN L7 S17

Question 16

what is the secretory IgA release?

Answer 16

Secretory IgA is the antibody response associated with mucous membranes and is trancytosed with the help of Polymeric Ig R

DIAGRAM IN L7 S18

Question 17

The 3 functions of IgA on epithelial surfaces

Answer 17

• secreted IgA 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

Question 18

The mucosal response to infection and regulation of mucosal immune responses

Answer 18

The major role of mucosal immunity is to protect against a huge variety of enteric pathogens

The response must be able to recognise and respond to any pathogen, but must not produce the same response to harmless antigens (eg food) or commensal organisms

The mucosal immune response has to balance these competing demands

Question 19

Enteric pathogens cause a local inflammatory response

Answer 19

The innate immune system is usually sufficient to eliminate the variety of gut infections that can take place

Pattern recognition receptors (PRRs) like the toll-like receptors (TLR) present on epithelial cells are important in this process

Ligation of TLR stimulates release of cytokines & chemokines which attract monocytes eosinophils and T cells out of the blood and the release of antimicrobial peptides

Tissue resident dendritic cells are also attracted
– Stimulation of costimulatory molecules on the dendritic cells overcomes their normally relatively unresponsive state in the gut

Question 20

pathogens can harness what processes?

Answer 20

The inflammatory response and M cell transport can be harnessed by pathogens to aid their entry into gut epithelia-eg Salmonella enterica

salmonellae enter and kill M cells, and then infect macrophages and epithelial cells

Question 21

The GIT is a major source of antigen

Answer 21

The majority of antigens in the intestinal tract come either from food or commensal bacteria not from pathogenic organisms.

These do not raise an immune response even though they should be considered as non-self since not in the thymus when T cells are educated.

This phenomenon is known as oral tolerance and attempts have been made to harness it for the treatment of autoimmune disease.

Question 22

how is the mucosal immune system is balanced

Answer 22

protective immunity and mucosal tolerance

BY:
antigens
primary Ig production
primary T cell response
response to antigen reexposure

Question 23

how is the balance of microorganisms in the gut?

and the role of dendritic cells?

Answer 23

Peaceful coexistance of commensal organisms in the gut

Mucosal dendritic cells regulate the balance between the induction of tolerance or immunity in the intestine

Question 24

Reasons for a lack of response to food and commensals

Answer 24

The commensal organisms and food antigens do not carry the danger signals recognised by the TLRs on the surface of macrophages and dendritic cells (PAMPs).

Hence they do not stimulate an inflammatory response which is necessary to generate an immune response.

Commensal gut flora also inhibit the activation of dendritic cells, by production of molecules like prostaglandin- these cells give out weak co-stimulatory signals to CD4+ T cells making them differentiate into regulatory T cells and preventing them from activating to TH1 or TH2 cells.

Regulatory CD4+ T cells generate anti inflammatory cytokines and stimulate an anti inflammatory local IgA response by class switching.

Question 25

Can oral tolerance be useful in a medical environment?

Answer 25

Production of oral/mucosal tolerance increases levels of TGFβ which has many immunosuppressive properties.

Generation of mucosal tolerance in animal models of inflammatory disease has protective properties for that disease eg experimentally induced arthritis and encephalomyelitis.

This raises the possibility of using induced oral tolerance in treatment of human inflammatory disease, though trials have not been very promising for the treatment of established disease.