15. GI Mucosal Immunology

Question 1

What are the challenges of antigen processing in the GI tract?

Answer 1

1. Develop Self-tolerance: Non-responsiveness to self antigens
2. Develop exogenous tolerance: Non-responsiveness to an enormous array of newly encountered environmental antigens (Food and Microbes)
3. Develop an effective immune response: Elimination or control of infections, allergic and noxious agents

Question 2

How does the colon process the antigen?

Answer 2

1. Epithelial layer – specialized tight junctions that regulate permeability
2. Mucus layer – physical barrier keeping microbes from host cells
3. Innate immune responses = sensing of bacteria (eg TLRs) + anti-microbial peptides + IgA
4. Antigen presenting cells – dendritic cells and macrophage
5. Tolerance versus activation of adaptive immune response (T cell)
6. Soluble mediators of immunity – chemokines and cytokines

Question 3

What are the cells of innate immunity?

Answer 3

• Granulocyte (neutrophil (Major first-line defence against pathogens), eosinophil and basophil (role in allergy))
• Mast cell (role in allergy)
• Monocyte
• Dendritic cell
• Macrophage
• Natural killer cell

Question 4

What are the cells of adaptive immunity?

Answer 4

• CD4+ T cell
• CD8+ T cell
• B cell (memory) and plasma cell

Question 5

Outline what give rise to cells of immune system.

Answer 5

Bone marrow > hematopoietic stem cell > myeloid or lymphoid progenitor cell.

Myeloid progenitor cell: RBC, platelet, neutrophil, eosinophil, basophil, monocyte (gives rise to macrophage and dendritic cell).

Lymphoid progenitor cell: natural killer cell, lymphocytes (helper cells, regulatory cells, cytotoxic cells), B lymphocyte (> plasma cell > antibodies).

Question 6

What determines T cell differentiation i.e. whether a T cell becomes Th1 or Th2 or Treg?

Answer 6

Cytokine milieu.

Question 7

What are the soluble mediators of immune response?

Answer 7

Cytokines and chemokines are soluble mediators of immune response. Pleotropic (has different effects on different cells functions) – pro- versus anti-inflammatory functions. Amplification, cascade induction, antagonism, synergy.

Question 8

What is a major organised lymphoid structure in the gut?

Answer 8

Peyer’s Patches (contain large numbers of immune cells)

Question 9

Why are Peyer’s Patches important?

Answer 9

Important for immune responses to commensal bacteria (tolerance) and pathogens (active immunity). Allow efficient sampling of particulate antigens and deliver to APC.

Question 10

Macrophages:

1. What is their function?
2. What do they secrete?

Answer 10

1. Macrophages are phagocytic and ingest and kill foreign micro-organisms. First line defence system in the gut, sampling particulate antigens. Professional APCs to modulate adaptive immune response.
2. Secrete cytokines eg IL-10 required for the survival of FoxP3+ Treg cells

Question 11

Dendritic cells:

1. Where are they important?
2. T/F: Different DC subsets give rise to distinct T cell responses (e.g. Tolerance versus Immunity).
3. Different DC subsets are distinguished how?
4. DC present antigen to what?

Answer 11

1. Lamina propria and PP DCs are important for mucosal immune responses and for directing the function of T cells.
2. True
3. Distinguished by cell markers
4. Migrate to mesenteric lymph nodes and present antigen to naïve T cells.

Question 12

How does dendritic cells mature?

Answer 12

Immature DC are activated by microbiota, food etc. Activated DC secretes cytokines (e.g. IFN-alpha). On activation, the DC migrates to the local lymph node with the engulfed pathogen. During migration, the DC matures changing its shape, gene and molecular profile and function within a matter of hours to take on a mature form, with altered functions in particular increased expression of costimulatory molecules. Once in the lymph node, mature DC presents antigens to naïve T cells.

Question 13

What 3 signals determine T-cell response?

Answer 13

Signal 1: interaction between MHC/peptide with T cell receptor.

Signal 2 : co-stimulation through CD80 and CD86 interacting with CD28 on T cells

Signal 3 :  secretion of cytokines, notably IL-12.

Question 14

T/F: Gut health is maintained by balanced T cell responses.

Answer 14

True. T helper cells (Th1, Th2, Th17) = T regulatory cells (Th3, Tr1, Treg)

Question 15

Innate immune system:

1. T/F: It is a universal and evolutionarily conserved system of host defence.
2. How is it induced?
3. T/F: Plays no role in the induction and regulation of the adaptive immune response

Answer 15

1. True
2. Induced upon infection with microbes (e.g. intracellular pathogens) which is based on recognition of pathogen associated molecular patterns (PAMPS/MAMPS).
3. False. Plays a fundamental role.

Question 16

Adaptive immune system:

1. How is it induced?
2. What carries out its function?

Answer 16

1. Induced upon infection by specialized pathogens.
   Based on recognition of specific antigens presented by professional antigen presenting cells (eg. Dendritic cells).
2. Carried out by effector cells mainly, T and B cells

Question 17

1. Which cells are required for clearance of intracellular pathogens?
2. Which cells are required for maintaining immune homeostasis and tolerance
3. T/F: B cells through differentiation in plasma cells and IgA also contribute to mucosal tolerance.

Answer 17

1. Th1 cells
2. Tregs (Tregs, Tr1, Th3)
3. True

Question 18

Coeliac disease:

1. T/F: Inflammatory disorder of the small bowel
2. What are patients intolerant to?

Answer 18

1. True

2. Intolerance to dietary gluten in wheat & similar proteins

Question 19

How does coeliac disease present?

Answer 19

Malabsorption – failure to thrive as a child; iron deficiency anaemia, fatigue
GI symptoms – loose stool, abdominal pain or asymptomatic

Question 20

T/F: some patients have genetic susceptibility to developing coeliac disease.

Answer 20

True. Genetic susceptibility – HLA-DQ2/8 on antigen presenting cells.
HLA=human leukocyte antigen
‘Bar code’ to allow immune cells to identify self and non self antigens.

Question 21

Explain pathogenesis of coeliac disease.

Answer 21

1. Gluten peptides induce enterocytes to release zonulin.
2. Zonulin binds to receptor on enterocytes instructing the cells to looses up tight junctions
3. Gluten peptides translocate to the lamina propria.
4. They induce enterocytes to release IL15
5. TTG (tissue transglutaminase) released by enterocytes modifies gluten so it binds strongly to APC
6. Antigen presenting cells display modified gluten to T helper cells
7. Helper T cells secrete pro-inflammatory cytokines.
8. Killer T cells directly attack enterocytes
9. B cells release antibodies targeted to gluten and TTG.
   This results in changes in the gut mucosa:
   - Loss of villi – loss of absorptive capacity
   - Increase in intra-epithelial lymphocytes

Question 22

How is coeliac disease treated?

Answer 22

Some treatments work by hiding any accidently ingested gluten from the immune system while others dampen the immune response to gluten.

1. larazotide: Prevents zonulin from binding its target receptors so tight junction don’t become loose thus preventing gluten peptides from reaching immune system.
2. Glutenases (e.g. ALV003) degrade gluten into small non-immunogenic fragments.
3. Vaccine: exposes immune system to selected fragments of gluten with the aim of inducing T-cells to tolerate rather than react to gluten.