Mucosal Immunity

1. Challenges of the GI imune system

1.1. GI surface are is 400 metres squared

1.2. Single layer of epithelium covers this to allow for efficient nutrient absorption

1.3. Must discriminate between non-pathogenic antigens- dietary proteins and commensals- and pathogenic microbes

2. Muscosal Lymphoid Tissue

2.1. Mucosal associated lymphoid tissue across all mucosal surfaces (MALT)

2.2. Gastrointestinal associated lymphoid tissue in GI tract (GALT)

2.2.1. Mesenteric lymph nodes

2.2.2. Peyer's patches

2.2.3. Lamina propria

2.2.4. Murine cryptopatches

2.3. 70% of lymphocytes found in gut

3. Non- specific Immune Response

3.1. Mechanical responses

3.1.1. Epithelial integrity

3.1.2. Peristalsis

3.1.3. Diarrhoea

3.2. Humoral

3.2.1. Gastric acid

3.2.2. Lysozyme

3.2.3. Peroxidase

3.2.4. Mucin

3.2.5. Antimicrobial peptides

3.2.6. Defensins

3.2.7. Trefoil proteins

4. Antibody Response in the Intestine

4.1. IgM, IgG and IgE are all present in gut lumen

4.2. IgA is a major secreted antibody of gut lumen

4.2.1. Around 3g of IgA/day in normal adults

4.2.2. Prevents attachment of bacteria, toxins, viruses and absorption of foreign substances

4.3. Some bacteria produce proteases that attack hinge region of IgA and prevent this

5. GD vs T cells

5.1. AB and GD cells present in intestine

5.2. AB T cells tightly regulated in thymus whereas GD develop extrathymically in liver and gut

5.3. GD T cells express RAG1 and are homodimeric for CD8- AACD8

5.4. FCER1 acts as component of the GD T cell complex

5.5. GDT cells are oligoclonal- not diverse, far fewer TCR permutations

5.6. TCRGD polyclonal in newborns

5.6.1. GD T cells may be important in earl mucosal defense before AB T cells and IgA response is developed

6. Function of GD Intraepithelial Lymphocytes

6.1. Surveillance of intestinal epithelial layer against microbial invastion

6.1.1. Cytotoxic against microbial pathogens by lysing infected cells

6.1.2. Provide B cell help

6.1.3. Produce cytokines and chemokines

6.2. Support Epithelial cell growth and maintenance of barrier integrity

6.2.1. Production of growth factors- keratinocyte growth factor

6.2.2. Removal of damaged or transformed epithelial cells

6.3. Immunoregulatory functions

6.3.1. Abrogating/ promoting oral tolerance

6.3.2. Producing immunoregulatory cytokines

7. Peyer's Patches

7.1. Organised lymphoid Tissue aggregates composed of:

7.1.1. Specialised follicle associated epithelium (FAE)

7.1.2. Overlying a subepithelial Dome (SED)

7.1.3. Overlying B cell follicles containing germinal centres (GC)

7.1.4. Interfollicular regions (IFR) contain T cells, high endothelial venules (HEV) and efferent lymphatics

7.1.5. All lymphoid migration occurs from blood across HEV- no afferent lymphatics

8. M Cells

8.1. Primary site of antigen handling in gut

8.2. Specialised epithelial cells

8.2.1. Poorly developed brush border

8.2.2. No microvilli

8.2.3. Thin glycocalyx

8.2.4. No hydrolytic enzymes

8.2.5. Express MHCII on basolateral surface

8.2.6. Rich in pinocytotic vesicles

9. Fate of antigen in Gut

9.1. Preprocessed in gastric lumen

9.1.1. Gastric acid

9.1.2. Gastric enzymes

9.1.3. Pancreatic proteases

9.2. Antigen absorbed but doesn't evoke reponse

10. Antigen Sampling

10.1. Dendritic route

10.1.1. Dendritic cell samples luminal antigen from intestinal lumen and presents this to lymphatic cells

10.2. Epithelial cell route

10.2.1. Antigen translocates through epithelial cells of intestine

10.2.2. Can be taken by macrophages to be presented

10.2.3. Can directly enter into circulation by passing through lamina propria into capillaries

10.2.4. Sampled by dendritic cell where it's presented to T cells in interfollicular regions in follicles to stimulate IgA production

11. Lymphocyte Homing to Tissue

11.1. Tissue selective trafficking

11.2. Initial exposure to antigen in mucosal inductive sites- peyer's patches

11.3. Efferent lymphatics

11.4. Mesenteric lymph nodes

11.5. Blood

11.6. Mucosal homing- expression of a4b7 on lymphocytes

11.7. Expression of CAMS on lamina propria

12. Vascular Adhesion Molecules

12.1. MAdCAM-1

12.1.1. Mucosal addressin cell adhesion molecule- selectively expressed on postcapilarry venules in lamina propria

12.1.2. Also expressed on GALT

12.2. Intestinal homing receptor a4b7

12.2.1. Heterodimeric adhesion molecules, highly expressed on intestinal memory and effector cells, ligand for MAdCAM-1

13. Importance of Lymphocyte Homing

13.1. Vaccine Development

13.1.1. How do you direct lymphocytes in gut systemically

13.1.2. How do you direct immunised lymphocytes in gut

13.2. Therapeutic implications

13.2.1. Block interactions of MAdCAM1 and a4b7 to block inflammatory lymphocytes from entering gut