Mucosal Immunity

• What are mucosal surfaces?

  -Surfaces exposed to the environment

  
  

  -large surfaces specialised for absorption
• What are the surface areas of the gut and skin?

  Skin ~2m^2

  Gut ~400m^2
• What do most mucosal epithelia have?

  Resident microflora

  
  

  So mucosal surfaces are the main route of entry for infectious microorganisms
• What is the difference between the systemic & mucosal system?

  
• What is the importance of mucosal immunity?

  -Protection against pathogens

  
  

  -Prevention of hypersensitivity to foods, commensal

  
  

  -organisms, microbiota, etc.

  
  

  -Immunopathology

  
  

  -Vaccine development

  
  

  -Lymphocyte development

  
• What are the mucosal tissues of the body?

  - Lachrymal gland

  -Salivary gland

  -Mammary gland

  -Uro-genital tract

  -Kidney

  -Conjuctiva

  -Oral cavity

  -Esophagus

  -Stomach

  -Intestine

  -Sinus

  -Trachea

  -Lungs

  
• What are the non-immunological & immunological aspects of the mucosal barrier?

  Non-immunological:Natural barriers (e.g. stomach acid)MucinPeristalsisProteolysisMicrovillus membrane

  Immunological:Secretory IgA/IgM (IgG)IELsPhagocytes

  
• What 2 types can we divide secondary mucosal immune tissues into?

  Inductive sites-sites at which we induce an immune response

  Effector sites-where the immune cells/immune response has its impact, much as for systemic immunity
• What is MALT?

  Mucosal associated lymphatic tissue

  
  

  Each mucosal surface has its own e.g. NALT (nasal), GALT (gut)

  
• What is it meant by a 'common mucosal immune system'?

  -Mucosal immune system is a connected series of tissues

  
  

  -All the different mucosal surfaces of the body are part of a 'common' mucosal system.

  
• What are the 2 main inductive sites in GALT?

  Peyer's patches

  
  

  Isolated lymphoid follicle
• What are Peyer's patches?

  -Sub-epithelial follicles located throughout the SI and there are ~200 in man

  
• What do Peyer's patches contain?

  50% B cells, 30% T cells, 8% macrophages

  There are very few plasma cells
• How do Peyer's patches connect to the lymphatic system?

  Only by efferent lymph vessels, they have no afferent vessels
• What do the B lymphocytes from the Peyer's patches give rise to?

  They give rise to IgA producing plasma cells which home to all mucosal sites in the body
• How do Peyer's patches differ from ILFs?

  -Unlike Peyer's patches, which are preprogrammed genetically into an organism

  
  

  -ILFs are a response to an immunological response activator such as a microbe

  
  

  -Also ILFs are more numerous than Peyer's patches

  
• What are ILFs?

  -Isolated lymphoid follicles

  
  

  -Are induced products of commensal microorganisms
• How are ILFs similar to Peyer's patches?

  Their composition: ILFs are also mainly B cells, some T cells & some dendritic cells
• What are one of the key cells associated with both Peyer's patches & ILFs?

  M cells (microfold cells)
• What are M cells?

  They're a unique epithelial subset which exist within the main epithelial barrier & they specialise in the uptake & transepithelial transport of particulate antigens
• Do M cells have a brush border or microvilli?

  No
• What is the main M cell function?

  -To take up antigen by endocytosis & phagocytosis & to then transport it across to the basal surface via vesicles

  
  

  -Once at the basal surface, these are then released.

  
  

  -whether it's taken up by B cells, macrophages, dendritic cells etc. and presented to T cells to activate them

  
• Where are M cells located?

  Located in the epithelial layer above Peyer's patches & ILFs
• What is the function of a Peyer's patch?

  In peyer's patch:

  
  

  -T and B cells become fully activated

  
  

  -T and B cells switch expression from L-selectin and CCR7 to a4B7 integrin and CCR9.

  
• What is the lamina propria?

  Tissue which underlies the epithelial layer

  
• What are the cells of the mucosal immune system?

  Conventional cells:-Dendritic Cells-Macrophages-Neutrophils-Mast cells-Eosinophils-Basophils-T cells-B cells

  specific cells:-Epithelial cells-M cells-IntraEpithelial lymphocytes-gamma delta T cells

  
• What are the T cells you find in the lamina propria?

  Majority are CD4+ i.e. Treg cells

  
  

  They outnumber the CD8+ cells by a factor of 2:1

  
  

  Most of them express alpha4beta7 integrin which recognises the ligand MadCAM

  
  

  They produce cytokines dependent on their subset

  
• What are the lamina propria T cell subsets?

  
• What is the second type of lymphocytes associated with the mucosal tissue?

  IELs (intraepithelial lymphocytes)

  These are all T cells, majority is CD8+ (a large number are CD8alpha-alpha)

  Gammadelta T cells may also be quite frequent in this population

  Unlike the T cells in the lamina propria, these cells express alphaEbeta7 integrin which recognises the ligand E-cadherin, which is particularly associated with enterocytes & epithelial cells

  Many of them are unresponsive to TCR stimulation & many are extrathymically derived ( not gone through regular T-cell production in the thymus)
• How do we get these cells to their site of action?

  Chemoattraction

  Rolling adhesion

  Tight adhesion

  Arrest of rolling lymphocyte

  Diapedesis

  
• What happens in chemoattraction?

  Chemokines recruit lymphocytes & induce expression of adhesion molecules on these lymphocytes & on surrounding endothelial cells

  
  

  In a naive lymphocyte, they'll induce the production of L-selectin on the surface of the lymphocyte

  
  

  L-selectin will then come into contact with a MadCAM-1 on the surface of endothelial cells, which will be triggered to be highly expressed in areas where we have an infection by chemokines
• What happens in rolling adhesion?

  Lymphocyte binds loosely to endothelial cells & rolls along

  
• What happens in tight adhesion?

  Chemokine-mediated activation of alpha4beta7 integrin which binds to MadCAM-1

  
• What happens once you have arrest of the rolling lymphocyte?

  You then start to see the production of other cell surface molecules both in the endothelial cell & in the lymphocytes themselves

  
  

  LFA-1 binds ICAM-1 & ICAM-2

  
  

  Further tighter binding

  
• What happens in diapedesis?

  Junctions between endothelial cells become loose or the endothelial cell itself invaginates and allows the lymphocytes to penetrate through and into the surrounding tissues

  
  

  Thus the lymphocyte extravasates & gains access to the supplied tissue from which it can move to the point of infection

  
• What is the primary function of mucosal B cells?

  To produce IgA

  
  

  Under the influence of TGFBeta and IL-5, they switch production from IgM to IgA
• What is secretory IgA & where is it produced?

  -produced at mucosal sites

  
  

  -secreted across epithelial surfaces, found in all mucosal secretions (e.g. saliva)

  
  

  -It has different functions/activities to IgG

  
  

  -IgA is the most highly produced Ig

  
• What is a further function of IELs?

  IEL protect & maintain the epithelial barrier layer, protecting against infection

  
• Compare the structure of serum IgG and IgA antibodies

  IgG on top, IgA on bottom

  
  

  IgA = dimeric joined by J chain. 4 antigen binding sites instead of 2

  
• What are features of oral tolerance?

  Normal immune function

  Tolerance can be local or systemic

  It requires a functional immune system

  Symbiosis -in the absence of commensals, a poor immune response develops and oral tolerance cannot be induced