Immunology

• Mucins


  Form a thick viscoelastic protective coating over the epithelial layer of the gut
• Mucin formation


  Individual glycoproteins connect via di-sulfide bonds to form gigantic cross-linked polymeric networks that are viscous (sticky, tangled network traps microbes and other intestinal antigens)
• Glycosylation of mucins


  Results in mucins being negatively charged, and keeps them in an extended configuration that is well hydrated (to form a thick layer)
• Pathogens become entangled in mucins


  They are moved through the GI tract and out of the body
• Need to get rid of some of these every day!
• Beneficial commensal gut bacteria

  • Make vitamins, break down carbohydrates, degrade toxins, and prevent colonization by pathogens and communicate with the immune and nervous systems
• Waldeyer's Ring


  A protective ring of lymphoid tissue guards the entrance to the respiratory and GI tracts
• Tonsillitis


  1. Waldeyer's ring in action

  2. Day 4

  3. Day 5

  4. Day 6

  5. Day 7

  6. Innate

  7. Adaptive
• Appendix


  Packed with lymphoid follicles
• Secondary lymphoid tissue in the gut

  • Isolated lymphoid follicles
  • Peyer's patches
• Isolated lymphoid follicles


  Mostly composed of B cells
• Peyer's patches


  Like a mini-lymph node, with a dome area that projects into the lumen, populated by B cells, T cells and dendritic cells
• Peyer's patches are visible as a small bulge in the side of the small intestine
• Gut microbes and their hosts have coevolved into a symbiotic relationship
• When mice are raised in a germ-free environment, their GI tracts and immune systems do not develop or function normally
• Malnourished children who are given a nutritious diet are unable to absorb nutrients normally. Their gut lining is underdeveloped, and their microbial profile is abnormal (more pathogens than commensals)
• Colonization and maintenance of the gut microbiota during early childhood is vital for proper endothelial development and immune function
• Inflammatory response


  Part of the arsenal used by the systemic immune system to fight infection
• Mucosal immune system


  Does not use the inflammatory response
• Mucosal immune system response

  1. Continuously samples the microbial population

  2. Activates effector cells and molecules (IgA) accordingly to be ready and waiting to be ramped up if and when they are needed
• Systemic immune system


  Can't anticipate the type of infection it will have to respond to, so it must begin the response from scratch: from innate to adaptive response
• Mucosal immune system


  Constantly anticipates the type of infection that it might have to respond to (by continuously sampling and activating cells in the Peyer's patches), so it has effector cells already waiting to respond immediately if the epithelial lining is breached by microbes
• Epithelial cells in the gut lining


  • Play an important role in the innate immune response, since they have various TLRs that bind to bacterial ligands. Binding to pathogen markers triggers the production of chemokines and cytokines that attract neutrophils and macrophages to the area
• The inflammatory response is localized, and usually gets cleared quickly. These epithelial cells turnover and are shed every two days, so the debris from the infection and inflammation will be carried away
• If not, then an adaptive immune response will occur in the draining mesenteric lymph node
• Intestinal macrophages


  Do phagocytose and kill pathogens, but they do not promote inflammation or activate other cells of the immune system
• While they present antigens with MHC-II, they lack the B7 co-stimulator so they can't activate naïve T cells
• They also turn over every few months so new monocytes get recruited to the area
• Inflammatory response in the gut

  Highly regulated, since inflammation and the consequent tissue damage would provide an opening for microbes to enter the tissues. Inflammation is prevented by Treg cells which secrete IL-10, an anti-inflammatory cytokine
• Intestinal macrophage development


  Blood monocytes that enter the intestinal lamina propria from the blood develop into intestinal macrophages (under the influence of TGF-b and other cytokines secreted by intestinal epithelium and stromal cells). As they mature into macrophages, they change their surface marker profile, so they are no longer receptive to pro-inflammatory signals such as bacterial LPS or the Fc portions of IgGs
• Intestinal macrophages do not activate NFKB, which is the master regulator of the inflammatory response
• M cells


  Have a ruffled surface that captures microbes from the lumen and transports them to the Peyer's patches and lymphoid follicles that are located underneath them
• Microbe transport by M cells


  A sample of microbes from the lumen is transported to the intra-epithelial pocket on the basolateral side of the M cell. Microbes can be taken up by receptor-mediated endocytosis or macropinocytosis and transported through the cell
• Antigen presentation in the intra-epithelial pocket

  B cells and DCs take up and then present antigens to activate antigen-specific effector T cells and plasma cells
• Plasma cells


  Secrete IgM and dimeric IgA specific for gut microbes and other gut antigens
• Shigella and other pathogens take advantage of the easy entry point provided by M cells
• Dendritic cells


  Can sample the lumen using their dendrites and do so without disturbing the junctions between epithelial cells
• Sampling of the intestinal antigens occurs continuously via M cells and dendritic cell antigen capture and transport to the underlying lymphoid tissue
• Homing of mucosal lymphocytes


  Naïve B and T cells enter the Peyer's patch via the HEV, become activated and proliferate. They move from the Peyer's patch to the mesenteric lymph node, into the circulation and back to the mucosa through the lamina propria. There they reside and carry out their effector functions (killing or secreting IgA)
• Homing signals


  • Integrins and chemokines
  • Integrins are produced by vascular endothelial cells (this helps slow down the homing immune cells so they can extravasate into the lamina propria)
  • Chemokines like CCL25 are produced by intestinal epithelial cells. Immune cells follow the chemokine gradient in order to reach their destination (the intestinal epithelium)