Week 12 immune signalling

• Macrophages are professional phagocytes (cells that engulf and digest foreign materials)

  • Macrophages that encounter bacteria will engulf them.
  • Cytokines are released to increase the permeability of blood vessels, allowing fluids and proteins to pass into the tissues.
  • Chemokines are released to direct the migration of neutrophils to the site of infection

  
• Pathogen-associated molecular patterns (PAMPS )-> These are non-human molecules that macrophages recognize to be foreign.

  • PAMPS are recognized by PRRs found in macrophages and dendritic cells
• PAMPS interaction with:

  • Macrophages: pathogen phagocytosis and elimination
  • Dendritic cells: are specialized phagocytes that are also antigen-presenting cells
  • this allows the connection between the adaptive immune system
  • it stimulates Naive T-cells and forms an immunity
  • this creates B-cells that make specific antibodies

  
• Innate immune system:

  • Phagocytic cells
  • includes macrophages, neutrophils, and dendritic cells.
  • Use phagocytosis to engulf foreign particles, leading to pathogen/particle destruction, as well as presentation of the degraded particles to adaptive immune system cells
  • Granulocytes
  • includes mast cells, eosinophils, neutrophils and others
  • Responds to pathogens by de-granulation (exocytosis of vesicles that contain material to promote inflammation)

  
• All innate immune cells can recognize foreign particles trigger pathogen destruction and promote inflammation
• Adaptive immune system:

  • includes B-cells and T-cells, each of which there are 100 million different cells each able to recognize and target specific epitopes

  
• part of the innate immune response involves the recognition of (1) foreign molecules or (2) molecules indicating damage to cells, and the release of factors that promote inflammatory response (can be pro or anti)

  
• Cytokines can be pro/anti-inflammatory

  • pro: TNFa , IL1, IL6
  • anti: IL 10
• Collectively, pro-inflammatory signals lead to:

  1. vasodilation to promote blood flow (deliver more immune cells to the affected area)
  2. Increase vascular permeability (leukocytes can leave blood vessels and enter tissues)
  3. increased binding and targeting of certain cells (neutrophils) at the site of infection.
  4. Increase in cell death at the site of infection ( to eliminate damaged or infected cells.)
• Not all PAMPs are the same, which means we need different PAMP receptors to identify them

  • toll like receptors (TLR) recognize specific forms of PAMPs
  • TLR2: poly glucan, porins
  • TLR4: mannan, fibrinogen
  • TLR3: dsRNA
  • TLR5: Flagellin
  • TLR6: Lipoteichoic acids, zymosan

  
• Damage-associated molecular patterns (DAMPs) --> when normal cellular components are spotted in abnormal cellular location. this alerts the cell that there might be infected/damaged cells.

  
• TLRs can be plasma membrane-bound or intracellular

  • plasma membrane-bound TLR check for PAMPs or DAMPs outside the cell
  • intracellular TLR checks for things that are already inside the cell like DNA or RNA

  NLRs and RLRs are also a thing

  
• There are many different molecules that are accessible outside of cells upon cell damage and trigger immune response, these are called damage-associated molecular patterns (DAMPs). These result in sterile activation of the adaptive immune system

  • DAMPs include molecules such as ATP, cytochrome c (usually only in mitochondria), cardiolipin ( a lipid found in mitochondria)

  
• While each PAMP/DAMP recognition by a cellular sensor is unique, most will lead to activation of an NFkB signalling pathway

  
• TLR and other PAMP/DAMP sensors activate NFkB

  • in the basal state (not activated by DAMPs/PAMPs), the NFkB protein is tightly bound by IkB. This results in NFkB being kept inactive
  • Upon binding to PAMP/DAMP, it either takes the MyD88 pathway if extracellular (TLR1/2/4) or the TRIF pathway if intracellular (TLR3/7)
  • once IK is activated it phosphorylated IkB which allows it to be a target for degradation by proteosome.
  • NFkB is free and moves to the nucleus to turn on NFkB target genes.
  • usually will be pro-inflammatory cytokines and other immune mediators.

  
• they did an experiment with mice where they did a bunch of TLR knockouts and MyD88 knockouts to see what happens to them when salmonella is present.

  • salmonella is a extracellular PAMP
  • knockout of MyD88 (extracellular pathway) caused most of the mice to die faster
  • assumed NEMO is needed since it leads to NEMO

  
• Cytokines are an important signalling molecule for immune cells

  • There are many different types of cytokines, which are small protein hormones that act as a local mediator in cell-cell communication between immune cells.
  • Cytokines include chemokines, interferons, interleukins, lymphokines, and tumour necrosis factor.
• Cytokine (IL-B)

  • cytokine receptor are similar to tyrosine kinase
  • cytokine presence dimerizes cytokine receptor and JAK trans phosphorylates each other
  • JAK then phosphorylates cytokine receptor tyrosine residue allowing STAT1/2 to bind
  • STAT 1/2 gets phosphorylated by JAK
  • STAT dissociates from receptor and forms a complex together
  • STAT is TF
  • alpha-importants leads STAT insde nucleus

  
• JAK-STAT pathway cancer-related disease

  • overall this signalling can lead to excessive inflammation and/or excessive cell growth both contributing to invasive dysplasia
• if there's too much JAK-STAT signalling you end up with tumour and cancer. If there's too little JAK-STAT signalling you become susceptible to disease.