Summary - Class notes - MOD1

• 1504476000 Thema 1 Hoorcolleges

• How does the B cell recognize an antigen, and a T cell?

  B cell recognizes an antigen by the antibody. This antibody can be on the membrane (= B cell receptor) or free form (antibody). 
  
  T cell receptor binds the antigen when it is bound to a MHC molecule
• How is the development of T cells?

  Precursors in the bone marrow. they go to the thymus, there they get their education. THey generate their repetoire and go int he circulation and different lymph node most of those T cells will never react to the antigen they are mode for.
  
  progenitor cels - proliferation - double-negtive  Tcells commit to T lineage
  rearrangement bèta genes - checkpoint for pre-TCR
  proliferation double negative pre-T cell
  rearrangement alfa genes - checkpoint for TCR
  mature double positive cells
• How do we generate diversity in T cell receptors?

  Somatic recombination. all resions held lots of gens and combine in a random way.
• Which selection of T cells is in the thymus?

  Positive selection: T cells that not bind to a MHC molecule will die
  Negative selection: select those T cells that are able to recognize self antigens, to avoid auto-immunity.
• What stages are there in B cell development?

  Repertoire assembly: generation of diverse and clonally expressed B cell recpetors in the bone marrow
  Negative selection --> alteration, elimination or inactivation of B cell receptors that bind to components of the human body
  Positive selection -> promotion of a fraction of immature B cells to become mature B cells in the secondary lymphoid tissues
  Searching for infection in the lymph node and blood and secondary lymphoid tissues
  Finding infection: activation and clonal expansion of  B cells by pathogen-derived antigens in secondary lymphoid tissues
  Attacking infection : differentation to antibody-secreting plasma cells and memory B cells in secondary lymphoid tissue
• How is the structure of an immunoglobulin/antibody molecule?

  Heavy chain = 4 domains
  Light chain = 2 domains
  Heavy chains have disulfide bonds
  one antibody can recognize two different type of epitopes at the Ntermini
• Hoe ontstaat B cell diversity?

  somatic recombination
  junctional diversity --> changes in nucleotide sequence and anddition of nucleotides
  somatic hypermutation in proliferation B cells
  affinity maturation: B cells bearing mutatnt immunoglobulin moleucles on their surface are selected and those with the best binding survive
  Once a B cell found the receptor, sponaneous utations start and they generate even more diversity
• Welke soort pathogenen reageren B cellen op, welke pathogen reageren T cellen op?

  B cells react to extracellular pathogens. The antibody and B cell receptor recognize the native pathogen
  T cells react to intracellular pathogen
• What is the different of T cells and B cells recognizing the pathogen?

  B cell receptors recognize the native pathogen with their antibodies or B cell receptors
  
  T cell receptors recognize peptide antigens produced by degradation of pathogen proteins by dendritic cells. A fragment must be presented by an MHC molecule
• Welke T cell bindt MHC I en welke MHC II?

  MHCI class binds CD8
  MHC II class binds CD4
• How is the process of a MHC class I and II molecule presenting an antigen?

  Antigen outside of the cell, the antisgen will be in an endosme and in the cell fisue with a lysosome. This lysosome contains enzyms that will degrade in the antigen. 
  Golgi aparatus makes the peptides at the class II molecules go to the outside
  
  Virusintected cell. Peptides are generated in the cell itself. The golgi apaprates will encouter MHC class I molecules, which will be loaded with those pepstides and trnasposrted to the sruface.
• What kind of pathogens do MHCI molecules binds, MHC II molecules? what is the exception?

  MHC I: peptides derived from protein synthesis by the presenting cell
  MHC II: peptides derived from endocytosed proteins (extracellular)
  Exception: cross-presentation of endocytosed proteins on MHC class I molecules.
  Cancer cells present antigens antigens in class
• What is the role of a dendritic cell?

  Dendritic cells pick up antigen, transport it to the draining lymph node, where they stimulate adaptive immunity. 
  Some molecules will be degraded by the dendritic cells, other molecules will activate dendritic cells.
  
  The dangerous signal indcated that we need the immune system.
  The dendritic cell is then able to migrate through the lymph vessels through the lymph node.
  
  So  a dendritic cell is thanks to the pathogen able to:
   - migrate to the lymph node
  -  in creased the expression of co-stiulatory molecules
• What pathways do dendritic cells use to process and present antigen?

  receptor-mediated endocytosis of bcteria
  macropinocytosis of bacteria and viruses
  viral infection
  cross-presentation of exogenous viral antigens
  transfer of viral antigens from infected dendritic cell to resident dendritic cell
• What do T cells when they're not activated?

  They patrol the immune system. 
  T cells enter a lymph node by across high endothelial venules in the cortex
  They monitor antigens presented by macrophages and dendritic cells.
  T cells that do not encouter specific antigen leave the lymph  node in the efferent lymph
  T cells that encounter specific antigen profliferate and differentatie to effector cells    
  
  There is a antigen-spcecific signal and co-stimulatory signal required to activate a naive T cell.
• which cells produce the co-stimulatory signal which is needed?

  antigen presenting cells
• How do immunosuppressive drugs act?

  Suprresing IL-2 production or action.
  Naïve T cells express a low affinity IL=2 receptor
  Activated T cells express the high affinity receptor
  
  IL2 stimulates proliferation and differentation of activated naive T cells
• What happens to T cells when there is no co-stimulation?

  T cell does not respond to antigens any more, it becomes anergic.
  T cell is silenced. Next stimulation will not be activating the T cells.
  The T cells stays anergic even when their is after that a specific antigen and  co-stimulator
• Which CD4 T cells are there, what is their function?

  Th1: macrophage activation; intracellular pathogens; autoimmunity; IFN-gamma
  Th2: B cell help; extracellular pathogens, allergy (IL-4/5/13)
  Th17: extracellular bacteria, fugni, tissue inflammation, autoimmunity (IL-17)
  Treg: immune tolerance, regulation of immune respone (TGF bèta, IL-10)
• What is the function of Th1 cells?

  Th1 cells activate infected macrophages to increase their antimicrobial activity.
• What do Treg cells?

  Regulatory function .
  They can suppress the autoreactive T cells by interacting with the same antigen-presenting cells the T cells reacts to
• What is the difference between CD8 cells and CD4 cells?

  Naive CD8 cells need a stronger co-stimulatory activity. 
  Because the consequences of an unwanted CD8 cells are big.
  
  When there is a weak co-stimulatory signal, CD4 cells help
  - CD4 derived cytokines increase co-stimulation by increase B7 on APC
  - CD4 derived cytokines such as IL-2 may activate CD8 cells directly
• Activation of effector T cells is less demanding that activation of naïve T cells explain.

  Activation of naive CD8 T cell is first to recognize the antigen. 
  Needs an MHC class I molecule and an co-stimulatory factor.
  Proliferation and differenation of activated CD8 T cells
  Effector Cd8 T cells recognize and kill virus-infected epithelial target cells that is the effetor functions
• How many cells can a cytotoxic T cell kill?

  One CD8 T cell is able to recognize different virus-infected cells. 
  It programs cells to die.
• So, what do you need to activate a B cell?

  Crosslinking of B cell receptor: antigen specific signal
  Additional signal:
  - b cell co-receptor complex
  - t-cell independent and t cell dependent antigens   -> specialized Th2 cells stimulate the proliferation and differentation of naïve B cells
  
  T folicular helper cells recognizes a peptide derived from the B cells antigen. Naive B ella nd t follicular helper cells exchange signals that begin the process of B cell activation
• What are T cell independent antigens?

  they do not require help from T cells for activation of B cells. 
  - no induction of B cell memory
  - no class swithcing, you only have IgM
  
  there is a problem for vaccin development.
  
  eg: bacterial polysaccharide with repeating epitopes
• What are T cell dependent antigens?

  Antgiens that evoke B cells respones need CD4 cells. THey put the antigen peptide on a MHCII class molecule
  Induction of B cell memory
  class swithcing from IgM to IgA or IgB
• How are B and T cells respones regulated after the cells have left the primary lymphoid organs?

  anergy, regulatory  Tcells
• What happens when a T or B cell recognized the own cells (auto-immunity)?

  Immature B cells in bonemarrow: binding to self antigen can lead to deletion or inactivation
  T cells that recgonize self molecules: positive selection
  T cells that bind too strongly to self antigens: negative selection in thymus
• What are the functions of antibodies?

  neutralization of toxins (pathogens produce toxic molecules. antibodies bind to those to prevent them from acting)
  
  inhibion of adherence -> pathogens have to bind to the mucosa. antibodies inhibit the adherence of pathogens to the mucosa surface
  
  complement activation
  
  opsonization: role of Fc receptors and complement receptors, binding pathogens in a way that macrophges, neutrophils are able to recognize those pathogens in a better way
• What is the classical pathway of the complement system?

  antibody binds to an antigen, this forms an immune complex and activates the classical pathway as well
• How is the lctin MBL pathway activated?

  when MBL binds to carbohydrate antigens,
• Hoe is de opbouw van de glomerulus?

  Lots of capillaries
  Red blood clel is inside the capillary
  all our vessels are lined by endothelial cells, it is fenestrated, that is why it is possible to filter the blood
  Glomerular basement membrane and on the other side: specialized epithelium = podocytes. They have foot processes and those podocytes take care that not too much protein is lost   
  
  Mesangial clels give supe to the capillary loop
• What is another name for podocytes?

  visceral epithelium of the glomerulus
• which lines the endothelial cell in the glomerulus?

  Bowman's capsule
• What is the function of commensal flora?

  Protects harmful pathogens from collanisation of this tissues. 
  It is a very important barrier function displayed by the body.
• Which airway epithelial functions form a major host defense?

  Antimicrobial peptides, proteins and reactive oxygen and nitrogen intermediates
  Mucus barrier and biochemical properties
  Mucociliary clearance and cough
  
  Instan release of chemokines and growth factors upon infection LT3     by innate immune cells
• What mechanical, chemical and micribological mechanisms does the skin have?

  Mechanical: epithelial cells joined by tight junctions; longitudinal flow of air or fluid
  Chemicals: fatty acids; antimicrobial peptides
  Microbiological: normal microbiota
• What mechanical, chemical and micribological mechanisms does the gut have?

  Mechanical: epithelial cells joined by tight junctions; longitudinal flow of air or fluid
  lChemical: low pH; antimicrobial enzymes; antimicrobial peptides
  Microbiological: normal microbiota
• What mechanical, chemical and micribological mechanisms does the lung have?

  Mechanical: epithelial cells joined by tight junctions; movement of mucus by cilia
  Chemical: pulmonary surfactant; antimicrobial peptides
  Microbiological: normal microbiota
• What mechanical, chemical and micribological mechanisms does the eyes/nose/oral cavity have?

  Mechanical: epithelial cells joined by tight junctions; tears; nasdal cilia
  Chemical: antimicrobial enzymes in tears and saliva; antimicrobial peptides
  Microbiological: normal microbiota
• Which cells are leukocytes?

  Common lymphoid precurosr geeft: B cell, plasmacel, T cell, effector T cell, NK cel
  
  Common myeloid precursor geeft:
  monocyte, macrophage, dnedritic cell, granulocytes, mastcell
• Common myeloid precurosr:

  Megakaryocyte; erythroid progenitor and granulocyte macrophage progenitor
  
  Megakaryocyte;erythorid progenitor: megakaryocyte, erythroblast
  
  Granulocyte-macrophage progenitor: neutrophil, eosinophil, basophil, macrophgae and dendritic cell recuror and unknown precursor
  
  macrophage and dendritic cell precuror: monocyte and macrophage and dendritic cell
• What are the largest proportion of leukocytes?

  neutrophils, lymphocytes, monocytes, eosoinphils, basophils
• What are innate immue cells?

  monocyte, macrophage, NK cell
  neutrophil, eosinophil, basophil
  mastcell
• What are adaptive immune cells?

  B cell; plasma cell
  T cell; effector T cell
• What are differences between innate immune system and adaptive immunity?

  rapid respones (hours) - slow response (days to weeks)
  fixed - variable
  limited number of specificities - numerous highly selective specificites
  constant during response - improve during reponse
  
  common effector mechanisms for the destruction of pathogenes
• What happens when you have lack of innate immunity?

  Pathogens replicate and patient will die
• What happens when you have lack of adaptive immunity?

  quite okay for the first few days, but than pathogen wins the battle, replication rate will go up again. 
  Normal humans: initial replication, but controls it to a certain level. It is cordinated way of responding to invading pathogens
• What are primary lymphoid tissues?

  Cells are generated and/or matured = bone marrow and thymus for T cells