Lecture 22

Lecture 22 – Immunity Continued: http://en.wikipedia.org/wiki/Antibody

 
 

• There are different classifications of immunoglobins.
  

Immunoglobin	Heavy Chain	Classification	Properties
Ig-G	Gamma	Monomer	There is more Ig-G immunoglobin than any other Ig in the body. 75% to 80% of all circulating antibodies are Ig-G. Only one that can cross the placenta. Only occurs in humans, not in horses. The baby born full of antibodies, even though the immune system does not start for 60 day, it will have immunity.  This has a flexible hinge. Ig-G's switcher is T Helper Cell 2 (TH2), but also TH1 can stimulate some of the Ig-G immunoglobins. A colt must drink the very first milk (colostrum) – has its antibodies.
Ig-M	Mu	Pentomer – five monomers	Ig-M and Ig-M spikes are the only things a B cell can make when it is first activated.  The B cell has to be Switched to activate all the other immunoglobins.  Early in the production of the B cell, its surface stuck out an Ig-M, but it was a monomer when it did that.  .  When released in the blood stream, it was a Pentomer (it is always a monomer at the surface of the cell).  Disulfide bond bind/stick all of the monomers together. There are disulfide bonds between each on of them except the last two, they were originally lined up in a row and then a J chain came by – the J chain came around and made it into a circle. This has ten active sites for binding.  Ig-M has no hinge. If it was presented at the cell it was a monomer, but if it was secreted it was a Pentomer with a J chain.
Ig-A	Alpha	Monomer that changes to a dimer	It was created as a Monomer, but it is changes to Dimer with a J chain attaching between it. It becomes a Dimer before it gets out into the secretions. There is a special protein that attaches to the J-chain and allows the Dimer to go out with the secretions.  The secretary components in Ig-A are: tears, saliva, intestinal juice, sweat, and milk.  In order for these to be secreted they need this component attached to the J chain itself.  This has a flexible hinge.
Ig-D	Delta	Monomer	It is a B-cell receptor; it is always attached to the surface of a B-cell; it is never floating free/never released from the B-cell.
Ig-E	Epsilon	Large Monomer	Is created from Ig-G (which is the second switcher). It has no hinge, so it has a C domain where the hinge would be.  The switching agent is TH2.  This is secreted by skin, tonsils, GI tract, or Respiratory mucosa.  Ig-E attaches to eosinophils and mast cells. This has to do with an allergy response/non-specific immunity.

 
 

• The first exposure, the primary antibody production is Ig-M, and the Ig-M will appear approximately 5 days after the exposure to the antigen/5 days before kicking out antibodies of any kind. This is called the Lag Time
  
• With continued exposure the TH cells and B cells will switch to Ig-G production. Upon re-exposure to the same antigen the Lag Time will be cut to about 1/3 of what it was on its original exposure. So when we see it again it will occur much faster.
  

 
 

How do antibodies destroy the antigen:

• Agglutination – binding of many antibodies together into a functionless clump. The clump is then eaten by phagocytes (macrophages).
  
• Neutralization – Some antigens will have toxic binding sites, and the antibodies can be set to specifically bind to the toxic site. Then the toxic site cannot bind to wherever it is suppose (the toxic thing) to and it is rendered neutral.
  
• Compliment Activation – antibodies work also through the activation of compliment proteins
  

 
 

These things bind to Eosinophils and Mast Cells

• Eosinophils work mainly binding Ig-E at their surface, which is an immunoglobin that is programmed for a specific antigen, and thus it is part of the Adaptive Immunity. 
  
• The Eosinophils and Mast Cells fall under non-specific immunity b/c they can bind any Ig-E (although Ig-E may be programmed for specific antigen, the Eosinophils and Mast Cells can bind any Ig-E, there is no specific one); however the Eosinophils and the Mast cells, since they are using Ig-E, which didn't evolve until after the Adaptive Immunity came into being, they are really part of the Adaptive System
  
• Eosinophils and Mast Cells are both stimulated by IL5 to be activated from TH2 cells
  
• Eosinophils: attack mainly parasites, and they have a Low Affinity Ig-E Receptor that means that Eosinophils will not bind Ig-E until there is a lot of Ig-E.  There will not be a lot of Ig-E until you are actually having a reaction. By the time they come to this they will bind Ig-E, Ig-G, or Compliment Coated parasites. Ig-E is already on the parasite by the time it gets to bind an Eosinophil, but that activates the Eosinophil. The activated Eosinophils will increase the number of receptors at their surface, they will increase the production and release of free radicals, and they will release the contents of their granules (the granules contain free radicals and inflammatory chemicals) Free radicals kill??????
  
• Mast Cells: have High Affininty Ig-E Receptors are attacking allergens, but Ig-E don't need to be attached to the allergen to attach, these are High Affininty, they will bind to Ig-E even when there is only a little bit of Ig-E present, whereas an Eosinophil will not. When an allergen comes on to an Ig-E attached to the cell, the Mast cell is activated and it releases the contents of granules into the surrounding. The Chemicals of a Mast Cell are Chemotaxic -- they will attract other white cells, and cause the inflammation response (ex. Histamine). The Mast cells have no other effect/activity other than attract white cells or cause the inflammation response.
  

 
 

The Immune response is what is actually doing our blood typing:

• No blood type when you are born until after 60 days when your immune system kicks in. Not genetically determined.
  
• Carbohydrate markers on the surface of RBC's called Agglutinogens
  
• ABO system -- 4 blood types, differ according to their Agglutinogens at their surface:
  
  • Blood – O = H Agglutinogen at the surface (with nothing else stuck to it)
    
  • Blood – A = H Agglutinogen on top of it is a N-acetylgalactoseamine (A-Agglutinogen)
    
  • Blood – B = H Agglutinogen on top of it is a Galactose (B-Agglutinogen)
    
  • Blood – AB = has both A and B Agglutinogens.
    
• This is termed the ABO System of Blood Typing.
  

   
   

  
  

   
   

  Screen clipping taken: 3/31/2009, 8:55 PM
  

   
   

• A and B Agglutinogens commonly found on the surface of intestinal bacteria. Antibodies that are produced to attack those bacteria will attack A and B, but thanks to hypermutation it is going to match perfectly.
  
• These antibodies that are being produced are called Agglutinins
  
• Agglutinogens are on the surface, and Agglutinins are in the plasma (the humorus)
  
• Immune system starts up 60 days after birth, it starts to make antibodies and look at all the different bacteria that are around. There are bacteria in the gut, that have carbohydrates in their cell walls similar to A or B agglutinogens. There is not one that is similar to the H-agglutinogen alone.
  
• Naïve B-cell is in bone marrow, as part of its maturation, it sticks Ig-M onto its surface and that Ig-M has active sites for recognizing as an antigen. If stimulated by itself, it will die a programmed cell death. People who have type A blood cannot make type A-Agglutinins (cannot make anti-A), people who have type B cannot make type B-Agglutinins (cannot make anti-B), people who have type AB don't have either A or B Agglutinins (cannot make anti-A or anti-B), and people who have type O make both A and B Agglutinins (make both antibodies).
  
• Antibodies are termed agglutinins.
  
  • Anti-A or Anti-B.
    
  • Giving blood to a person/transfusion of 1 unit/pint of blood it does not matter what the Agglutinins (antibodies) are b/c they get so diluted that they don't make a difference to the receiver.
    
  • The receiver's Agglutinins are what matters. It is the agglutinins of the receivers blood going to attack the blood coming in and that will turn very toxic for the person if improperly matched
    
  • Type O is thought to be the Universal Donor no reactive agglutinogen
    
  • Type AB is the Universal Receiver no Agglutinins.
    
  • All of the above is only true when we are talking about a transfusion of only one unit of blood, but if you are putting a great amount of blood into a person then the agglutinins of the donor will matter, you want it to match. The Agglutinins will start compacting the cells and they will take the plasma off and they will only give the person cells only
    
• Type and Cross Match
  
  • Type – determine the type
    
  • Cross Matching – mix blood with blood of person who is going to get the blood, and see if a reaction is produced. If there is no reaction then they will give the blood.
    
  • If you are giving a lot of blood, they might pack the red cells, by draining the plasma off, because that is where the antibodies are. This means they can give more blood that is not quite right to the person because they are getting rid of the antibodies.
    

The Rh Factor (Rhesus Monkey):

• You didn't have a blood type for the first 60 days of your life b/c your immune system wasn't working in those first 60 days.
  
• There are at least 8 Rh factors, but only C, D, and E most common Rh factors
  
• Rh + have D factor at their surface, and Rh – don't have D factor at their surface  – it is an agglutinogen and it is on the surface of the RBC's.
  
• Those who have the D are Rh+ and those who do not have the D are Rh-.
  
• Rh – people do no produce anti-A agglutinins unless they are exposed to Rh+  blood, see the Rh – people can make agglutinins b/c they are not used to seeing the D, but they have to have an exposure
  
• There is nothing to automatically stimulate the production of antibodies here. There must be exposure to the blood.
  
  • An Rh- is initially exposed to Rh+ blood, everything will be okay because they don't have any antibodies against it (hasn't made any agglutinins). But the second exposure to the blood will cause problems because there are now antibodies present.
    
  • Pregnant Women: Rh+ baby in Rh- mother; mother has no antibodies against the Rh and the first baby is fine. In birthing lots of tissues are stretching and ripping, the blood from the baby and mom are going to mix.
    
  • Now the mom gets pregnant for a second time, the baby is Rh+, now she has Ig-G's that will cross the placenta that will kill the second baby.
    
  • After the first baby is born there are 48 hours to inject the mother with a Rho-gam shot (rho – rh factor, gam – gamma globulin) to prevent the mother killing a second baby with an Rh+. Rho-gam is a gamma globulin that has agglutinins in it. What they are doing is killing the antibodies off that were produced by the first baby's blood causing the mother to make agglutinins. After 30-60 days all those agglutinins will be gone and the woman is ready to have another baby without a problem, as long as she gets a Rho-Gam shot after each Rh+ baby.
    
• Only blood factors A, B, and D cause significant blood transfusion reactions.
  

-Everything above was Humoral Immunity (those things that are outside a cell)- 

 
 

Cellular Immunity: Defense against antigens that have entered into a cell (how to attack things that have gone inside a cell – ex. Viruses)

• Any nucleated Somatic cell (is a cell that is not a germ cell) in the body that is invaded by an antigen can be an Antigen Presenter –  we might find an antigen inside a Somatic cell, and it will break the antigen into pieces and stick them out onto a MHC Class I protein at the surface of the cell.
  
• A T8 Cell (has a CD-8 at surface) – CD-8 – will react with the MHC Class I
  
  • Recall: CD-4 cells bound to MHC class II proteins, but MHC class I proteins are virtually on all somatic cells
    
  • The T8 cell will bind to the MHC class I protein.  The T8 cell has a T-cell receptor (TCR), which can find the pieces of antigens.
    
    • This cell will migrate into lymphoid tissue – T8 cells are doing a lot of the bumping around looking for match.
      
  • When the TCR is bound to what it is recognizing, it is going to stick out and IL-2 receptor, and IL-2 will bind on it.  But the IL-2 is not made from the T8 cell, it is made from the TH0 cell - this is the Peracrine Effect – the next person down the line is getting activated.
    
  • The T8 cell becomes activated when the IL-2 binds to it, and makes a TK cell (T Killer cell) (k=killer, t= memory cell), which has more CD-8 with the same T-cell receptor. The TK cells go around and kill the cell that have the antigen within them, but they will slowly change to Memory cells, and they cane proliferate and become something called a T-Regulator Cell (they used to be called Suppressor cells).
    
  • Memory Cells look for the same antigen to appear again.
    
  • T-Regulator Cells = shut system down, suppress plasma cells, T-helper cells, and TK cells = only the memory cells remain after the regulatory cells have come around.
    
• TK cells kill by Apoptosis (programmed cell death (Cell suicide) in the target cell, triggered by a cascade of proteases which are initially inactive within the cell itself called Caspases, activated by the TK cells.  The Caspases destroy the nuclear envelope and the DNA of the cell – killing the cell.  Also, the TK cell will place a phagocytic marker on the cell surface and it will free the cell from the surrounding cells and that will easily by phagocized by Macrophages.
  
• T Killer cells can activate this Caspase Cascade in 2 ways:
  
  • 1.) They can insert a protein called Perforin – a protein that makes holes in the cell plasma membrane, and the hole is about 10 to 20nm in size, and they will inserts and enzyme called Granzyme B, which activates the caspase cascade – this kills the cell.
    
  • 2.) The TK cell has an FAS ligand (can bind FAS) – some cells are trying to commit suicide b/c they are inhabited by something that is not good.  The cell with the antigen can stick out FAS at its surface, and when in contact each other the Caspase cascade occurs and the cell dies.
    

 
 

• There are migratory cells that are similar to Naïve T cells
  
• T Memory Cells are migratory cells similar to Naïve T cells but they react more quickly when they are stimulated with another encounter with the same antigen
  
  • Naïve T Cells migrate only to lymphoid tissues
    
  • Activated T cell can activate throughout non-lymphoid tissues
    
• As the reaction slows down (b/c the T8 cells are winning the immune response), the activated T8 cells will become Memory T8 cells.  These cells will migrate preferentially to tissues that are connected to the lymphoid tissues where the antigen was first encountered. These Memory T8 cells can live very long lives.
  
• When we talked to you about the blood we talked about T lymphocyte production, and we said that Naïve T lymphocytes can live a very long life, but in order to do so they have to be Tickled in order to be maintained by running into a MHC I protein in order to be maintained anymore, they can just keep running into these MHC I proteins they can live a very long time.  But these Memory T8 cells don't require Tickling in order to live for a very long time.
  
• T4 Memory cells come in the same manner, but the activated T helper cells are going to slowly change to Memory cells. But a T4 Memory cells (in about a year or a little more than a year) they will be gone. Some of them will die and some will revert to become T Naïve cells again (Naïve T4 cells) as though they were never exposed to an antigen, but either way they will be gone in a year or year and ½, but they can come back with another exposure to the antigen so long as they are being produced.
  
• T Regulatory Cells are referred TR Cells, but they used to be known as T Suppressor Cells
  
• we haven't found T Regulatory/suppressor cells in humans, so we haven't been able to find them rats and mice, and we do a lot of immune response research in rats and mice, but we don't find them in humans
  
• The TR cells that are found (in the animals that have them) will proliferate more slowly than the other T cells
  
• Their role is to suppress Plasma Cells, TH cells, and T killer cells
  
• The TR cells in number will increase until only Memory Cells remain, and they won't attack those that are Memory Cells
  
• We can't find TR cells in human beings, but that is what they are doing in other animals
  

 
 

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Agglutinin = antibody

 
 

Agglutinogen = antigen