(From Dr. Cain’s lecture, 12 Sept 2000, by Brian Buschman)
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Endogenous antigens are phagocytosized and mixed with MHC II and placed on the surface of the APC’s surface to show them off for presentation. When a virus or other antigen ends up within any cell it will get digested, mixed with MHC I and displayed so that cytotoxic T-cells can come and gobble it up.
When an APC meets with a T-cell the T-cell has a TCR which binds the Ag which the APC is presenting on MHC II. The T-cell also has a CD 4 molecule which binds directly to the MCH II to further stabilize the interaction. The combination of those two connections is called dual recognition and both must be present for the T-cell to do it’s work.
The T-cell/APC interaction is also stabilized by the interactions of other CDs, ICAM, LFAs and B7s.
LTLA-4 is a molecule that replaces CD28 to stop the activation of the T-cells that are induced by the APCs. The lack of LTLA-4 is the cause of some allergies because the T-cells keep on mediating the immune response long after they should have stopped.
B-cells also show off antigens to T-cells using MCH II and the T-cells still use their TCR and CD 4 in the process. The difference is that the interaction is stabilized by CD40-CD40L. This has been and will probably be an exam question to know that CD40 and CD40L are only found in the B-cell/T-cell interaction, not the APC/T-cell interaction.
We know that both B-cell/T-cell interactions and APC/T-cell interactions make use of MHC II, CD 4, TCR as well as CD28-B7.
There is a type of antigen called a superantigen that causes non-specific binding of MHC II to T-cells. That means that superantigen allows APCs to activate T-cells when there is no antigen present. The TCR sits directly against MHC II and Vb stabilizes the interaction rather then CD 4. This is the mechanism that is seen in TSS. It causes a polyclonal response.
Tolerance is a natural mechanism by which clonal deletion (anergy) removes clones that would fight self if released to the body. Thymic nurse cells bind to the T-cells as they develop. If the nurse cells sense that the T-cell will bind to self then the nurse cell will bind tightly to the T-cell which is the signal for deletion of that T-cell. If it notices that the T-cell will not bind self then it will bind the T-cell lightly which allows it to develop and be released to the system.
Autoimmunity diseases may be organ specific or systemic. Many diseases appear organ specific like SLE with it’s effects on the kidneys but are really systemic diseases. Most autoimmune diseases have some genetic HLA (chromosome 6) link. Inheritance is multifactoral.
Autoimmune disease is a result of antibodies that are produces to self. In Baselow’s disease or Graves disease antibodies are produced against thyroid cells. Male infertility, in some rare cases, can be caused by antibodies to sperm. In pernicious anemia antibodies are produced to intrinsic factor and gastric parietal cells. This prevents necessary uptake of vitamin B12 and hence this type of megaloblastic anemia.
When a self antigen is presented on the surface of an APC it can be in high or low concentration. If the antigen appears in high concentration then it is a dominant antigen and the clone will be deleted. On the other hand if the antigen appears in low concentration the deletion mechanisms will overlook it and allow it’s release into circulation. This is a cryptic self antigen because of the way it hides while going through the thymus.
There is a default down regulation which helps suppress the activity of some cryptic antigens. But it requires enough Ag for it to be able to respond. Hence when cryptic antigens try to slip by they might get caught but they might not.
Some autoantibodies are made because microbial Ags will be presented by the APCs to the TH-cells and at the last minute a self antigen will slip into the mechanism and will cause Abs to be produced against itself.
Other autoantibodies come when the process presents an antigen that has both a domain that does not resemble self and another that resembles self. In this case the APC may grab the Ag by a part that does not resemble self and when it shows it off to the T-cell the T-cell will clone the part that resembles part of our body. This will cause production of autoantibodies.
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