In this video, we're going to introduce and differentiate central immune tolerance and peripheral immune tolerance. It's important to note that sometimes our adaptive immune response can make a mistake, and it can mistakenly produce what are known as self-reacting T and B cells. Self-reacting here just means that these T and B cells will react to our own self cells that are healthy and uninfected. These self-reacting T and B cells will actually harm our own healthy cells, which is a bad thing. Again, this is a mistake that our adaptive immune system can do occasionally.
In order to prevent this mistake from happening, our body has to be able to build up a tolerance by strictly controlling T and B cell development to make sure that these self-reacting T and B cells are not produced. There are two types of tolerance mechanisms that control T and B cell development: central immune tolerance and peripheral immune tolerance. Central immune tolerance is going to occur via negative selection of mature T and B cells before leaving the primary lymphoid organs. Recall that the primary lymphoid organs include the bone marrow for the B cells and the thymus for the T cells. The negative selection of the mature T and B cells involves the elimination or the removal of the self-reacting T and B cells by apoptosis, essentially killing any cell that binds self or harmless antigens.
Peripheral immune tolerance, on the other hand, involves the selection of mature T and B cells after leaving the primary lymphoid organs and making their way to the secondary lymphoid organs. Peripheral immune tolerance involves both negative selection as well as positive selection. It will positively select T cells that bind any major histocompatibility complex (MHC), promoting T and B cells that bind their antigen, and it will negatively select T cells that bind harmless antigens. Positive selection refers to promoting cells that do something, and negative selection refers to inhibiting or killing cells that do something.
These self-reacting T and B cells will actually become anergic or unresponsive, and eventually, they will undergo apoptosis, negatively selecting for those T cells that bind harmless antigens. Between these two tolerance mechanisms, central tolerance and peripheral tolerance, these mechanisms are so strict that approximately 95% of all the T and B cells that we initially create are going to undergo apoptosis, and only 5% of the T and B cells will be able to make it through these tolerance mechanisms. This small 5% of the T and B cells that make it through are going to be very effective at doing their job appropriately and targeting harmful antigens appropriately.
If we take a look at this jigsaw down below, we can better distinguish between negative selection and positive selection. Negative selection, as its name implies, is going to involve something negative here. If you do this, whatever this may be, then you die. Negative selection means that it's going to be killing or eliminating cells that do something specific. In the case we're discussing here, negative selection is applied to T and B cells, where if the T and B cells bind to harmless and self antigens, then they will die. Positive selection, on the other hand, is somewhat positive: if you do this, you get to survive, and if you don't do it, then you die. Positive selection involves reinforcement for something that is happening. In our discussion, positive selection is promoting and allowing cells that bind any MHC to proceed forward and survive.
Notice on the left hand side of this image we're focusing on central tolerance, occurring before the immune cells leave the primary lymphoid organs. For T cells, that would be the thymus. On the right hand side of our image, we're showing you peripheral tolerance after the immune cells leave the primary lymphoid organs and go to secondary lymphoid organs such as the lymph nodes. Central tolerance involves negative selection, meaning that if cells do something, they will be eliminated, and that something in this case is binding to self antigens.
Notice that most of the self-reacting T cells here are going to be eliminated via apoptosis, which is a good thing. However, sometimes negative selection can fail, allowing a self-reacting T cell to leave the primary lymphoid organ. But notice that these T cells down here are not self-reacting T cells, so they are not going to be eliminated and will be able to leave the primary lymphoid organs. After these T cells leave, they will be exposed to peripheral tolerance mechanisms in the secondary lymphoid organs. Positive selection is going to be, if you do this then you get to survive, and this in this case is going to be binding to the appropriate antigen.
After these cells are exposed to positive selection, then they will be exposed to negative selection. Again, cells that do something are going to be eliminated. This cell is self-reacting, so in this peripheral tolerance, it's going to be exposed to more harmless self antigens. When it responds to harmless self antigens, it will become anergic and ultimately undergo apoptosis. Notice that the cell responding appropriately to something that is harmful will proceed forward and survive, ultimately generating an immune response. So, in the very beginning, we had a total of 6 T cells produced. However, of these 6 T cells, only one is able to make it through both central and peripheral tolerance mechanisms and generate an immune response.
This concludes our brief lesson on central versus peripheral tolerance mechanisms, and we'll be able to get some practice applying these concepts as we move forward in our course. So, I'll see you all in our next video.
