Microbiology

1. Red bone marrow stem cells give rise to B cells with IgM and IgD on their surfaces, which recognize
specific epitopes.
2. For T-independent antigens: a clone of B cells is selected by free antigens.
3. For T-dependent antigens: the B cell’s immunoglobulins combine with an antigen, and the antigen
fragments combined with MHC class II activate TH cells. The TH cells activate a B cell.
4. Activated B cells differentiate into plasma cells and memory cells.
5. B cells that recognize self are eliminated by clonal deletion.

Development of self-tolerant immune cells is a natural outcome of the lymphocyte (T-cell, B-cell, NK cell) maturation process, if everything is working correctly. Since it is impossible to encode in DNA all the instructions to create the billions and billions of receptors or antibodies necessary to recognize the "intruders" your body may encounter in a lifetime, lymphocytes are actually created using a huge process of trial and error. There are a relatively small set of "parts" encoded in DNA, and these parts are combined randomly to create a huge variety of receptors. As a result of this, it is inevitable that many of these random combinations will result in receptors that are reactive to the host's own cells, and many of the others won't work at all, so the immune system makes these new cells undergo essentially a series of tests in a controlled environment before they even make it into the circulation.

The process for B-cells is pretty straightforward - in the bone marrow, if at any point in its maturation the antibody created by a B-cell recognizes a self-antigen, that cell either sent a signal to die (apoptosis), or is inactivated (anergy). Non-functioning cells also undergo apoptosis. As a result, the only B-cells that reach maturity and leave the bone marrow into circulation are those that do not react to the host. T-cells are a bit more complicated. The T-cell receptors (TCRs) need some degree of self-recognition, as they must recognize and bind the appropriate receptors on the host's cells (MHC I and II) in order to do their job. As such, as the T-cells mature in the thymus, they first undergo a process of positive selection in the thymic cortex, where the ones that do not react to MHC undergo apoptosis. However, the immune system doesn't want TCRs that react to the host's MHCs *too* strongly (i.e. enough to activate the T-cell on its own), so from there, the cells move to the thymic medulla, where cells that react too strongly are also killed off (negative selection). Something on the order of 98% of T-cells fail one of these tests and never make it into the circulation, so it is easy to see how there is a very delicate balance between autoimmunity and no immunity. Of course, these processes aren't perfect, and mistakes do occur, which is why we can and do end up having various autoimmune conditions as a result of self-recongizing B and T cells.

(Note: I left out basically all the details of lymphocyte maturation processes here, but there are plenty of good resources to be found that can do a much better job than I can - just search for "T-cell maturation" or "B-cell maturation" or "VDJ recombination" for example)