Self vs. non-self...do we know the difference? - (Mar/10/2011 )

Dear Forum members,

I am new in the field of immunology and I am learning to make monoclonal antibodies. I am puzzled by the self vs. non-self antigen recognition topic because as I progress in the reading of the literature, I get the impression that there is nothing clear. This topic is important for me to know if I have any limits in producing antibodies in mice. So, to start with, self-recognizing B-cells are killed or simply desensitized? If the latter, if there any clear way to reactivate the cells? How does the antigen-presenting route affect the immunogen response (i.e. subcutaneous, i.p., in vein)? If I want to make antibodies against a mouse protein...is it better to work with knock-out mice for that protein (if available)?
In the same venue...why a mother does not reject her child when she is pregnant?
I will appreciate your help to disclouse -at least- part of this puzzle.

Chelo,

first of all, you have to know that self vs. non-self is not absolute, that is why we have autoimmune disorders. Generally there are mechanisms of central tolerance (where autoreactive T or B-cell clones are deleted or turned into regulatory cells) and peripheral tolerance (where autoreactive cells either become anergic or inducible regulatory cells). There is a myriad mechanisms that determine whether a foreign protein will be immunogenic or tolerogenic, but at least for peripheral tolerance a pretty much accepted theory is the danger hypothesis, that says that if a protein is presented in a milieu that activates cells, then the immune system will be activated. For example if the TLR receptors of dentritic cells are activated when they bind and process the antigen, then they express much more costimulatory molecules when they present the antigen to T cells and thus activate them. If the antigen is presented without costimulation then the reactive T cells become anergic or Tregs. Even though there is considerable plasticity between various effector Th cells I don't know of a way to restimulate them. But I am no expert.
The antigen presenting route is one of the best studied. The i.v route is the less immunogenic than i.p. and subcutaneous is the most immunogenic. Supposedly that is because the antigen is presented to the DCs the longest if it is applied subcutaneously.
As for the pregnant mother, the womb is a very tolerogenic environment. It has to be from an evolutionary point of view, because the fetus carries many foreign antigens for the mother. The gut is also a tolerogenic environment with various regulatory T cell populations, that is why the oral route is the least immunogenic route of all.