Self-nonself discrimination

The whole immune response is thus based on "recognizing" antigens, intruders, and so on. How is this recognition accomplished? At the site where microbes rush in, one can find dead cells, all kinds of soluble molecules that the body uses to fill the breach, other microbes, dead or alive etc. How do phagocytes know what to take up? A simple solution, which is to some extent what happens, is to take up just about anything. This may still require that the phagocyte itself be "activated". It is, in fact, known that the phagocytic capacity of these cells is stimulated by bacterial products, or by various molecules that are associated with cell damage. In this case, there is nothing that would prevent a phagocyte from presenting molecules that are produced by the host and just happen to be witnessing the scene of cellular destruction. If the phagocyte starts presenting peptides of these molecules, what prevents the immune system from becoming activated and destroying the host? To a large extent, this seems to be due to the deletion of self-specific T cells before they get the chance to move through the body. T cells are produced in a special lymphoid organ, the thymus. Once they acquire the antigen receptor on their surface, T cells are "tested" here against MHC-peptide complexes which reflect the proteins that the host produces. The peptides resulting from the fragmentation of the proteins produced in the host are called self peptides, and are to be distinguished from foreign or non-self peptides that derive from the proteins that are synthesized in the microorganism. T cells that bind tightly to self peptide-MHC complexes (called autoreactive) during this period of T cell development undergo apoptosis. To a certain extent, autoreactive B cells are also weeded out before they leave the bone marrow, where they are produced. So, even though antigen presenting cells may present self-antigens, there are no lymphocytes to react to them, in particular, no T helper cells. Without T helper cells no immune response can proceed, and so self-nonself discrimination is realized. This is the view advocated, for example, in Langman and Cohn (1993). Recently, Matzinger (1994) challenged this view, arguing that immune responses directed against self structures (cells or molecules) occur for as long as there is damage, side by side with immune responses against the foreign microorganisms that caused the damage. To explain the self-limiting nature of the immune response, the argument is made that the immune system effectors induce cell death through apoptosis. The difference between apoptosis, the cellular equivalent of suicide, and other forms of death, is that the content of the cell is not released into the environment. Apoptotic cells are recognized by phagocytes, and inconspicuously removed. This way, the immune system is not further triggered. The effector cells eventually die, or return to their resting state, from which they can be restimulated only in the presence of damage.