TERMINATION OF TOLERANCE
If tolerance depends on the maintenance of a state of anergy, there are several possible sce-narios that could explain the termination of tolerance.
Because new B lymphocytes are constantly produced from stem cells, if a tolerogenic dose of antigen is not maintained, the immune system will eventually replace aging tolerant cells by young, nontolerant cells and recover the ability to mount an immune response.
Exposure to an antigen that cross-reacts with a tolerogen may induce the activation of T-helper lymphocytes specific for the cross-reacting antigen. As a consequence, the activated TH cells will provide autoreactive B lymphocytes with the necessary co-stimulatory signals necessary to initiate a response against the tolerogen.
It was discussed above that anergy may be the result of incomplete stimulation of T lym-phocytes. Thus, it can be postulated that proper stimulation of T lymphocytes may reestablish the co-stimulatory pathways, terminate anergy, and initiate the autoreactive process. Experimental evidence supporting this concept was obtained in studies of trans-genic mice expressing a lymphocytic choriomeningitis viral glycoprotein on the pancre-atic cells. These transgenic mice have T lymphocytes that recognize the glycoprotein but remain anergic. However, the state of anergy in these transgenic mice can be terminated by an infection with the lymphocytic choriomeningitis virus. The infection stimulates the immune system, terminates the state of peripheral T-cell unresponsiveness, and the pre-viously tolerant animals develop inflammatory changes in the Langerhans islets (insuli-tis) caused by lymphocytes reacting with the viral antigen expressed on the pancreatic cells. Those changes precede the development of diabetes. This model supports the con-cept of tolerance resulting from the lack of co-stimulatory signals and also supports the role of infections, by generating a microenvironment favorable to the induction of an ac-tive immune response, as an initiating factor indirectly responsible for the activation of autoreactive clones.
A special type of infection that may be involved in termination of tolerance involves superantigen-producing bacteria. These superantigens react with most MHC-II molecules and with the TcR of specific variable-region families. Those TcR families are expressed by as much as one third of the total T-cell population. The cross-linking of TcRs on large num-bers of T lymphocytes in close apposition with activated antigen-presenting cells delivers strong activating signals to T lymphocytes. The consequence is that previously anergic self-reactive T cells will be activated (as evidenced by the active expression of the IL-2 recep-tor gene) and a previously downregulated autoimmune response becomes active.
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