Immunological Tolerance Revisited in the Molecular Era

Controlling autoimmunity—Lessons from the study of red blood cells as model antigens

“…In the last two decades, with the application of modern methods of cellular, molecular and transgenic biology, a number of different mechanisms responsible for the state of self-tolerance have been demonstrated in animal models [28]. These include the "censorship" of potentially autoreactive cells by killing them or rendering them inherently unresponsive, lack of effective presentation of autoantigens, and various forms of active immune regulation.…”

Controlling Autoimmunity: Lessons from Responses to Red Blood Cells

“…Now, with the application of modern methods of cellular and molecular biology, important advances have been made in understanding the mechanisms responsible for the state of self-tolerance (Nossal et al 1993;Elson and Barker 2000). These include the 'censorship' of potentially autoreactive cells by killing them or rendering them inherently unresponsive, lack of e¡ective presentation of autoantigens, and various forms of active immune regulation.…”

“…A corollary proposed that 'forbidden clones' with the potential for autoreactivity are eliminated in the prenatal period, but a more modern concept is that such selection occurs throughout the life of the organism at a critical point in the di¡erentiation of lymphocytes. With the advent of techniques, including transgenic mice, to follow in vivo the fate of antigen-speci¢c lymphocytes, formal proof has been obtained that Th-cells reactive with at least some classes of selfcomponents are indeed clonally deleted during their development in the thymus (Nossal et al 1993). However, it remains controversial as to whether this is the major mechanism responsible for Th-cell self-tolerance, or only relevant for certain autoantigens, particularly those that are available in the thymus.…”

“…Another hypothesis put forward to explain self-tolerance is that any autoreactive Thcells escaping the thymus become functionally inactivated (anergic) after encountering the corresponding antigens in the periphery (Nossal et al 1993). Anergy, rather than activation, results from stimulation of Th-cells by antigen in the absence of crucial co-stimulatory signals from APC, and appears to be permanent unless high concentrations of the autocrine growth factor interleukin-(IL-) 2 are present.…”

“…Anergy, rather than activation, results from stimulation of Th-cells by antigen in the absence of crucial co-stimulatory signals from APC, and appears to be permanent unless high concentrations of the autocrine growth factor interleukin-(IL-) 2 are present. Despite the experimental support for anergy as a means to silence autoreactive Th-cells in murine models (Nossal et al 1993), there is no evidence that this is an important mechanism for maintaining selftolerance to RBC. As discussed above, Thcells reactive with RBC autoantigens can be detected in the repertoire of healthy humans, dogs and mice, and the relative ease with which these cells can be stimulated in vitro, without the need for exogenous IL-2, indicates that they are not anergic (Barker and Elson 1994;Elson et al 1995).…”