DEFINITION AND GENERAL CHARACTERISTICS OF TOLERANCE
Tolerance is best defined as a state of antigen-specific immunological unresponsiveness. This definition has several important implications.
a. When tolerance is experimentally induced, it does not affect the immune response to antigens other than the one used to induce tolerance. This is a very important feature that differentiates tolerance from generalized immunosuppression, in which there is a depression of the immune response to a wide array of different antigens. Tolerance may be transient or permanent, while immunosuppression is usually transient.
b. Tolerance must be established at the clonal level. In other words, if tolerance is anti-gen-specific, it must involve the T- and/or B-lymphocyte clone(s) specific for the anti-gen in question and not affect any other clones.
c. Tolerance can result from clonal deletion or clonal anergy. Clonal deletion involves different processes for T and B lymphocytes:
1. T lymphocytes are massively produced in the thymus and, once generated, will not rearrange their receptors. Memory T cells are long-lived, and there is no clear evidence that new ones are generated after the thymus ceases to function in early adulthood. Therefore, elimination of autoreactive T cells has been postulated to occur at the production site (thymus) at the time the cells are differentiating their TcR repertoire.
2. B-cell clonal deletion involves different mechanisms than T-cell clonal deletion. B cells are continuously produced by the bone marrow through life and initially express low-affinity IgM on their membranes. In most instances interaction of these resting B cells with circulating self molecules neither activates them nor causes their elimination. Selection and deletion of autoreactive clones seem to take place in the peripheral lymphoid organs during the onset of the immune re-sponse. At that time, activated B cells can modify the structure of their mem-brane immunoglobulin as a consequence of somatic mutations in their germline immunoglobulin genes. B cells expressing self-reactive immunoglobulins of high affinity can emerge from this process, and their elimination takes place in the germinal centers of the peripheral lymphoid tissues.
Both T-cell and B-cell clonal deletion fail to eliminate all autoreactive cells. In the case of T cells, clonal deletion on the thymus will not affect clones that recognize self anti-gens not expressed in the thymus. Furthermore, as the thymic function declines with age, alternative mechanisms have to be in place to ensure the inactivation of autoreactive clones emerging from the differentiation of lymphoid stem cells. The causes of B-cell escape from clonal deletion are not as well defined, but they exist nonetheless. Thus, peripheral toler-ance mechanisms must exist to ensure that autoreactive clones of T and B cells are neu-tralized after their migration to the peripheral lymphoid tissues.
One of the postulated peripheral tolerance mechanisms is known as clonal anergy, a process that incapacitates or disables autoreactive clones that escape selection by clonal deletion. Thus, anergy can be experimentally induced after the ontogenic differentiation of immunocompetent cells has reached a stage in which clonal deletion is no longer possible.
By definition, anergic clones lack the ability to respond to stimulation with the cor-responding antigen. Thus, the most obvious manifestation of clonal anergy is the inability to respond to proper stimulation. Anergic B cells carry IgM autoreactive antibody in their membrane but are not activated as a result of an antigenic encounter. Anergic T cells ex-press TcR for the tolerizing antigen, but fail to properly express the IL-2 and IL-2 receptor genes in response to antigenic stimulation.
The mechanisms responsible for anergy have been the object of considerable inter-est. In a simplistic way it can be stated that anergy results from either an internal block of the intracellular signaling pathways or from down-regulating effects exerted by other cells. One major mechanism that is involved in anergy is the incomplete signaling of an im-munocompetent cell. This may result in either a block of the intracellular activation path-ways or in the developmental arrest of autoreactive clones, which fail to fully differentiate into mature clones of effector cells. As for immunoregulatory cells, emphasis has been placed on those that release IL-10 and or TGF-β .
As is often the case, when several mechanisms leading to a similar end result are de-fined, they end up not being mutually exclusive. Indeed there is ample evidence suggesting that tolerance results from a combination of clonal deletion and clonal anergy. Both pro-cesses must coexist and complement each other under normal conditions so that autoreac-tive clones, which escape deletion during embryonic development, may be downregulated and become anergic. The failure of either one of these mechanisms may result in the de-velopment of an autoimmune disease.
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