Self-reactive T-cell clones should be deleted in the thymus during ontogeny (central tolerance) or inactivated peripherally through anergy by inappropriate antigen presentation (peripheral tolerance). High-affinity interactions of self-reactive T cells in the thymus with self-epitope-loaded MHC molecules on thymic epithelium or medullary dendritic cells result in clonal deletion of the autoreactive clones (negative selection). Interactions between T cells and self-MHC with nonspecific epitopes are not of high enough avidity to cause apoptosis of the developing T cell but provide sufficient signal to retain the lymphocyte in the thymus (positive selection) for further differentiation. The problem with this form of tolerance is that it depends on self-antigens being present in the thymus during T-cell ontogeny. This could be true for common cellular molecules present in all cells, but would not necessarily be true for specialized or sequestered antigens, such as thyroglobulin, cardiac myosin, or myelin basic protein, the presumed autoantigens in autoimmune thyroiditis, myocarditis, and multiple sclerosis, respectively. Furthermore, autoreactive T-cell clones having low avidity TCR for MHC self-antigen would not be deleted. Peripheral tolerance can be induced either by deleting autoreactive T cells through high-dose antigen exposure in tissues22'33-35 or by exposing self-reactive T cells to antigen-loaded MHC molecules without appropriate secondary signals (cytokines or adhesion molecules such as CD28 and B7) (anergy).36-38 Finally, self- reactive T cells may not be deleted or anergized. Immunologic "ignorance" occurs because the self-antigen is either sequestered or present at concentrations below threshold levels required to initiate immunity.22'33'34'39'40 If these antigens become available to the immune system under conditions favoring normal immune responses, autoimmunity should result.
"Cryptic" antigen is one form of sequestered antigen.41,42 These are antigenic epitopes that are not readily available to T lymphocytes either because of low concentration, poor MHC binding avidity, or destruction of the epitope during antigen processing under normal circumstances. In the first case, certain molecules may be present in limited amounts in healthy tissues. However, extensive tissue damage, such as might occur during virus infection or traumatic injury, could release substantial quantities of these self-molecules and raise concentrations of the relevant epitope to immunogenic levels. Furthermore, antigen might be concentrated during antigen processing. Although antigen presentation usually begins with basically "nonspecific" phagocytosis or pinocytosis of materials in the extracellular milieu, uptake of antigens can become more "directed," provided antibodies to these self-molecules are present. APCs having Fc receptors could selectively bind antigen-antibody complexes causing disproportional uptake of these antigens.
Furthermore, B lymphocytes, which also have the potential to process and present antigens to T lymphocytes, would preferentially internalize antigens to which they react via the immunoglobulin on their cell surface. Autoreactive B cells are relatively common, and their numbers actually increase with age. The frequency of autoreactive B cells likely reflects the fact that tolerance of B cells is usually difficult to accomplish and easily overcome. Thus, the autoreactive B lymphocyte might have a crucial role in autoimmunity induction.
A second form of cryptic epitope reflects epitopes that are not readily seen in whole proteins, but which become immunogenic as individual peptides.43 Use of different proteases by the various APC cell types or induction of new proteases during activation of APC can change the way protein antigens are processed and result in either destruction of some epitopes or production of new ones by changing cleavage sites during protein degradation.42'44 Cryptic epitopes have been found in several human autoimmune diseases and in animal disease models: autoimmune hemolytic anemia,45 multiple sclerosis,46 myasthenia gravis,47 and Graves disease,48 among others.49,50
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