Recognition of Self and Immune Tolerance
The immune system has evolved to distinguish between self and non-self antigens and to largely eliminate self-reactive lymphocytes. Because the repertoire of immune specificities is vast and largely random, it is not surprising that many nascent lymphocytes possess receptors for self-antigens. The mechanism of intrauterine tolerance is not well understood, but much has been learned about the mechanisms for excluding or inactivating self-reactive lymphocytes, particularly by using the model of experimentally induced immune tolerance to foreign antigens. When an antigen is introduced into immunologically immature newborn animals, they may, upon reaching maturity, become unresponsive to immunization with that antigen (neonatal tolerance). This immunological tolerance is characterized by the absence of both antibody and cell-mediated responses, and it is specific for the original antigen.
Subsequent experiments revealed that the induction of antigen-specific tolerance is not always restricted to immature organisms. Unresponsiveness can also be induced in adults by using relatively higher doses of soluble antigen (high dose tolerance). The induced state of unresponsiveness to the antigen is sometimes accompanied by the appearance of suppressor T cells that actively and specifically inhibit the responses of B and T cells. Recent studies also reveal that IgM+IgD– B cells and mature T lymphocytes may be directly inactivated by small doses of antigen in vitro (low dose tolerance). In that model, short exposure of lymphocytes to the antigen, either at a critical concentration or in a certain modality, leads to an inactivation rather than a stimulation of the cells.
Collectively, the experiments on tolerance induction demonstrate that the unresponsiveness to self is likely to be achieved at several levels. During normal development, the self-reactive lymphocyte clones may be inactivated or deleted by exposure to self macromolecules during the early stages of maturation in the thymus (). The autoselection is dependent upon MHC class I molecules for CD8+ T cells and class II molecules for CD4+ T cells. Those cells that are not eliminated and reach their full immunological potential may be inactivated, when self molecules are presented to these cells at high concentrations or in a form that is tolerogenic rather than immunogenic. Also, it is possible that some self-reactive lymphocytes are suppressed by other regulatory cells, such as CD8+ suppressor T cells.
Subsequent experiments revealed that the induction of antigen-specific tolerance is not always restricted to immature organisms. Unresponsiveness can also be induced in adults by using relatively higher doses of soluble antigen (high dose tolerance). The induced state of unresponsiveness to the antigen is sometimes accompanied by the appearance of suppressor T cells that actively and specifically inhibit the responses of B and T cells. Recent studies also reveal that IgM+IgD– B cells and mature T lymphocytes may be directly inactivated by small doses of antigen in vitro (low dose tolerance). In that model, short exposure of lymphocytes to the antigen, either at a critical concentration or in a certain modality, leads to an inactivation rather than a stimulation of the cells.
Collectively, the experiments on tolerance induction demonstrate that the unresponsiveness to self is likely to be achieved at several levels. During normal development, the self-reactive lymphocyte clones may be inactivated or deleted by exposure to self macromolecules during the early stages of maturation in the thymus (). The autoselection is dependent upon MHC class I molecules for CD8+ T cells and class II molecules for CD4+ T cells. Those cells that are not eliminated and reach their full immunological potential may be inactivated, when self molecules are presented to these cells at high concentrations or in a form that is tolerogenic rather than immunogenic. Also, it is possible that some self-reactive lymphocytes are suppressed by other regulatory cells, such as CD8+ suppressor T cells.
The failure of any of the mechanisms involved in self recognition and elimination or down regulation of self-reactive clones may result in autoimmunity. Autoimmune disorders in genetically prone individuals may be generated by a) changes in the expression of self macromolecules or alterations in their presentation to lymphocytes, b) release of sequestered self-antigens into the circulation, or access of immunogens to normally immunologically privileged sites, and c) alterations in lymphocyte maturation and immune regulation. In addition, foreign antigens such as bacteria and viruses that cross-react with self antigens may augment or initiate any of the above mechanisms.