ABSTRACT
Abrogation of tolerance to self antigens often leads to autoimmunity. This may result from altered regulation of lymphocytes reactive with self or in aberrations in selfantigen presentation. Many factors participate in the generation of autoimmunity. Autoimmune reactants may be a consequence, and not a cause, of a disease process. Autoimmune diseases may be organ-specific, such as autoimmune thyroiditis, or systemic, such as systemic lupus erythematosus. Different hypersensitivity mechanisms, classified from I to IV, may represent mechanisms by which autoimmune diseases are produced. Thus, antibodies or T cells may be the effector mechanisms mediating tissue injury in autoimmunity. Helper T cells control the immune response to protein antigens. Therefore, defects in this cell population may lead to high-affinity autoantibody production specific for self antigens. MHC molecules, which are often linked genetically to the production of autoimmune disease, present peptide antigens to T lymphocytes. Various immunologic alterations may lead to autoimmunity. Experimental evidence supports the concept that autoimmunity may result from a failure of peripheral T lymphocyte tolerance, but little is known about whether or not loss of peripheral B-cell tolerance is a contributory factor in autoimmunity. Processes that activate antigen-presenting cells in tissues, thereby upregulating their expression of costimulators and leading to the formation of cytokines, may abrogate T-lymphocyte anergy. The mouse model of human systemic lupus erythematosus involves
lpr/lpr
and
gld/gld
mice that succumb at 6 months of age from profound systemic autoimmune disease with nephritis and autoantibodies. The
lpr/lpr
is associated with a defect in the gene that encodes
Fas
,
which determines the molecule that induces cell death. The
gld/gld
is attributable to a point mutation in the
Fas ligand
, which renders the molecule unable to signal. Thus, abnormalities in the Fas and Fas ligand prolong the survival of helper T cells specific for self antigens since they fail to undergo activation-induced cell death. Thus, this deletion failure mechanism involves peripheral tolerance rather than central tolerance. A decrease of regulatory T cells which synthesize lymphokines that mediate immunosuppression and maintain self-tolerance might lead to autoimmunity even though no such condition has yet been described.
