Notes

HOMEOSTASIS IN THE IMMUNE SYSTEM
Discrimination between self and nonself is an important characteristic of the
immune system, and alterations in the mechanisms that normally maintain
self-tolerance can lead to a disease state called autoimmunity. Even when
there is a failure in the selection processes that delete immature self-reactive
lymphocytes, the peripheral mechanisms should be able to maintain unresponsiveness to many self antigens. Autoimmunity may therefore be the
result of a failure in peripheral tolerance, in which the anergy or deletion of
autoreactive lymphocytes is altered. Encephalomyelitis and insulindependent diabetes mellitus (IDDM) are examples of autoimmune diseases
due to T cell anergy breakdown. T cell anergy failure may occur because of
abnormalities in the T cells themselves or to defects induced by inflammation,
which may occur after certain infections, due to induction of tissue necrosis.
Autoimmune diseases may also result from inappropriate cell death, for
instance, failure of activation-induced cell death. A defect in the Fas system
is intimately linked to autoimmune diseases caused by the impaired removal
of autoreactive lymphocytes. As already mentioned, the human autoimmune
disease systemic lupus erythematosus resembles that found in lpr and gld
mice, with a dysfunction of Fas or FasL, respectively (53, 54). Children with
autoimmune lymphoproliferative syndrome (ALPS), also called Canale–
Smith syndrome, have massive nonmalignant lymphadenopathy, hepatosplenomegaly, altered T cell populations, and other manifestations of
systemic autoimmunity (81). The loss-of-function phenotype therefore indicates that Fas plays an important role in the regulation of the immune
response and maintenance of self-tolerance.
Conversely, inappropriate induction of apoptosis may also lead to
pathological conditions. Fas is critically involved in the progression of viral
diseases such as HIV-1 or hepatitis B virus infection, in which massive apoptosis occurs. It was shown that indirect mechanisms lead to sensitization of
noninfected T cells toward AICD after HIV-1 infection (82, 83). The two HIV-
1-derived proteins gp120 and Tat activate FasL expression in T cells, causing
the death of uninfected T lymphocytes. This results in the continuous depletion of CD4+ T cells during AIDS disease.
FasL is also responsible for the maintenance of immune privilege, which
characterizes the ability of certain organs to suppress graft rejection, even
when transplanted in nonmatched individuals (84). In this case, FasL acts by
killing infiltrating lymphocytes of the host, preventing the resulting inflammation from destroying the tissue (85–87). FasL-mediated depletion of cytotoxic T lymphocytes may not only be beneficial, however, but may also have
a role in aiding tumor cells to escape host immune surveillance. High constitutive FasL expression has been found in distinct tumor lineages, such as
colon, lung, renal carcinoma, melanoma, hepatocellular carcinoma, astrocytoma, and T cell- and B cell-derived neoplasms (88–94). This suggests that
the same mechanisms responsible for protecting tissues from autoimmune
destruction may be used by tumors to eliminate activated lymphocytes
which attempt to attack tumor cells.
Maintenance of immune system homeostasis thus depends on the strict
control of cell proliferation and cell death through apoptosis, and many
disease states result from errors in the regulation of apoptosis.