THE Β-CELL LESION: NATURE OF EFFECTOR CELLS
IDDM is
characterized by the selective destruction of β cells (other islet cells,
notably glucagon-producing cells remain intact). The β-cell destruction is due to
apoptosis. It is preceded by a long phase of prediabetes that has been well
charac-terized in animal models. Initial insulitis is essentially of peripheral
nature (perinsuli-tis) without β-cell
aggression. It becomes progressively more active, resulting in “malignant”
insulitis. Even at a late stage (diabetes onset), much of this aggression is
reversible because of T-cell-mediated inflammation. One can thus explain that
hyperglycemia in recently diagnosed dia-betic mice is corrected within
twenty-four to forty-eight hours by treatment with an anti-T-cell antibody
(anti-TCR or anti-CD3) and that islets derived from recently diagnosed diabetic
NOD mice recover the capacity to produce insulin after in vitro culture in the
absence of T cells or autoan-tibodies.
The
nature of the cellular and molecular events at the origin of β-cell inflammation and
destruction is still a matter of debate. The role of T cells is unquestionable.
Dia-betes can be transferred to NOD-SCID mice (which do not spontaneously
develop diabetes because they lack T cells) after infusion of purified T cells
or T-cell clones. Both CD4 and CD8 T cells are necessary to obtain diabetes
transfer when using poly-clonal T cells, even though transfer can be obtained
with CD4+ or CD8+ T-cell clones injected alone. Emphasis
has recently been put on the role of CD8+ T cells, but there has not
yet been a clear demonstration of islet-specific cytotoxic T lymphocytes
capable of destroying β cells in
a FAS or a perforin-dependent manner (probably because of the difficulties met
in using 51Cr release assay with β cells).
Using major histocompatibility complex (MHC) class I tetramers with islet
antigen mimetopes, it was shown that diabetes progression in the NOD mouse is
associated with increasing numbers of high-avidity islet-specific CD8 T cells.
CD4+ T cells are also important. They may have direct diabetogenic
action through cytokine release. They may also intervene as helper T cells for
CD8 T cells. A number of studies have attempted to dis-sect the molecular
events leading to β-cell
apoptosis. The role of free radicals and var-ious cytokines, notably IL-1, has
been the matter of particular attention.
No role
for islet-specific autoantibod-ies has been demonstrated so far. Transfer of
sera from diabetic mice does not induce diabetes onset. Pure T-cell populations
derived from diabetic mice injected into syngeneic recipients still induce
diabetes when the recipients have previously been rendered agammaglobulinemic
by post-natal anti-IgM antibody treatment. These observations do not preclude
the possi-bility that B cells may play a role in the pathogenesis of IDDM since
B-cell-less NOD mice (Ig do not develop
diabetes. One may assume that in this context, B cells act as
antigen-presenting cells, rather than as producers of diabetogenic
autoantibodies. The only evidence in favor of the pathogenic role of
autoanti-bodies is the observation that newborns from diabetic
autoantibody-positive NOD mouse mothers develop diabetes more rapidly than
newborns from antibody-negative mothers. This intriguing obser-vation does not
fit with clinical studies showing the higher IDDM incidence in descendants of
diabetic fathers than of diabetic mothers and with the absence of difference in
the incidence of diabe-tes in children from antibody-positive or
antibody-negative mothers.
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