Autoantibodies to the neuroendocrine
protein insulinoma-associated protein 2 (IA-2), a member of the
tyrosine phosphatase family, have been observed in individuals with or at increased risk for
IDDM. Because this disease is thought to result from a T-cell-mediated autoimmune destruction of the
insulin-producing pancreatic beta-cells, we analyzed humoral and cellular immune reactivity to this
autoantigen to further define its role in the pathogenesis of
IDDM. Peripheral blood mononuclear cells (PBMC) from individuals with newly diagnosed
IDDM or at varying levels of risk for the disease were stimulated in vitro with the entire 42-kDa internal domain of IA-2 (
amino acids 603-979), a series of control
antigens (glutathionine-S-
transferase,
tetanus toxoid, Candida albicans,
mumps,
bovine serum albumin), and a
mitogen (
phytohemagglutinin). The frequency and mean stimulation index of PBMC proliferation against IA-2 was significantly higher in newly diagnosed
IDDM subjects (14 of 33 [42%]; 3.8+/-4.5
at 10 microg/ml) and
autoantibody-positive relatives at increased risk for
IDDM (6 of 9 [66%]; 3.9+/-3.2) compared with
autoantibody-negative relatives (1 of 15 [7%]; 1.8+/-1.0) or healthy control subjects (1 of 12 [8%]; 1.5+/-1.0). The frequencies of cellular immune reactivities to all other
antigens were remarkably similar between each subject group. Sera from 58% of the newly diagnosed
IDDM patients tested were
IA-2 autoantibody positive. Despite investigations suggesting an inverse association between humoral and cellular immune reactivities against islet-cell-associated
autoantigens, no such relationship was observed (rs=0.18, P=0.39) with respect to IA-2. These studies support the autoantigenic nature of IA-2 in
IDDM and suggest the inclusion of cellular immune responses as an adjunct marker for the disease.