Insulin-dependent diabetes mellitus (
IDDM) is a T-cell-mediated
autoimmune disease directed against the
insulin-secreting beta cells of the islets of Langerhans of the pancreas. We have previously shown that in organ-specific
autoimmune diseases,
Graves' disease (GD), and
IDDM, the
antigen that is specific for each of these disorders (i.e.,
TSH receptor for GD,
glutamic acid decarboxylase-65 (GAD65) for
IDDM) does not activate the disease-specific CD8+ cells as fully as CD8+ cells from normal persons. In order to identify the specific
antigen responsible for triggering or maintaining autoimmunity in patients afflicted with the disease, we have studied the effects of islet (beta) cell-specific
antigens GAD65,
insulin, pancreatic
antigen (P69),
T cell epitope 69 (Tep69), and a milk-derived
bovine serum albumin (BSA)-
peptide-
ABBOS (pre-BSA positions 157-169) on the activation of CD8+ T lymphocytes in
IDDM patients. We compared the patterns of T cells activation with those mediated by an irrelevant
peptide antigen, P348 (amino-terminal region of human
cardiac myosin light chain-1), and also
tetanus toxoid. We also studied the responses of CD8+ T lymphocytes to these
IDDM-relevant and -irrelevant
antigens in Hashimoto's
thyroiditis patients (HT),
rheumatoid arthritis patients (RA), and normal control subjects (N) to compare the pattern of responses in the other
autoimmune diseases. Activation of lymphocytes was monitored by measuring the expression of the activation molecule-major histocompatibility complex
class II antigen (
HLA-DR) on the surfaces of CD8+ T lymphocytes by flow cytometry. Peripheral blood mononuclear cells (PBMC) obtained from 14 patients with
IDDM, 14 N, 14 with HT, and 13 with RA were cultured for 7 days in the presense or absence of
antigens. The stimulation index (SI) of activation of the lymphocytes was determined. When the response of CD8+ T lymphocytes of
IDDM patients to each of the
IDDM-relevant
antigens was compared to that of the irrelevant
antigen, only GAD65 and
ABBOS showed a significantly reduced activation compared to P348 and
tetanus toxoid. Other relevant
antigens,
insulin, P69, and Tep69, did not show any significant differences in their SI compared to those of the irrelevant
antigens. In the N, HT, and RA groups, there was no significant difference in the SI of the responses of CD8+ cells to any of the relevant
antigens compared to that of the irrelevant
antigens. Moreover, CD8+ T lymphocytes of
IDDM patients showed a significantly lower activation by GAD65 than those from N, HT, and RA. In conclusion, our data suggest that CD8+ T lymphocytes of
IDDM patients but not those from N, HT, and RA groups have specifically reduced potential for activation in response to GAD65 but not to
insulin, P69, and Tep69, whereas
ABBOS exerts a less well-defined reductive effect on the activation of CD8+ lymphocytes of
IDDM patients. Since CD8+ cells have been shown to contain suppressor activity, our data support the notion that a disease-specific defect in GAD65 autoantigenic induction of suppressor T lymphocytes may be important in the pathogenesis of
IDDM.