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Cellular immunity to a determinant common to glutamate decarboxylase and coxsackie virus in insulin-dependent diabetes

Atkinson, M A; Bowman, M A; Campbell, L; Darrow, B L; Kaufman, D L; Maclaren, N K
Insulin-dependent diabetes (IDD) results from the autoimmune destruction of the insulin-producing pancreatic beta cells. Autoreactive T-lymphocytes are thought to play a pivotal role in the pathogenesis of IDD; however, the target antigens of these cells, as well as the inductive events in the disease, are unclear. PBMC in persons with or at increased risk for IDD show elevated reactivity to the beta cell enzyme glutamate decarboxylase (GAD). To identify the T-lymphocyte-reactive determinants of GAD, an overlapping set of synthetic peptides was used to stimulate the PBMC from these individuals, PBMC responsiveness to GAD peptides was not restricted to those with IDD, and a number of peptides elicited responses in PBMC. However, the major determinant of GAD recognized by persons at increased risk for IDD was amino acids 247-279, a region which has significant sequence similarity to the P2-C protein of Coxsackie B virus (47% of 15 increased risk [islet cell autoantibody-positive relatives]; 25% of 16 newly diagnosed IDD patients; and 0% of 13 healthy control subjects). Responses to tetanus and insulin antigens were not different between the study groups. In addition, PBMC from individuals responding to GAD peptides within 247-279 also responded to a Coxsackie viral peptide (i.e., P2-C amino acids 32-47), an observation supporting potential molecular mimicry in this immune response. Although the role of environmental agents in the pathogenesis of the disease remains unclear, these cellular immunological findings support the epidemiological evidence suggesting an inductive role for enteroviruses like Coxsackie B in the autoimmunity underlying IDD
PMCID:294659
PMID: 7962558
ISSN: 0021-9738
CID: 123384

Islet cell cytoplasmic autoantibody reactivity to glutamate decarboxylase in insulin-dependent diabetes

Atkinson, M A; Kaufman, D L; Newman, D; Tobin, A J; Maclaren, N K
Individuals with or at risk for insulin-dependent diabetes (IDD) frequently have autoantibodies against an islet cell cytoplasmic (ICA) antigen thought to be a sialoglycolipid. However, we now report that preabsorption of ICA-positive sera with recombinant glutamate decarboxylase (human GAD 65 and/or GAD 67) reduced or blocked the ICA reactivity of 5/18 (27%) new-onset IDD patients and 7/18 (39%) prediabetics. Interestingly, nondiabetic subjects with ICA of > or = 5 yr in duration had GAD-reactive ICA significantly more often (16/24, 67%, P < 0.04) than the diabetic groups. ICA reactivity to GAD was not related to serum ICA titer nor the age of the individual, and in all cases tested was blocked by GAD 65 or GAD 67 with equivalent efficiency. The ICA observed in 21/25 (84%) IDD patients with ICA long after clinical onset of disease (9-42 yr) was reactive to GAD. A natural history analysis of three individuals showed conversions from ICA which was reactive to GAD to a non-GAD-reactive ICA nearer to their clinical onsets of IDD. This study further defines the autoantigens reactive to ICA, and suggests that, whereas ICA that are not reactive to GAD may identify an advanced and more prognostic lesion, GAD-reactive ICA may typify the early or inductive lesion that may or may not progress to clinically significant beta cell injury
PMCID:330033
PMID: 8423231
ISSN: 0021-9738
CID: 123392

Response of peripheral-blood mononuclear cells to glutamate decarboxylase in insulin-dependent diabetes

Atkinson, M A; Kaufman, D L; Campbell, L; Gibbs, K A; Shah, S C; Bu, D F; Erlander, M G; Tobin, A J; Maclaren, N K
Insulin-dependent diabetes is characterised by autoantibodies to several pancreatic-islet-cell antigens, including glutamate decarboxylase. We measured the proliferative responses to this antigen of peripheral-blood mononuclear cells from patients with newly diagnosed insulin-dependent diabetes, relatives of diabetic patients, and healthy controls. The likelihood of a positive response was substantially greater among the diabetic patients and relatives positive for islet-cell autoantibodies (ICA) than among subjects at low risk of diabetes (controls and ICA-negative relatives). Glutamate decarboxylase may have a pathogenetic role in insulin-dependent diabetes
PMID: 1346821
ISSN: 0140-6736
CID: 123397

Autoimmunity to two forms of glutamate decarboxylase in insulin-dependent diabetes mellitus

Kaufman, D L; Erlander, M G; Clare-Salzler, M; Atkinson, M A; Maclaren, N K; Tobin, A J
Insulin-dependent diabetes mellitus (IDDM) is thought to result from the autoimmune destruction of the insulin-producing beta cells of the pancreas. Years before IDDM symptoms appear, we can detect autoantibodies to one or both forms of glutamate decarboxylase (GAD65 and GAD67), synthesized from their respective cDNAs in a bacterial expression system. Individual IDDM sera show distinctive profiles of epitope recognition, suggesting different humoral immune responses. Although the level of GAD autoantibodies generally decline after IDDM onset, patients with IDDM-associated neuropathies have high levels of antibodies to GAD, years after the appearance of clinical IDDM. We note a striking sequence similarity between the two GADs and Coxsackievirus, a virus that has been associated with IDDM both in humans and in experimental animals. This similarity suggests that molecular mimicry may play a role in the pathogenesis of IDDM
PMCID:442846
PMID: 1370298
ISSN: 0021-9738
CID: 123399