Evidence for superantigen involvement in insulin-dependent diabetes mellitus aetiology

Abstract

Insulin-dependent diabetes mellitus (IDDM) is a T-cell-mediated autoimmune disease whose onset is believed to be triggered by unknown environmental factors acting on a predisposing genetic background. Islet-infiltrating T (IIT) cells from two IDDM patients, who had died at the onset of the disease from brain swelling as a complication of ketoacidosis, were analysed. The results provided evidence for the involvement of a pancreatic islet cell membrane-bound superantigen as a diabetes aetiopathogenetic factor. There was a selective expansion of a T-cell receptor (TCR) variable segment of the beta-chain (V beta 7) in these IIT cells in association with unselected V alpha-chain segments; extensive junctional diversity of the TCR V beta 7 chains; and evidence of positive selection, after exposure to diabetic islet cell membrane preparations, of V beta 7+ T-cell clones among peripheral blood lymphocytes from non-diabetic individuals.

Recognition of a subregion of human proinsulin by class I-restricted T cells in type 1 diabetic patients

“…CD8 ϩ T cells are responsible for beta cell destruction in transgenic mice over expressing beta cell-specific CD8 ϩ T cells (2). In man, CD8 ϩ T cells and IFN-␥-positive cells are major components of insulitis (4)(5)(6)(7)(8)(9). Recurrent diabetes in recipients of isografts from a discordant identical twin is accompanied by predominant CD8 ϩ T cell infiltration (10).…”

Gene- and cell-based therapeutics for type I diabetes mellitus

“…[7][8][9] A number of earlier hypotheses with some supporting evidence have been put forward to explain the possible mechanism of action of the environmental trigger including b-cell death secondary to virally triggered inflammation, molecular mimicry, superantigens and diet. [10][11][12][13][14][15][16][17][18][19] What is certain is that at some point postnatally, the immune system of a genetically predisposed individual is activated to infiltrate chronically the islets of Langerhans. While the initial phase of infiltration may not involve b-cell destruction, a number of studies in vivo and in vitro suggest that immune cells become able to render b-cells dysfunctional through the actions of cytokines they produce such as interleukin-1b.…”

Hyperexpression of GAD in the islets may be relevant but is it sufficient to induce autoimmune insulitis?

“…Islet infiltrating T cells from the pancreases of two children who died in diabetic ketoacidosis were examined for the T-cell receptor Vb gene usage [6]. In both cases there was an expansion of the Vb7 gene segment and normal peripheral blood T cells could be expanded, selecting the same gene segment, by membrane preparation from islets of patients but not control subjects.…”

“…These cells include macrophages and antigen-specific CD8-positive T lymphocytes; the T cells show enrichment for certain Vb T-cell receptors [6]. An increased expression of intercellular adhesion molecules on the vascular endothelium may enhance the accumulation of mononuclear cells in the islets [7].…”