Human pancreatic islet cell specific 38 kilodalton autoantigen identified by cytomegalovirus-induced monoclonal islet cell autoantibody

Abstract

Our previous finding that about 15% of newly diagnosed patients with Type 1 (insulin-dependent) diabetes mellitus had human cytomegalovirus genome in their lymphocytes and islet cell autoantibodies in their sera, suggests that autoimmune Type 1 diabetes is associated with persistent cytomegalovirus infection under certain circumstances. This investigation was initiated to see if cytomegalovirus can induce islet cell autoantibodies and if the autoantibodies react with any specific islet protein(s). Monoclonal antibodies were generated after immunizing Balb/c mice with human cytomegalovirus. When these monoclonal antibodies were tested for the presence of islet cell antibodies were tested for the presence of islet cell antibodies, one (MCMVA-51) of 13 monoclonal antibodies reacted strongly with the islets. The titer of islet cell antibodies was 1:2000. When this monoclonal antibody was reacted with the proteins from the solubilized fraction of human pancreatic islets using the western immunoblotting technique, a band with a molecular weight of 38 kilodalton was detected. The 38 kilodalton band was not observed when the monoclonal antibody was reacted with the proteins prepared from pancreatic islet tissues of rats and mice or from other human organs including stomach, liver, spleen and brain, indicating that the 38 kilodalton protein is human islet cell-specific. It is concluded that human cytomegalovirus can induce islet cell antibodies that react with a 38 kilodalton human islet cell protein and that this protein component may represent islet cell-specific target antigens associated with persistent cytomegalovirus infection.

Serological evaluation of the role of cytomegalovirus in the pathogenesis of IDDM: a prospective study

“…This has been supported by observations that the presence of the CMV genome and islet cell antibodies (ICA) are correlated in patients with newly-diagnosed IDDM [2], and that high titres of IgG class antibody against CMV are associated with ICA in healthy siblings of diabetic children [3]. Furthermore, immunological cross-reactivity between CMV and an islet cell 38 kDa autoantigen has been described [4]. Characteristic inclusion bodies have been observed in islets of children with fatal CMV infections providing evidence that CMV may be able to cause direct damage in human beta cells [5].…”

“…The role of CMV in the pathogenesis of IDDM has been proposed in some earlier reports [2][3][4][5]13]. However, such a connection has not been found in all studies, for example in two separate reports there was no evidence of recent CMV infection in patients with newly-diagnosed IDDM [14,15].…”

Transcription Factor jun-B is Target of Autoreactive T-Cells in IDDM

“…Pak et al (16) described a monoclonal antibody to human CMV that immunoblotted a 38,000-H human (but not mouse or rat) islet protein. Molecular mimicry, the sharing of an epitope between a CMV protein and a 38,000-H islet protein, could result in anti-CMV immunity being directed against the islet.…”

“…In the autoimmune BB rat, a model of IDDM, antibodies to a 38,000-M r islet protein are reported to precede the onset of diabetes (15). Finally, a mouse monoclonal antibody raised against human CMV by Pak et al (16) reacted by immunoblotting with a 38,000-M r human islet-specific protein; Pak et al (16) referred to unpublished data and claimed that antibodies to a 38,000-M r islet protein were present in IDDM subjects carrying CMV genome.…”

The role of T-cells in the pathogenesis of Type 1 diabetes: From cause to cure

“…Autoimmune beta-cell destruction in pancreatic allografts was associated with recurrent insulitis with a predominant fraction of infiltrating T-cells reactive to hCMV [87]. Also, hCMV infection of mice resulted in the generation of autoantibodies directed to the islets of Langerhans [88]. The mechanism by which hCMV infection contributes to neuroendocrine autoimmunity is unknown.…”