%0 Journal Article
%T Etiopathogenesis of Insulin Autoimmunity
%A Norio Kanatsuna
%A George K. Papadopoulos
%A Antonis K. Moustakas
%A £¿ke Lenmark
%J Anatomy Research International
%D 2012
%I Hindawi Publishing Corporation
%R 10.1155/2012/457546
%X Autoimmunity against pancreatic islet beta cells is strongly associated with proinsulin, insulin, or both. The insulin autoreactivity is particularly pronounced in children with young age at onset of type 1 diabetes. Possible mechanisms for (pro)insulin autoimmunity may involve beta-cell destruction resulting in proinsulin peptide presentation on HLA-DR-DQ Class II molecules in pancreatic draining lymphnodes. Recent data on proinsulin peptide binding to type 1 diabetes-associated HLA-DQ2 and -DQ8 is reviewed and illustrated by molecular modeling. The importance of the cellular immune reaction involving cytotoxic CD8-positive T cells to kill beta cells through Class I MHC is discussed along with speculations of the possible role of B lymphocytes in presenting the proinsulin autoantigen over and over again through insulin-carrying insulin autoantibodies. In contrast to autoantibodies against other islet autoantigens such as GAD65, IA-2, and ZnT8 transporters, it has not been possible yet to standardize the insulin autoantibody test. As islet autoantibodies predict type 1 diabetes, it is imperative to clarify the mechanisms of insulin autoimmunity. 1. Introduction The pancreatic islets constitute about 2-3% of the pancreas weight that is about 100 grams in adults [1]. The islets represent the endocrine portion of the pancreas and are present as more than a million well-defined cellular clusters throughout the pancreas [2, 3]. Each pancreatic islet (Figure 1) is composed of about 54% beta cells, 35% alpha cells, and 11% delta cells in addition to connective tissue and capillary cells [4]. Proinsulin, converted to insulin (Figure 2), is the major hormone produced in the beta cells while glucagon and GLP-1 are produced by the alpha cells, somatostatin by the delta cells, and pancreatic polypeptide by the PP cells. Pancreatic islet cells are also reported to produce ghrelin [5], apelin [6, 7], and CART [8¨C10]. These polypeptide hormones may be coexpressed with insulin in the beta cells or with other hormone-producing cells [8]. PP cells are more often seen in the head of the pancreas, while alpha cells dominate the tail [11, 12]. Insulin is the life-saving hormone for people suffering from type 1 and at times type 2 diabetes (see what follows). More beta cells are available than necessary to main blood glucose at normal levels. However, loss of insulin has catastrophic consequences. It has been estimated that 50% of the pancreas may be removed by surgery without a development of diabetes [13, 14]. Type 1 diabetes (T1D) is an autoimmune disease leading to a
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