Molecular Pathology of Type 1 Diabetes mellitus /

Type 1 diabetes as well as multiple sclerosis are thought to be T cell mediated autoimmune diseases that involve a detrimental action of inflammatory cytokines and autoaggressive T lymphocytes. They still pose many unsolved puzzles, and the precise etiology as well as prevention have remained elusive. It is clear that genetic factors can predispose for developing diabetes, however, based on significant disease discordance found in monozygotic twins, additional environmental factors have to be postulated. Viruses are good candidates because they induce strong cellular and humoral immune responses, but no single etiologic agent has been identified. Several animal models are presented which have been used to study the activation of naive autoreactive lymphocytes. It is shown that regulation of the autoaggressive process occurs prior to clinical diabetes and is mediated by a complete network of cytokines, as well as regulatory circuits/cells. The spreading of autoimmunity to self-antigens not involved in the initial phase of islet destruction is not necessarily detrimental and can carry benefits. Therapeutically, counter-regulation of aggressive responses has been demonstrated via various means in animal models preventing diabetes or rejection of transplanted islets.All these findings are being discussed in this volume, which presents a state-of-the-art overview of the pathogenesis and intervention of type 1 diabetes. Authoritative and up-to-date, it will be of great value to any investigator interested in understanding autoimmunity.An authoritative and up-to-date overviewType 1 diabetes as well as multiple sclerosis are thought to be T cell mediated autoimmune diseases that involve a detrimental action of inflammatory cytokines and autoaggressive T lymphocytes. They still pose many unsolved puzzles, and the precise etiology as well as prevention have remained elusive. It is clear that genetic factors can predispose for developing diabetes, however, based on significant disease discordance found in monozygotic twins, additional environmental factors have to be postulated. Viruses are good candidates because they induce strong cellular and humoral immune responses, but no single etiologic agent has been identified. Several animal models are presented which have been used to study the activation of naive autoreactive lymphocytes. It is shown that regulation of the autoaggressive process occurs prior to clinical diabetes and is mediated by a complete network of cytokines, as well as regulatory circuits/cells. The spreading of autoimmunity to self-antigens not involved in the initial phase of islet destruction is not necessarily detrimental and can carry benefits. Therapeutically, counter-regulation of aggressive responses has been demonstrated via various means in animal models preventing diabetes or rejection of transplanted islets.All these findings are being discussed in this volume, which presents a state-of-the-art overview of the pathogenesis and intervention of type 1 diabetes. Authoritative and up-to-date, it will be of great value to any investigator interested in understanding autoimmunity.Print version recor

The healthy exocrine pancreas contains preproinsulin-specific CD8 T cells that attack islets in type 1 diabetes.

Preproinsulin (PPI) is presumably a crucial islet autoantigen found in patients with type 1 diabetes (T1D) but is also recognized by CD8(+) T cells from healthy individuals. We quantified PPI-specific CD8(+) T cells within different areas of the human pancreas from nondiabetic controls, autoantibody-positive donors, and donors with T1D to investigate their role in diabetes development. This spatial cellular quantitation revealed unusually high frequencies of autoreactive CD8(+) T cells supporting the hypothesis that PPI is indeed a key autoantigen. To our surprise, PPI-specific CD8(+) T cells were already abundantly present in the nondiabetic pancreas, thus questioning the dogma that T1D is caused by defective thymic deletion or systemic immune dysregulation. During T1D development, these cells accumulated in and around islets, indicating that an islet-specific trigger such as up-regulation of major histocompatibility complex class I might be essential to unmask beta cells to the immune system

Heterogeneity and Lobularity of Pancreatic Pathology in Type 1 Diabetes during the Prediabetic Phase

Stemcel biology/Regenerative medicine (incl. bloodtransfusion

Human herpesvirus-6 is present at higher levels in the pancreatic tissues of donors with type 1 diabetes.

Human herpesvirus-6 (HHV-6) is a ubiquitous pathogen associated with nervous and endocrine autoimmune disorders. The aim of this study was to investigate the presence of HHV-6 in pancreatic tissue sections from nondiabetic, auto-antibody positive (AAB +), and donors with type 1 diabetes (T1D) and explore whether there is any association between HHV-6 and MHC class I hyperexpression and CD8 T cell infiltration.HHV-6 DNA was detected by PCR and its protein was examined by indirect immunofluorescence assay followed by imaging using high-resolution confocal microscopy. Viral DNA (U67) was found in most pancreata of non-diabetic (3 out of 4), AAB+ (3 out of 5) and T1D donors (6 out of 7). Interestingly, HHV-6 glycoprotein B (gB) was more expressed in islets and exocrine pancreas of donors with T1D. However, gB expression was not directly associated with other pathologies. Out of 20 islets with high gB expression, only 3 islets (15%) showed MHC class I hyperexpression. Furthermore, no correlation was found between gB expression and CD8 T cell infiltration on a per-islet basis in any of the groups.Our observations indicate that HHV-6 DNA and protein are present in the pancreas of non-diabetic subjects but gB expression is higher in the pancreas of donors with T1D. The possible role of HHV-6 as a contributory factor for T1D should therefore be further investigated