Role of Peritoneal Macrophages in Cytomegalovirus‐induced Acceleration of Autoimmune Diabetes in BB‐rats

Abstract

Background: As one of the natural perturbants, infection with cytomegalovirus (CMV) is believed to play a role in the development of Type I diabetes. Using the DP-BB rat model for autoimmune diabetes, we here report about possible mechanisms responsible for R(at)CMV-induced accelerated onset of diabetes.Methods: Rats were i.p. infected with 2 £ 10 6 plaque forming units (pfu) RCMV and followed for diabetes development. Presence of RCMV antigens and DNA was analyzed by immunohistochemistry and PCR on pancreatic tissue and isolated islets. The effect of viral infection on peritoneal macrophages (pMF) and diabetes development was studied by analyzing numbers of pMF, virus permissiveness and by depletion of this subset by peritoneal lavage.Results: RCMV accelerated onset of diabetes without infecting pancreatic islets. Immunohistochemistry and PCR on pancreas and isolated islets indicated that islets are non-permissive for RCMV. Infection results in an influx of pMF 1 day p.i. of which ,0.05% showed signs of reproductive infection. Depletion of pMF on days 1 -3 p.i. completely counteracted the accelerating effect of RCMV.Interpretation: RCMV accelerates onset of diabetes without infecting pancreatic islets. pMF might function as an carriage to disseminate virus to the pancreas where they enhance activation of autoreactive T cells resulting in accelerated onset of diabetes.Keywords: BB rats; Cytomegalovirus; Diabetes; Macrophages; RCMV; Virus INTRODUCTIONType 1 diabetes or Insulin Dependent Diabetes Mellitus (IDDM) (accounting for 10% of all cases of diabetes) is an organ-specific autoimmune disease, which results from the selective destruction of pancreatic b-cells. This destruction is histologically characterized by an inflammatory infiltrate around or within the islets (insulitis) containing large numbers of mononuclear cells and CD8 þ T cells (Notkins and Lernmark, 2001). Clinically, Type 1 diabetes presents as rapid onset polyuria, polydipsia, polyphagia, weight loss and hyperglycaemia .Although genetic factors are believed to be an important component in the pathogenesis of Type 1 diabetes (She, 1996;Field, 2002), also non-genetic factors appear to be required for disease onset since concordance rates among identical twins are only 30 -50% (Redondo et al., 2001). Among the non-genetic factors, viral infections are one of the leading candidate agents involved in the pathogenesis of Type 1 diabetes and a variety of different human viruses have been reported to be associated with human Type 1 diabetes, including CoxsackieB virus, rubella virus, mumps virus and several Herpesviridae (Jun and Yoon, 2001). Cytomegalovirus (CMV), a double stranded DNA virus belonging to the b-herpes virus family, is one of the Herpesviridae thought to be involved in the pathogenesis of Type 1 diabetes. This widespread virus (seropositivity varies from 60 to 90%) (Numazaki, 1997) causes latent and persistent infection without clinical symptoms in the immunocompetent host. In the immunocompromised host, however, primary infections and r...

Susceptibility of Human Pancreatic β Cells for Cytomegalovirus Infection and the Effects on Cellular Immunogenicity

“…This observation is of clinical importance because persistent low-grade infection of native pancreatic A cells may explain the absence of overt A-cell CMV infection in vivo, despite clear cut effects of the CMV infection on A-cell function and survival. 1,45 We demonstrate not only that human pancreatic A cells are susceptible to HCMV infection but also that the virus induced the release of proinflammatory cytokines and increased the cellular immunogenicity. This increased cellular immunogenicity may enhance the intrinsic capacity of pancreatic A cells to activate T cells, making HCMV-infected A cells even more prone to (auto-and/or allo-) immune-mediated destruction.…”

“…9Y11 Because direct CMV infection of the pancreatic islets was never indisputably proven, the diabetogenic potential of CMV still remains a subject of debate and the exact mechanism of CMV-induced Acell dysfunction remains to be clarified. In most studies addressing the effect of CMV infection on the development of diabetes, the accelerating effect of CMV has been interpreted as a CMV-induced reinforcement of existing autoimmune responses, 1,5 rather than direct cytolytic infection of A cells. 1Y4 However, knowledge on the cellular and molecular basis of these observations is largely lacking.…”

Infection With Viruses From Several Families Triggers Autoimmune Diabetes in LEW.1WR1 Rats

“…In some experiments, RCMV antigens were visualized on 4-μm formalin-fixed, paraffin-embedded sections of pancreas and salivary glands by reacting with RCMV early antigen monoclonal antibody (mAb8) as described ( 31 ). In all experiments involving RCMV, serum was obtained from diabetic animals to confirm the absence of KRV serologically (Charles River Laboratories, Wilmington, MA).…”

Viral infections as potential triggers of type 1 diabetes

“…As described above, so far no causal relation has been demonstrated between HCMV infection and the development of human T1D; the role HCMV plays in the diabetogenic process is therefore still elusive. We were, however, able to demonstrate a causal relation between CMV infection and acceleration of the development of T1D using the well‐established BB rat model for T1D (see also section on BioBreeding (BB) Rat Model for TID) 89, 90. Infection of BBDP rats with RCMV at the age of 35 days resulted in a significant acceleration of diabetes onset.…”