Role of peritoneal macrophages in cytomegalovirus-induced acceleration of autoimmune diabetes in BB-rats.

Jan-Luuk Hillebrands,Nienke Van Der Werf,Jan Rozing,Cathrien A Bruggeman,Flip A Klatter

doi:10.1080/10446670310001626517

Jan-Luuk Hillebrands, Nienke Van Der Werf + Show 3 more

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https://doi.org/10.1080/10446670310001626517

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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 × 106 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 (pMΦ) and diabetes development was studied by analyzing numbers of pMΦ, 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 pMΦ 1 day p.i. of which ~0.05% showed signs of reproductive infection. Depletion of pMΦ on days 1-3 p.i. completely counteracted the accelerating effect of RCMV. Interpretation: RCMV accelerates onset of diabetes without infecting pancreatic islets. pMΦ 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.

Highlights

Type 1 diabetes or Insulin Dependent Diabetes Mellitus (IDDM) is an organ-specific autoimmune disease, which results from the selective destruction of pancreatic b-cells
To get more insight into the underlying mechanism by which RCMV accelerates the onset of diabetes, we first analyzed whether RCMV could be detected by specific immunohistochemistry in the islets in pancreatic tissue from animals which had become diabetic after infection
Natural perturbants like viral infections are believed to play a role in the pathogenesis of Type 1 diabetes

Summary

Introduction

Type 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. 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. 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

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