Pathological changes in the islet milieu precede infiltration of islets and destruction of beta-cells by autoreactive lymphocytes in a transgenic model of virus-induced IDDM

J Autoimmun. 1997 Jun;10(3):231-8. doi: 10.1006/jaut.1997.0131.

Abstract

RIP-LCMV transgenic mice that express the viral glycoprotein (GP) or nucleoprotein (NP) from lymphocytic choriomeningitis virus (LCMV) under control of the rat insulin promoter (RIP) in pancreatic beta-cells develop autoimmune diabetes (IDDM) after infection with LCMV. Previous reports have described that the viral infection activates naive, potentially autoreactive CD8+ cytotoxic T-lymphocytes (CTL) that are present in the periphery of these mice, thus leading to the breaking of immunological unresponsiveness to the viral self-antigen expressed on beta-cells. However, we find that adoptive transfer of such CTL that were active in vitro and in vivo into uninfected RIP-LCMV recipients rarely resulted in hyperglycemia nor in insulitis, despite their ability to home to the islets and induce peri-insulitis. These observations indicated that, in addition to activated autoreactive lymphocytes, other factor(s) were required for beta-cell destruction. The present study shows that upregulation of MHC class II molecules associated with the attraction/activation of antigen presenting cells (APCs) to the islets occurs as soon as 2 days after LCMV inoculation of transgenic mice, clearly before CD4+ and CD8+ lymphocytes are found entering the islets (days 6 and 7 after LCMV inoculation). In contrast, although some MHC class II upregulation is also found in islets of non-transgenic mice 2-4 days after LCMV infection, no insulitis or IDDM develops and MHC is downregulated to normal (pre-infection) levels by day 7-10 in these mice. Associated with the activation of APCs and MHC upregulation observed in transgenic mice, viral (LCMV) infection of islets was detectable 2 days post-viral inoculation in some mice. Thus, beta-cell destruction by activated autoreactive lymphocytes is a multifactorial process that is likely to require changes within the islet milieu or dysfunction of islets.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adoptive Transfer
  • Animals
  • Autoantigens / immunology
  • Cell Death / immunology
  • Cell Line
  • Cell Movement / immunology*
  • Crosses, Genetic
  • Diabetes Mellitus, Type 1 / etiology*
  • Diabetes Mellitus, Type 1 / pathology
  • Diabetes Mellitus, Type 1 / virology*
  • Disease Models, Animal
  • Disease Susceptibility
  • Histocompatibility Antigens Class II / biosynthesis
  • Histocompatibility Antigens Class II / immunology
  • Islets of Langerhans / immunology*
  • Islets of Langerhans / pathology*
  • Islets of Langerhans / virology
  • Lymphocytic Choriomeningitis / genetics
  • Lymphocytic Choriomeningitis / immunology
  • Lymphocytic Choriomeningitis / pathology
  • Lymphocytic choriomeningitis virus / immunology*
  • Lymphocytic choriomeningitis virus / isolation & purification
  • Macrophage Activation
  • Macrophages, Peritoneal / immunology
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Inbred NOD
  • Mice, Transgenic
  • Rats
  • T-Lymphocytes, Cytotoxic / immunology*
  • T-Lymphocytes, Cytotoxic / pathology
  • T-Lymphocytes, Cytotoxic / virology
  • Up-Regulation / immunology

Substances

  • Autoantigens
  • Histocompatibility Antigens Class II