Pancreatic islets under attack: Cellular and molecular effectors

M. Pearl-Yafe, Ayelet Kaminitz, Esma S. Yolcu, Isaac Yaniv, Jerry Stein, Nadir Askenasy*

*Corresponding author for this work

Research output: Contribution to journalReview articlepeer-review

Abstract

Abundant information is available on the involvement of various cellular and molecular mechanisms in β cell apoptosis. The experimental evidence is controversial and difficult to reconcile, and the mechanisms of evasion of the autoreactive clones from immune surveillance are poorly understood. Multiple apoptotic pathways play a role in destructive insulitis, including perforin/granzyme, Fas/Fas-ligand (FasL), and other members of the necrosis factor superfamily. These pathways present redundant behaviors in both the initial and late stages of β cell injury, and at the same time, each molecular mechanism is dispensable in the evolution of autoimmune diabetes. There may be a preferential use of perforin/granzyme in CD8+ T cell-mediated lysis, which participates in onset of autoimmunity, and a predominance of FasL in CD4+ T cell-mediated insulitis. Several cytokines released in the inflammatory infiltrate induce Fas expression in β cells, priming them to FasL-mediated apoptosis. In this review, we focus on the possible participation of multiple cell subsets and molecular mechanisms in the pathogenesis of diabetes to the point where inflammation incites an irreversible vicious cycle that perpetuates β cell death.

Original languageEnglish
Pages (from-to)749-760
Number of pages12
JournalCurrent Pharmaceutical Design
Volume13
Issue number7
DOIs
StatePublished - Mar 2007
Externally publishedYes

Keywords

  • Antigen presenting cells
  • Autoimmune diabetes
  • Fas-ligand
  • Inflammatory infiltration
  • Insulitis
  • Perforin/granzyme
  • T cells
  • Tumor necrosis factor
  • β cells

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