Pancreatic islets under attack: cellular and molecular effectors.
Abundant information is available on the involvement of various cellular and molecular mechanisms in beta 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 beta 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 beta 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 beta cell death.
Pearl-Yafe
Michal
M
Center for Stem Cell Research, Schneider Children's Medical Center of Israel, Petach Tikva, Israel.
Kaminitz
Ayelet
A
Yolcu
Esma S
ES
Yaniv
Isaac
I
Stein
Jerry
J
Askenasy
Nadir
N
D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology; D017209:Apoptosis / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D003922:Diabetes Mellitus, Type 1 / Q000209:etiology / Q000276:immunology / Q000473:pathology; D053222:Fas Ligand Protein / Q000276:immunology; D006801:Humans; D007515:Islets of Langerhans / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008264:Macrophages / Q000276:immunology
D053222:Fas Ligand Protein