Mechanisms of pancreatic beta-cell destruction in type I diabetes.
The pathogenetic mechanisms leading to beta-cell destruction and insulin-dependent diabetes mellitus (IDDM) are major histocompatibility complex (MHC) nonrestricted and are MHC associated and beta-cell specific. The macrophage peptide hormone interleukin 1 (IL-1) may be the primary MHC-nonrestricted beta-cell-destructive molecule. Beta-Cell death most likely results from free radical induction by IL-1. Thus, islet cell-specific antibodies and cytotoxic T-lymphocytes are secondary in importance and time. The potentiation of IL-1 effects on beta-cells by tumor necrosis factor alpha (TNF), another macrophage hormone controlled by a gene in the HLA region on chromosome 6, may account for the MHC association of IDDM. In the experimental model of IDDM etiopathogenesis described, release of beta-cell antigen, processed and presented by macrophages to helper T-lymphocytes, initiates a self-perpetuating and self-limiting circuit of cytokine production of which IL-1 is beta-cell cytotoxic. As postulated, the IL-1 effect is potentiated by TNF, whereas IL-1 and/or TNF production is controlled in a quantitative way by HLA-D genes.
Nerup
J
J
Steno Memorial Hospital, Gentofte, Denmark.
Mandrup-Poulsen
T
T
Mølvig
J
J
Helqvist
S
S
Wogensen
L
L
Egeberg
J
J
D003922:Diabetes Mellitus, Type 1 / Q000276:immunology / Q000473:pathology*; D006801:Humans; D007515:Islets of Langerhans / Q000276:immunology / Q000473:pathology*; D008954:Models, Biological