Type I Diabetes Mellitus Signaling


Pathway Description

Type I diabetes mellitus is a disease that results from autoimmune destruction of the insulin-producing beta-cells. Certain beta-cell proteins (Eg Ins, CPE, IA-2, ICA1) act as autoantigens after being processed by antigen-presenting cells (APC), such as macrophages and dendritic cells, and presented in a complex with MHC-II molecules on the surface of the APC. Then immunogenic signals from APC activate CD4+ T cells, predominantly of the Th1 subset. Antigen-activated CD4+ Th1 cells produce IL-2 and IFNγ. These two cytokines activate macrophages and cytotoxic CD8+ T cells and these effector cells may kill islet beta-cells by different mechanisms:The activation of macrophages and cytotoxic CD8+ T cells leads to the production of Il-1β, TNFα, TNFβ, and IFNγ. IL-1β and TNF induce beta-cell apoptosis mainly through the NF-κB pathway, whereas IFNγ signaling via JAK/STAT pathway synergizes with IL-1β signaling to trigger beta-cell apoptosis. The activation of the transcription factors NF-κB and STAT1 leads to the production of nitric oxide (NO) by beta-cells. Nitric oxide and oxygen/nitrogen free radicals directly produced by the activated macrophages cause destruction of islet beta-cells.

Furthermore, the direct interaction of TCR/CD3 complex on the cytotoxic CD8+ T cell and the MHC-I-autoantigen complex on the surface of beta-cells triggers the release of perforin and granzyme B from cytotoxic granules. The perforin proteins polymerize and form pores in the membrane of beta-cells. The pores increase membrane permeability leading to osmotic cell death. The perforin pores allow also granzyme B to penetrate beta-cells. Once in the beta-cell cytoplasm, granzyme B cleaves Bid to produce tBid, which activates the caspase cascade leading to apoptosis.

Cytotoxic CD8+ T cells trigger also apoptosis of beta-cells through FasL/Fas receptor interactions. Fas recruits the FADD adapter protein to form the death-inducing signaling complex, causing the activation of caspase 8, which, in turn, activates the downstream caspases leading to apoptosis of the beta-cells.

Type 1 diabetes mellitus and beta-cell destruction depend on the interaction between CD4+ T cells, CD8+ T cells and macrophages that create a chronic inflammatory lesion, in which cytokine-mediated mechanisms contribute to beta-cells dysfunction and death and soluble mediators such as NO and oxygen/nitrogen free radicals are important effector molecules.


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