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Accelerated Type 1 Diabetes Induction in Mice by Adoptive Transfer of Diabetogenic CD4+ T Cells
Published on: May 6, 2013
Abnormal NF-kappa B function characterizes human type 1 diabetes dendritic cells and monocytes.
Zia U A Mollah1, Saparna Pai, Craig Moore
1Diamantina Institute for Cancer, Immunology, and Metabolic Medicine, University of Queensland, Department of Diabetes and Endocrinology, Princess Alexandria Hospital, Brisbane, Queensland, Australia.
Journal of Immunology (Baltimore, Md. : 1950)
|February 23, 2008
Summary
Abnormal dendritic cell (DC) differentiation in type 1 diabetes mellitus (T1DM) involves impaired NF-kappaB signaling. Targeting SHP-1, a negative regulator, may restore normal immune cell function in T1DM patients.
Area of Science:
- Immunology
- Endocrinology
- Cell Biology
Background:
- Dendritic cell (DC) differentiation abnormalities are observed in type 1 diabetes mellitus (T1DM).
- The precise link between these DC abnormalities and T1DM pathogenesis remains unclear.
- Investigating immune cell signaling pathways is crucial for understanding T1DM.
Purpose of the Study:
- To investigate the lipopolysaccharide (LPS) response in monocytes and monocyte-derived DCs from T1DM patients.
- To identify molecular mechanisms underlying impaired immune cell function in T1DM.
- To explore potential therapeutic targets for restoring immune homeostasis in T1DM.
Main Methods:
- Monocytes and monocyte-derived DCs were isolated from T1DM patients and controls.
- Lipopolysaccharide (LPS) response was assessed, focusing on NF-kappaB pathway activation (RelA, p50, c-Rel, RelB).
- Expression of SHP-1 (a negative regulator of NF-kappaB) and DC surface marker induction (CD40, MHC class I) were analyzed.
Main Results:
- T1DM patients exhibited impaired late LPS-mediated nuclear DNA binding by NF-kappaB proteins.
- Impaired DC CD40 and MHC class I induction was observed in T1DM, alongside normal cytokine production.
- Monocytes from T1DM patients showed constitutive RelA and RelB activation and SHP-1 overexpression.
Conclusions:
- The NF-kappaB response to LPS in monocytes and DCs serves as a novel phenotypic and likely pathogenetic marker for T1DM.
- SHP-1 overexpression is implicated in the dysregulated NF-kappaB signaling observed in T1DM monocytes.
- Inhibition of SHP-1 partially restored LPS responsiveness in differentiating DCs from T1DM patients, suggesting a therapeutic avenue.
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