Increased NF-kappa B activity in B cells and bone marrow-derived dendritic cells from NOD mice.
Type 1 diabetes results from the breakdown of peripheral tolerance. As regulators of T cell activation, antigen-presenting cells (APC) modulate peripheral tolerance and hence contribute to the immune dysregulation characteristic of insulin-dependent diabetes mellitus (IDDM). We initially observed an increased importance of NOD B cell APC function in a T cell priming assay as compared to non-autoimmune strains. Consistent with this increased APC function, we found that NF-kappa B nuclear translocation is increased in unmanipulated NOD and NOD.B10Sn-H2(b) B cells and that, in addition, NOD B cells are more sensitive to NF-kappa B-activating stimuli. We obtained similar results using NOD bone marrow-derived dendritic cell (BMDC) cultures. As costimulatory molecules have been shown to be NF-kappa B responsive, we examined the expression of these markers on NOD APC. Both B cells and BMDC expressed elevated levels of CD80 and CD40. Finally, NOD B cells provided better allostimulation than B cells from non-autoimmune strains. Therefore, hyperactivation of NF-kappa B and increased expression of CD80 and CD40 by NOD B cells and BMDC may be a contributing factor in the selection of effector T cells observed in IDDM.
Wheat
William
W
Barbara Davis Center for Childhood Diabetes, University of Colorado Health Sciences Center, Denver, 80262, USA.
Kupfer
Rene
R
Gutches
Diane G
DG
Rayat
Gina R
GR
Beilke
Joshua
J
Scheinman
Robert I
RI
Wegmann
Dale R
DR
D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology; D001324:Autoantigens / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D001854:Bone Marrow Cells / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D003713:Dendritic Cells / Q000378:metabolism*; D007328:Insulin / Q000276:immunology; D008565:Membrane Proteins / Q000276:immunology; D051379:Mice; D016688:Mice, Inbred NOD; D016328:NF-kappa B / Q000378:metabolism*; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases / Q000276:immunology; D054635:Receptor-Like Protein Tyrosine Phosphatases, Class 8; D013601:T-Lymphocytes / Q000276:immunology
D001324:Autoantigens; D007328:Insulin; D008565:Membrane Proteins; D016328:NF-kappa B; C102889:PTPRN2 protein, human; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases; D054635:Receptor-Like Protein Tyrosine Phosphatases, Class 8