Reduced regulatory T cells are associated with higher levels of Th1/TH17 cytokines and activated MAPK in type 1 bipolar disorder.

Bipolar disorder (BD) has been associated with an immunologic imbalance shown by increased peripheral inflammatory markers. The underlying mechanisms of this phenomenon may include changes in circulating cells and differential activation of mitogen-activated protein kinases (MAPKs). Twenty-seven euthymic female subjects with BD type I (all medicated) and 24 age- and sex-matched controls were recruited in this study. Lymphocytes were isolated and stimulated in vitro to assess Th1/Th17/Th2 cytokines (IL-2, IL-4, IL-6, IL-10, IL-17, IFN-γ and TNF-α) and MAPK phosphorylation. The expression of phospho-MAPKs, a large panel of lymphocyte subsets and cytokines were assessed by multi-color flow cytometry. BD patients had reduced proportions of natural T regulatory cells (CD4+ CD25+ FoxP3+) (p<0.01) in parallel to higher cytokine production (all p<0.01) than healthy controls. In particular, BD was associated with a strong bias to Th1 rather than Th2 profile. There was an expansion of senescence-associated cells (CD8+ CD28-) in BD (p<0.0001). T cells of BD patients had an increased p-ERK signaling (p<0.0001), indicating lymphocyte activation. Our data suggest that multiple molecular and cellular mechanisms may contribute to the immunologic imbalance observed in BD. In addition, our data concur to an early senescence process in these patients.