SUMMARY Autoreactive B cells play critical roles in a large diversity of autoimmune diseases, but the molecular pathways controlling these cells remain poorly understood. We performed an in vivo functional screen of a lymphocyte-expressed miRNA library and identified the microRNA miR-148a as a potent regulator of B cell tolerance. Elevated miR-148a expression impaired B cell tolerance by promoting the survival of immature B cells upon B cell receptor engagement via suppressing the expression of Gadd45a, Pten and Bcl2l11, which encodes the pro-apoptotic factor Bim. Furthermore, increased expression of miR-148a, which occurs frequently in lupus patients and lupus-prone mice, facilitated the development of lethal autoimmune disease in a lupus mouse model. These studies demonstrate that miR-148a functions as an important regulator of B cell tolerance and autoimmunity.

Objective- Cardiac progenitor cells reside in the heart in adulthood, although their physiological relevance remains unknown. Here, we demonstrate that after myocardial infarction, adult Bmi1 (B lymphoma Mo-MLV insertion region 1 homolog [PCGF4]) cardiac cells are a key progenitor-like population in cardiac neovascularization during ventricular remodeling. Approach and Results- These cells, which have a strong in vivo differentiation bias, are a mixture of endothelial- and mesenchymal-related cells with in vitro spontaneous endothelial cell differentiation capacity. Genetic lineage tracing analysis showed that heart-resident Bmi1 progenitor cells proliferate after acute myocardial infarction and differentiate to generate de novo cardiac vasculature. In a mouse model of induced myocardial infarction, genetic ablation of these cells substantially deteriorated both heart angiogenesis and the ejection fraction, resulting in an ischemic-dilated cardiac phenotype. Conclusions- These findings imply that endothelial-related Bmi1 progenitor cells are necessary for injury-induced neovascularization in adult mouse heart and highlight these cells as a suitable therapeutic target for preventing dysfunctional left ventricular remodeling after injury.

Results. Phosphorylation of p38 on Tyr 323 was higher in T cells from patients with active RA (P ‫؍‬ 0.008 versus healthy controls) than in patients with RA in remission or in patients with AS. Tyr 323 p38 phosphorylation was associated with disease activity determined by the DAS28 (P ‫؍‬ 0.017). Enhanced p38 phosphorylation was linked to Lck-mediated activation of the Tyr 323 -dependent pathway in the absence of upstream MAPKK activation.Conclusion. Our results indicate that phosphorylation status on Tyr 323 p38 correlates with RA disease activity and suggest that the Tyr 323 -dependent pathway is an attractive target for down-regulation of p38 activity in RA patients.

The p38 mitogen-activated protein kinase (MAPK) pathway is involved in the regulation of immune and inflammatory processes. We used p38α-conditional, p38β-deficient and p38α/β double-null mouse models to address the role of these two p38 MAPK in CD4 T cells, and found that p38α deficiency causes these cells to hyperproliferate. Our studies indicate that both p38α and p38β are dispensable for T helper cell type 1 (Th1) differentiation but, by controlling interferon (IFN)γ and tumor necrosis factor (TNF)α production, are critical for normal Th1 effector function. We found that both p38α and p38β modulate T-cell receptor-induced IFNγ and TNFα production, whereas only p38α regulates cytokine-induced IFNγ production. The lack of p38α and p38β did not affect transcription and mRNA stability of Ifng. However, the absence of p38α in Th1 cells resulted in a decreased MNK1 phosphorylation after cytokine activation, and MNK1 inhibition blocked IFNγ production. Our results indicate that p38α regulates IFNγ secretion through the activation of the MNK1/eIF4E pathway of translation initiation and identify specific functions for p38α and p38β in T-cell proliferation.

Autoreactive B cells are major contributors to autoimmune disease pathogenesis, but the molecular pathways responsible for the break of B cell tolerance in these patients remain largely unknown. In this study, we performed an in vivo functional screen of a lymphocyte-expressed miRNA library and identified miR-148a as a key regulator of this process. Elevated miR-148a expression impaired B cell tolerance by protecting immature B cells from BCR engagement-induced apoptosis, through downregulation of its targets Gadd45a, Bcl2l11, and Pten. Moreover, increased expression of miR-148a, which has been consistently found in lupus patients and lupus-prone mice, accelerated the development of lethal autoimmunity in a lupus mouse model. These results demonstrate that miR-148a functions as an important regulator of B cell tolerance and autoimmunity.