Although B cells expressing the IFNγR or the IFNγ-inducible transcription factor T-bet promote autoimmunity in Systemic Lupus Erythematosus (SLE)-prone mouse models, the role for IFNγ signaling in human antibody responses is unknown. We show that elevated levels of IFNγ in SLE patients correlate with expansion of the T-bet expressing IgDnegCD27negCD11c+CXCR5neg (DN2) pre-antibody secreting cell (pre-ASC) subset. We demonstrate that naïve B cells form T-bethi pre-ASCs following stimulation with either Th1 cells or with IFNγ, IL-2, anti-Ig and TLR7/8 ligand and that IL-21 dependent ASC formation is significantly enhanced by IFNγ or IFNγ-producing T cells. IFNγ promotes ASC development by synergizing with IL-2 and TLR7/8 ligands to induce genome-wide epigenetic reprogramming of B cells, which results in increased chromatin accessibility surrounding IRF4 and BLIMP1 binding motifs and epigenetic remodeling of IL21R and PRDM1 loci. Finally, we show that IFNγ signals poise B cells to differentiate by increasing their responsiveness to IL-21.

Although viral infections elicit robust interferon-g (IFN-g) and long-lived antibody-secreting cell (ASC) responses, the roles for IFN-g and IFN-g-induced transcription factors (TFs) in ASC development are unclear. We showed that B cell intrinsic expression of IFN-gR and the IFN-g-induced TF T-bet were required for T-helper 1 cell-induced differentiation of B cells into ASCs. IFN-gR signaling induced Blimp1 expression in B cells but also initiated an inflammatory gene program that, if not restrained, prevented ASC formation. T-bet did not affect Blimp1 upregulation in IFN-g-activated B cells but instead regulated chromatin accessibility within the Ifng and Ifngr2 loci and repressed the IFN-g-induced inflammatory gene program. Consistent with this, B cell intrinsic T-bet was required for formation of long-lived ASCs and secondary ASCs following viral, but not nematode, infection. Therefore, T-bet facilitates differentiation of IFN-g-activated inflammatory effector B cells into ASCs in the setting of IFN-g-, but not IL-4-, induced inflammatory responses.

Lysosomes critically regulate the pH-dependent catabolism of extracellular and intracellular macromolecules delivered from the endocytic/heterophagy and autophagy pathways, respectively. The importance of lysosomes to cell survival is underscored not only by their unique ability effectively to degrade metalloproteins and oxidatively damaged macromolecules, but also by the distinct potential for induction of both caspase-dependent and -independent cell death with a compromise in the integrity of lysosome function. Oxidative stress and free radical damage play a principal role in cell death induced by lysosome dysfunction and may be linked to several upstream and downstream stimuli, including alterations in the autophagy degradation pathway, inhibition of lysosome enzyme function, and lysosome membrane damage. Neurons are sensitive to lysosome dysfunction, and the contribution of oxidative stress and free radical damage to lysosome dysfunction may contribute to the etiology of neurodegenerative disease. This review provides a broad overview of lysosome function and explores the contribution of oxidative stress and autophagy to lysosome dysfunction-induced neuron death. Putative signaling pathways that either induce lysosome dysfunction or result from lysosome dysfunction or both, and the role of oxidative stress, free radical damage, and lysosome dysfunction in pediatric lysosomal storage disorders (neuronal ceroid lipofuscinoses or NCL/Batten disease) and in Alzheimer's disease are emphasized. Antioxid. Redox Signal. 11,[481][482][483][484][485][486][487][488][489][490][491][492][493][494][495][496]

34Although B cells expressing the IFNgR or the IFNg-inducible transcription factor T-bet drive autoimmunity 35 in Systemic Lupus Erythematosus (SLE)-prone mouse models, the role for IFNg signaling in human 36 antibody responses is unknown. We show that elevated levels of IFNg in SLE patients correlate with 37 expansion of the T-bet expressing IgD neg CD27 neg CD11c + CXCR5 neg (DN2) pre-antibody secreting cell 38 (pre-ASC) subset. We demonstrate that naïve B cells form T-bet hi pre-ASCs following stimulation with 39 either Th1 cells or with IFNg, IL-2, anti-Ig and TLR7/8 ligand and that IL-21 dependent ASC formation is 40 significantly enhanced by IFNg or IFNg-producing T cells. IFNg promotes ASC development by 41 synergizing with IL-2 and TLR7/8 ligands to induce genome-wide epigenetic reprogramming of B cells, 42 which results in increased chromatin accessibility surrounding IRF4 and BLIMP1 binding motifs and 43 epigenetic remodeling of IL21R and PRDM1 loci. Finally, we show that IFNg signals poise B cells to 44 differentiate by increasing their responsiveness to 45 46 50 adaptive arms of the immune system, which ultimately leads to loss of immune tolerance in B and T 51 lymphocytes and the production of autoantibodies (Abs) by Ab-secreting B cells (ASCs) (1). The hallmark 52 SLE autoAbs recognize nuclear proteins and nucleic acids (2), which are also ligands for TLR7 and TLR9 53 that are expressed by innate immune cells and B cells (3). SLE autoAbs bound to their autoAgs form 54 immune complexes, which are responsible for many of the clinical manifestations of SLE, particularly 55 those associated with organ damage (2). Consistent with the important role for B cells and ASCs in SLE 56 pathogenesis (4), the only new drug approved to treat SLE in decades, Belimumab, targets B cells. 58Inflammatory cytokines and chemokines also contribute to SLE pathogenesis (5). SLE patient PBMCs 59 often exhibit a type I interferon (IFN) transcriptional signature and systemic IFNa is elevated in many 60 patients (6). It is less well appreciated that IFNg is also increased in some SLE patients (7-9) and that a 61 distinct IFNg transcription signature can be detected in PBMCs from a portion of SLE patients (10, 11). 62Interestingly, elevated serum IFNg can be observed years before IFNa or autoAbs are detected in SLE 63 patients and much earlier than clinical disease (12, 13). Consistent with these observations, B cells from 64 SLE patients can exhibit signs of prior IFNg exposure. For example, CXCR3 and T-bet, two IFNg-inducible 65 proteins (14), are more highly expressed by circulating B cells from SLE patients compared to healthy 66 controls (8,(15)(16)(17)(18)(19). Moreover, data from mouse SLE models show that clinical disease is dependent on 67 B cell-specific expression of the IFNgR and the IFNg-induced transcription factors and T-68 bet in some (23, 24) but not all (21, 25) models. Taken together, these data suggest that IFNg-driven 69 inflammation may contribute to SLE B cell-driven pathophysiology. 71Two populations of...

Following the fate of antigen-specific memory B cells has been difficult. In this issue of Immunity, Krishnamurty et al. (2016) use a novel B cell tetramer to define Plasmodium-specific memory B cells in parasite-infected mice and demonstrate that after re-infection, somatically mutated IgM(+) memory B cells function as first responders by rapidly differentiating into T-cell-dependent plasmablasts and T-cell-independent plasma cells.