Signalling for B cell survival

The number of mature B cells is carefully controlled by signalling from receptors that support B cell survival. The best studied of these are the B cell antigen receptor (BCR) and BAFFR. Recent work has shown that signalling from these receptors is closely linked, involves the CD19 co-receptor, and leads to activation of canonical and non-canonical NF-κB pathways, ERK1, ERK2 and ERK5 MAP kinases, and PI-3 kinases. Importantly, studies show that investigation of the importance of signalling molecules in cell survival requires the use of inducible gene deletions within mature B cells. This overcomes the limitations of many earlier studies using constitutive gene deletions which were unable to distinguish between requirements for a protein in development versus survival

Antidepressants cheer up hepatic B1 B cells: Hope for the treatment of autoimmune liver diseases?

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BAFF activation of the ERK5 MAP kinase pathway regulates B cell survival

B cell activating factor (BAFF) stimulation of the BAFF receptor (BAFF-R) is essential for the homeostatic survival of mature B cells. Earlier in vitro experiments with inhibitors that block MEK 1 and 2 suggested that activation of ERK 1 and 2 MAP kinases is required for BAFF-R to promote B cell survival. However, these inhibitors are now known to also inhibit MEK5, which activates the related MAP kinase ERK5. In the present study, we demonstrated that BAFF-induced B cell survival was actually independent of ERK1/2 activation but required ERK5 activation. Consistent with this, we showed that conditional deletion of ERK5 in B cells led to a pronounced global reduction in mature B2 B cell numbers, which correlated with impaired survival of ERK5-deficient B cells after BAFF stimulation. ERK5 was required for optimal BAFF up-regulation of Mcl1 and Bcl2a1, which are prosurvival members of the Bcl-2 family. However, ERK5 deficiency did not alter BAFF activation of the PI3-kinase-Akt or NF-κB signaling pathways, which are also important for BAFF to promote mature B cell survival. Our study reveals a critical role for the MEK5-ERK5 MAP kinase signaling pathway in BAFF-induced mature B cell survival and homeostatic maintenance of B2 cell numbers

TLR4 signals in B lymphocytes are transduced via the B cell antigen receptor and SYK

Toll-like receptors (TLRs) play an important role in immune responses to pathogens by transducing signals in innate immune cells in response to microbial products. TLRs are also expressed on B cells, and TLR signaling in B cells contributes to antibody-mediated immunity and autoimmunity. The SYK tyrosine kinase is essential for signaling from the B cell antigen receptor (BCR), and thus for antibody responses. Surprisingly, we find that it is also required for B cell survival, proliferation, and cytokine secretion in response to signaling through several TLRs. We show that treatment of B cells with lipopolysaccharide, the ligand for TLR4, results in SYK activation and that this is dependent on the BCR. Furthermore, we show that B cells lacking the BCR are also defective in TLR-induced B cell activation. Our results demonstrate that TLR4 signals through two distinct pathways, one via the BCR leading to activation of SYK, ERK, and AKT and the other through MYD88 leading to activation of NF-κB

Syk tyrosine kinase is critical for B cell antibody responses and memory B cell survival

Signals from the BCR are required for Ag-specific B cell recruitment into the immune response. Binding of Ag to the BCR induces phosphorylation of immune receptor tyrosine-based activation motifs in the cytoplasmic domains of the CD79a and CD79b signaling subunits, which subsequently bind and activate the Syk protein tyrosine kinase. Earlier work with the DT40 chicken B cell leukemia cell line showed that Syk was required to transduce BCR signals to proximal activation events, suggesting that Syk also plays an important role in the activation and differentiation of primary B cells during an immune response. In this study, we show that Syk-deficient primary mouse B cells have a severe defect in BCR-induced activation, proliferation, and survival. Furthermore, we demonstrate that Syk is required for both T-dependent and T-independent Ab responses, and that this requirement is B cell intrinsic. In the absence of Syk, Ag fails to induce differentiation of naive B cells into germinal center B cells and plasma cells. Finally, we show that the survival of existing memory B cells is dependent on Syk. These experiments demonstrate that Syk plays a critical role in multiple aspects of B cell Ab responses

Long noncoding RNAs in B-cell development and activation

Long noncoding RNAs (lncRNAs) are potentially important regulators of cell differentiation and development, but little is known about their roles in B lymphocytes. Using RNA-seq and de novo transcript assembly, we identified 4516 lncRNAs expressed in 11 stages of B-cell development and activation. Most of these lncRNAs have not been previously detected, even in the closely related T-cell lineage. Comparison with lncRNAs previously described in human B cells identified 185 mouse lncRNAs that have human orthologs. Using chromatin immunoprecipitation-seq, we classified 20% of the lncRNAs as either enhancer-associated (eRNA) or promoter-associated RNAs. We identified 126 eRNAs whose expression closely correlated with the nearest coding gene, thereby indicating the likely location of numerous enhancers active in the B-cell lineage. Furthermore, using this catalog of newly discovered lncRNAs, we show that PAX5, a transcription factor required to specify the B-cell lineage, bound to and regulated the expression of 109 lncRNAs in pro-B and mature B cells and 184 lncRNAs in acute lymphoblastic leukemia

In vivo and ex vivo analyses of amyloid toxicity in the Tc1 mouse model of Down syndrome

RATIONALE: The prevalence of Alzheimer's disease is increased in people with Down syndrome. The pathology appears much earlier than in the general population, suggesting a predisposition to develop Alzheimer's disease. Down syndrome results from trisomy of human chromosome 21, leading to overexpression of possible Alzheimer's disease candidate genes, such as amyloid precursor protein gene. To better understand how the Down syndrome context results in increased vulnerability to Alzheimer's disease, we analysed amyloid-β [25-35] peptide toxicity in the Tc1 mouse model of Down syndrome, in which ~75% of protein coding genes are functionally trisomic but, importantly, not amyloid precursor protein. RESULTS: Intracerebroventricular injection of oligomeric amyloid-β [25-35] peptide in three-month-old wildtype mice induced learning deficits, oxidative stress, synaptic marker alterations, activation of glycogen synthase kinase-3β, inhibition of protein kinase B (AKT), and apoptotic pathways as compared to scrambled peptide-treated wildtype mice. Scrambled peptide-treated Tc1 mice presented high levels of toxicity markers as compared to wildtype mice. Amyloid-β [25-35] peptide injection in Tc1 mice induced significant learning deficits and enhanced glycogen synthase kinase-3β activity in the cortex and expression of apoptotic markers in the hippocampus and cortex. Interestingly, several markers, including oxidative stress, synaptic markers, glycogen synthase kinase-3β activity in the hippocampus and AKT activity in the hippocampus and cortex, were unaffected by amyloid-β [25-35] peptide injection in Tc1 mice. CONCLUSIONS: Tc1 mice present several toxicity markers similar to those observed in amyloid-β [25-35] peptide-treated wildtype mice, suggesting that developmental modifications in these mice modify their response to amyloid peptide. However, amyloid toxicity led to severe memory deficits in this Down syndrome mouse model

Tc1 mouse model of trisomy-21 dissociates properties of short- and long-term recognition memory

The present study examined memory function in Tc1 mice, a transchromosomic model of Down syndrome (DS). Tc1 mice demonstrated an unusual delay-dependent deficit in recognition memory. More specifically, Tc1 mice showed intact immediate (30sec), impaired short-term (10-min) and intact long-term (24-h) memory for objects. A similar pattern was observed for olfactory stimuli, confirming the generality of the pattern across sensory modalities. The specificity of the behavioural deficits in Tc1 mice was confirmed using APP overexpressing mice that showed the opposite pattern of object memory deficits. In contrast to object memory, Tc1 mice showed no deficit in either immediate or long-term memory for object-in-place information. Similarly, Tc1 mice showed no deficit in short-term memory for object-location information. The latter result indicates that Tc1 mice were able to detect and react to spatial novelty at the same delay interval that was sensitive to an object novelty recognition impairment. These results demonstrate (1) that novelty detection per se and (2) the encoding of visuo-spatial information was not disrupted in adult Tc1 mice. The authors conclude that the task specific nature of the short-term recognition memory deficit suggests that the trisomy of genes on human chromosome 21 in Tc1 mice impacts on (perirhinal) cortical systems supporting short-term object and olfactory recognition memory

Dissecting the contribution of human chromosome 21 syntenic regions to recognition memory processes in adult and aged mouse models of Down syndrome

Background: Trisomy of human chromosome 21 (Hsa21) results in a constellation of features known as Down syndrome (DS), the most common genetic form of intellectual disability. Hsa21 is orthologous to three regions in the mouse genome on mouse chromosome 16 (Mmu16), Mmu17 and Mmu10. We investigated genotype-phenotype relationships by assessing the contribution of these three regions to memory function and age-dependent cognitive decline, using three mouse models of DS, Dp1Tyb, Dp(17)3Yey, Dp(10)2Yey, that carry an extra copy of the Hsa21-orthologues on Mmu16, Mmu17 and Mmu10, respectively. Hypothesis: Prior research on cognitive function in DS mouse models has largely focused on models with an extra copy of the Mmu16 region and relatively little is known about the effects of increased copy number on Mmu17 and Mmu10 on cognition and how this interacts with the effects of aging. As aging is is a critical contributor to cognitive and psychiatric changes in DS, we hypothesised that ageing would differentially impact memory function in Dp1Tyb, Dp(17)3Yey, and Dp(10)2Yey, models of DS. Methods: Young (12-13 months and old (18-20 months mice Dp1Tyb, Dp(17)3Yey and Dp(10)2Yey mice were tested on a battery of object recognition memory test that assessed object novelty detection, novel location detection and associative object-in place memory. Following behavioral testing, hippocampal and frontal cortical tissue was analysed for expression of glutamatergic receptor proteins using standard immunoblot techniques. Results: Young (12-13 months and old (18-20 months mice Dp1Tyb, Dp(17)3Yey and Dp(10)2Yey mice were tested on a battery of object recognition memory test that assessed object novelty detection, novel location detection and associative object-in place memory. Following behavioral testing, hippocampal and frontal cortical tissue was analysed for expression of glutamatergic receptor proteins using standard immunoblot techniques. Conclusion: Our results show that distinct Hsa21-orthologous regions contribute differentially to cognitive dysfunction in DS mouse models and that aging interacts with triplication of Hsa21-orthologous genes on Mmu10

Critical requirement for BCR, BAFF, and BAFFR in memory B cell survival

Memory B cells (MBCs) are long-lived cells that form a critical part of immunological memory, providing rapid antibody responses to recurring infections. However, very little is known about signals controlling MBC survival. Previous work has shown that antigen is not required for MBC survival, but a requirement for the B cell antigen receptor (BCR) has not been tested. Other studies have shown that, unlike naive B cells, MBCs do not express BAFFR and their survival is independent of BAFF, the ligand for BAFFR. Here, using inducible genetic ablation, we show that survival of MBCs is critically dependent on the BCR and on signaling through the associated CD79A protein. Unexpectedly, we found that MBCs express BAFFR and that their survival requires BAFF and BAFFR; hence, loss of BAFF or BAFFR impairs recall responses. Finally, we show that MBC survival requires IKK2, a kinase that transduces BAFFR signals. Thus, MBC survival is critically dependent on signaling from BCR and BAFFR