The regulation of antibody production is linked to the generation and maintenance of plasmablasts and plasma cells from their B cell precursors. Plasmablasts are the rapidly produced and short-lived ...effector cells of the early antibody response, whereas plasma cells are the long-lived mediators of lasting humoral immunity. An extraordinary number of control mechanisms, at both the cellular and molecular levels, underlie the regulation of this essential arm of the immune response. Despite this complexity, the terminal differentiation of B cells can be described as a simple probabilistic process that is governed by a central gene-regulatory network and modified by environmental stimuli.
Scientists have long sought to characterize the pathophysiologic basis of schizophrenia and develop biomarkers that could identify the illness. Extensive postmortem and in vivo neuroimaging research ...has described the early involvement of the hippocampus in the pathophysiology of schizophrenia. In this context, we have developed a hypothesis that describes the evolution of schizophrenia-from the premorbid through the prodromal stages to syndromal psychosis-and posits dysregulation of glutamate neurotransmission beginning in the CA1 region of the hippocampus as inducing attenuated psychotic symptoms and initiating the transition to syndromal psychosis. As the illness progresses, this pathological process expands to other regions of the hippocampal circuit and projection fields in other anatomic areas including the frontal cortex, and induces an atrophic process in which hippocampal neuropil is reduced and interneurons are lost. This paper will describe the studies of our group and other investigators supporting this pathophysiological hypothesis, as well as its implications for early detection and therapeutic intervention.
Class-switch recombination (CSR) is a DNA recombination process that replaces the immunoglobulin (Ig) constant region for the isotype that can best protect against the pathogen. Dysregulation of CSR ...can cause self-reactive BCRs and B cell lymphomas; understanding the timing and location of CSR is therefore important. Although CSR commences upon T cell priming, it is generally considered a hallmark of germinal centers (GCs). Here, we have used multiple approaches to show that CSR is triggered prior to differentiation into GC B cells or plasmablasts and is greatly diminished in GCs. Despite finding a small percentage of GC B cells expressing germline transcripts, phylogenetic trees of GC BCRs from secondary lymphoid organs revealed that the vast majority of CSR events occurred prior to the onset of somatic hypermutation. As such, we have demonstrated the existence of IgM-dominated GCs, which are unlikely to occur under the assumption of ongoing switching.
Display omitted
•Germline transcripts peak prior to GC formation and rapidly decline in GCs•IgM-dominated clones are found in late GCs, arguing against ongoing Ig switching•CSR largely ceases upon the onset of somatic hypermutation•CSR decline due to low GLT and APE1 expression is possibly orchestrated by BCL6
Germinal centers (GCs) have long been considered sites in which Ig class-switch recombination (CSR) is favored. Roco et al. show that CSR occurs during the initial T cell:B cell interaction prior to GC formation and rapidly declines as B cells differentiate into GC cells and somatic hypermutation commences.
Comprehensive knowledge of immunoglobulin genetics is required to advance our understanding of B cell biology. Validated immunoglobulin variable (V) gene databases are close to completion only for ...human and mouse. We present a novel computational approach, IgDiscover, that identifies germline V genes from expressed repertoires to a specificity of 100%. IgDiscover uses a cluster identification process to produce candidate sequences that, once filtered, results in individualized germline V gene databases. IgDiscover was tested in multiple species, validated by genomic cloning and cross library comparisons and produces comprehensive gene databases even where limited genomic sequence is available. IgDiscover analysis of the allelic content of the Indian and Chinese-origin rhesus macaques reveals high levels of immunoglobulin gene diversity in this species. Further, we describe a novel human IGHV3-21 allele and confirm significant gene differences between Balb/c and C57BL6 mouse strains, demonstrating the power of IgDiscover as a germline V gene discovery tool.
Highlights • Competition for Tfh drives GC B cell proliferation, mutation and affinity maturation. • Relationship between IgA memory, the microbiota and maternally transmitted immunoglobulin. • New ...and old transcriptional regulators of GC and plasma cell biology. • Epigenetic modifiers fine tune antibody responses, and AID de-methylates DNA.
The hippocampus in schizophrenia is characterized by both hypermetabolism and reduced size. It remains unknown whether these abnormalities are mechanistically linked. Here we addressed this question ...by using MRI tools that can map hippocampal metabolism and structure in patients and mouse models. In at-risk patients, hypermetabolism was found to begin in CA1 and spread to the subiculum after psychosis onset. CA1 hypermetabolism at baseline predicted hippocampal atrophy, which occurred during progression to psychosis, most prominently in similar regions. Next, we used ketamine to model conditions of acute psychosis in mice. Acute ketamine reproduced a similar regional pattern of hypermetabolism, while repeated exposure shifted the hippocampus to a hypermetabolic basal state with concurrent atrophy and pathology in parvalbumin-expressing interneurons. Parallel in vivo experiments using the glutamate-reducing drug LY379268 and direct measurements of extracellular glutamate showed that glutamate drives both neuroimaging abnormalities. These findings show that hippocampal hypermetabolism leads to atrophy in psychotic disorder and suggest glutamate as a pathogenic driver.
Display omitted
► In psychotic disorder and a mouse model, hippocampal hypermetabolism predicts atrophy ► The longitudinal pattern of hypermetabolism and atrophy overlap and spread ► Excess extracellular glutamate drives hypermetabolism and leads to hippocampal interneuronal pathology and atrophy ► Regulating glutamate release in the model prevents hypermetabolism and atrophy
Schobel et al. use functional and structural MRI in individuals at high risk for psychosis to show that hippocampal hypermetabolism predicts hippocampal atrophy across progression to first episode psychosis. A rodent model shows that alterations in extracellular glutamate may contribute to these abnormalities.
When B cells encounter an antigen, they alter their physiological state and anatomical localization and initiate a differentiation process that ultimately produces antibody-secreting cells (ASCs). We ...have defined the transcriptomes of many mature B cell populations and stages of plasma cell differentiation in mice. We provide a molecular signature of ASCs that highlights the stark transcriptional divide between B cells and plasma cells and enables the demarcation of ASCs on the basis of location and maturity. Changes in gene expression correlated with cell-division history and the acquisition of permissive histone modifications, and they included many regulators that had not been previously implicated in B cell differentiation. These findings both highlight and expand the core program that guides B cell terminal differentiation and the production of antibodies.
TP53, PTEN, and RB1 tumor suppressor genes (TSGs) are recurrently altered in treatment-resistant prostate cancer. Cooperative loss of two or more TSGs may drive more aggressive disease.
To determine ...clinical outcomes of single and compound TSG alterations across the spectrum of prostate cancer.
Massively parallel targeted sequencing using castration-sensitive prostate cancer (CSPC; localized L and metastatic M1) and castration-resistant prostate cancer (CRPC) specimens (n=285). TSG altered (TSG-alt) was any copy number loss or deleterious mutation of one or more TSGs (TP53, PTEN, and RB1).
For L-CSPC, event-free survival (EFS) and time to CRPC were estimated. For M1-CSPC and M1-CRPC, overall survival (OS) was estimated. Cox regression models assessed the association between cumulative TSG hits (zero hits vs one hit vs two to three hits) and outcomes with multivariable analyses adjusted for clinicopathological factors.
TSG variants increased with advanced disease (L-CSPC: 39%; M1-CSPC: 63%, M1-CRPC: 92%). TSG-alt L-CSPC had shorter EFS (median 2.6yr, hazard ratio HR 1.95, 95% confidence interval CI 1.22–3.13) and time to CRPC (median 9.5mo, HR 3.36, 95% CI 1.01–11.16). Cumulative gene hits led to an incremental risk of relapse (EFS: one gene, HR 1.69, 95% CI 0.99–2.87; two to three genes, HR 2.70, 95% CI 1.43–5.08; both versus zero genes, p=0.004). There was evidence of inferior OS with increasing TSG hits in the metastatic cohorts. Only four (8%) patients in the M1-CRPC cohort were TSG-neg, one of whom died after 5.2yr. Multivariable analyses adjusting for mutational and copy number burden did not demonstrate a significant independent association of increasing gene hits and poorer outcomes.
Deleterious TSG variants are associated with an increased risk of relapse (L) and death (M1) in CSPC. Poorer outcomes are seen with compound gene hits in both early and advanced disease, and this may in part reflect increasing global genomic instability.
Men with prostate tumors with compound tumor suppressor gene mutations have poorer outcomes. These findings help identify patients with aggressive features who may benefit from intensified treatment.
Alterations of TP53, PTEN, and RB1 tumor suppressor genes are present across the clinical spectrum of prostate cancer and are particularly frequent in metastatic and castration-resistant disease. Alterations are associated with poorer outcomes, with incremental risk seen with compound loss, thereby identifying at-risk patient subgroups in the early and advanced disease settings.
Recognition of antigens by T cell receptors (TCRs) and B cell receptors (BCRs) is a key step in lymphocyte activation. T and B cells mediate adaptive immune responses, which protect us against ...infections and provide immunological memory, and also, in some instances, drive pathogenic responses in autoimmune diseases. TCRs and BCRs are encoded within loci that are known to be genetically diverse. However, the extent and functional impact of this variation, both in humans and model animals used in immunological research, remain largely unknown. Experimental and genetic evidence has demonstrated that the complementarity determining regions 1 and 2 (HCDR1 and HCDR2), encoded by the variable (V) region of TCRs and BCRs, also often make critical contacts with the targeted antigen. Thus, knowledge about allelic variation in the genes encoding TCRs and BCRs is critically important for understanding adaptive immune responses in outbred populations and to define responder and non-responder phenotypes.
PDF
