Biology subjects

Yu, X.

Publications and source records attributed to Yu, X..

18 recordsLinked to original sources

bioRxiv2018

MicroRNA-200c suppresses epithelial-mesenchymal transition of ovarian cancer by targeting cofilin-2

This study investigated the effects of microRNA-200c (miR-200c) and cofilin-2 (CFL2) in regulating epithelial-mesenchymal transition (EMT) in ovarian cancer. The level of miR-200c was lower in invasive SKOV3 cells than that in non-invasive OVCAR3 cells, whereas CFL2 showed the opposite trend. Bioinformatics analysis and dual-luciferase reporter gene assays indicated that CFL2 was a direct target of miR-200c. Furthermore, SKOV3 and OVCAR3 cells were transfected with miR-200c mimic or inhibitor, pCDH-CFL2 (CFL2 overexpression), or CFL2 shRNA (CFL2 silencing). MiR-200c inhibition and CFL2 overexpression resulted in elevated levels of both CFL2 and vimentin while reducing E-cadherin expression. They also increased ovarian cancer cell invasion and migration in vitro and in vivo and increased the tumor volumes. Conversely, miR-200c mimic and CFL2 shRNA exerted the opposite effects as those aforementioned. In addition, the effects of pCDH-CFL2 and CFL2 shRNA were reversed by the miR-200c mimic and inhibitor, respectively. This finding suggested that miR-200c could be a potential tumor suppressor by targeting CFL2 in the EMT process.

cancer biology↗

bioRxiv2018

Jackknife model averaging prediction methods for complex phenotypes with gene expression levels by integrating external pathway information

MotivationIn the past few years many novel prediction approaches have been proposed and widely employed in high dimensional genetic data for disease risk evaluation. However, those approaches typically ignore in model fitting the important group structures or functional classifications that naturally exists in genetic data.\n\nMethodsIn the present study, we applied a novel model averaging approach, called Jackknife Model Averaging Prediction (JMAP), for high dimensional genetic risk prediction while incorporating KEGG pathway information into the model specification. JMAP selects the optimal weights across candidate models by minimizing a cross-validation criterion in a jackknife way. Compared with previous approaches, one of the primary features of JMAP is to allow model weights to vary from 0 to 1 but without the limitation that the summation of weights is equal to one. We evaluated the performance of JMAP using extensive simulation studies and compared it with existing methods. We finally applied JMAP to five real cancer datasets that are publicly available from TCGA.\n\nResultsThe simulations showed that, compared with other existing approaches, JMAP performed best or are among the best methods across a range of scenarios. For example, among 14 out of 16 simulation settings with PVE=0.3, JMAP has an average of 0.075 higher prediction accuracy compared with gsslasso. We further found that in the simulation the model weights for the true candidate models have much smaller chances to be zero compared with those for the null candidate models and are substantially greater in magnitude. In the real data application, JMAP also behaves comparably or better compared with the other methods for both continuous and binary phenotypes. For example, for the COAD, CRC and PAAD data sets, the average gains of predictive accuracy of JMAP are 0.019, 0.064 and 0.052 compared with gsslasso.\n\nConclusionThe proposed method JMAP is a novel method that can provide more accurate phenotypic prediction while incorporating external useful group information.

genomics↗

bioRxiv2018

Predicting natural behavior from whole-brain neural dynamics

The activity of an animals brain contains information about that animals actions and movements. We investigated the neural representation of locomotion in the nematode C. elegans by recording population calcium activity during unrestrained movement. We report that a neural population more accurately decodes locomotion than any single neuron. Relevant signals are distributed across neurons with diverse tunings to locomotion. Two distinct subpopulations are informative for decoding velocity and body curvature, and different neurons activities contribute features relevant for different instances of behavioral motifs. We labeled neurons AVAL and AVAR and found their activity was highly correlated with one another. They exhibited expected transients during backward locomotion, although they were not always the most informative neurons for decoding velocity. Finally, we compared population neural activity during movement and immobilization. Immobilization alters the correlation structure of neural activity and its dynamics. Some neurons previously correlated with AVA become anti-correlated and vice versa. The activity of an animals brain contains information about that animals actions and movements. We investigated the neural representation of locomotion in the nematode C. elegans by recording brain-wide neural dynamics in freely moving animals. We report that a population of neurons more accurately decodes the animals locomotion than any single neuron. Neural signals are distributed across neurons in the population with a diversity of tuning to locomotion. Two distinct subpopulations are most informative for decoding velocity and body curvature, and different neurons activities contribute features relevant for different instances of behavioral motifs within these subpopulations. We additionally labeled the AVA neurons within our population recordings. AVAL and AVAR exhibit activity that is highly correlated with one another, and they exhibit the expected responses to locomotion, although we find that AVA is not always the most informative neuron for decoding velocity. Finally, we compared brain-wide neural activity during movement and immobilization and observe that immobilization alters the correlation structure of neural activity and its dynamics. Some neurons that were previously correlated with AVA become anti-correlated and vice versa during immobilization. We conclude that neural population codes are important for understanding neural dynamics of behavior in moving animals.

neuroscience↗

bioRxiv2018

Comparative genetic architectures of schizophrenia in East Asian and European populations

Author summarySchizophrenia is a severe psychiatric disorder with a lifetime risk of about 1% world-wide. Most large schizophrenia genetic studies have studied people of primarily European ancestry, potentially missing important biological insights. Here we present a study of East Asian participants (22,778 schizophrenia cases and 35,362 controls), identifying 21 genome-wide significant schizophrenia associations in 19 genetic loci. Over the genome, the common genetic variants that confer risk for schizophrenia have highly similar effects in those of East Asian and European ancestry (rg=0.98), indicating for the first time that the genetic basis of schizophrenia and its biology are broadly shared across these world populations. A fixed-effect meta-analysis including individuals from East Asian and European ancestries revealed 208 genome-wide significant schizophrenia associations in 176 genetic loci (53 novel). Trans-ancestry fine-mapping more precisely isolated schizophrenia causal alleles in 70% of these loci. Despite consistent genetic effects across populations, polygenic risk models trained in one population have reduced performance in the other, highlighting the importance of including all major ancestral groups with sufficient sample size to ensure the findings have maximum relevance for all populations.

genetics↗

bioRxiv2018

lncDIFF: a novel distribution-free method for differential expression analysis of long non-coding RNA

MotivationLong non-coding RNA expression data has been increasingly used in finding diagnostic and prognostic biomarkers in cancer studies. Existing differential analysis tools for RNA sequencing does not effectively accommodate low abundant genes, as commonly observed in lncRNA. We propose a novel and robust statistical method lncDIFF to detect differential expressed (DE) genes without assuming the true density on normalized counts.\n\nResultslncDIFF adopts the generalized linear model with zero-inflated exponential quasi likelihood to estimate group effect on normalized counts, and employs the likelihood ratio test to detect differential expressed genes. The proposed method and tool is suitable for data processed with standard RNA-Seq preprocessing and normalization pipelines. Simulation results illustrate that lncDIFF detects DE genes with more power and lower false discovery rate regardless of the data pattern. The analysis on a head and neck squamous cell carcinomas study also confirms that lncDIFF has better sensitivity in identifying novel lncRNA genes with relatively large fold change and prognostic value.\n\nAvailability and ImplementationlncDIFF is an R package available at https://github.com/qianli10000/lncDIFF.\n\nSupplementary InformationSupplementary Data are available at Bioinformatics online.

bioinformatics↗

bioRxiv2018

Different capsid-binding patterns of the β-herpesvirus-specific tegument protein pp150 (pM32/pUL32) in murine and human cytomegaloviruses

The phosphoprotein pp150 is a structurally, immunogenically, and regulatorily important capsid-associated tegument protein abundant in {beta}-herpesviruses including cytomegaloviruses (CMV), but absent in -herpesviruses and {Gamma}-herpesviruses. In human CMV (HCMV), bridging across each triplex and three adjacent major capsid proteins (MCPs) is a group of three pp150 subunits in a \"{bigtriangleup}\"-shaped fortifying configuration, 320 of which encase and stabilize the genome-containing capsid. Because murine CMV (MCMV) has been used as a model for HCMV pathogenesis and therapeutic studies, one might expect that pp150 and the capsid in MCMV and HCMV have similar structures. Here, by cryoEM and sub-particle reconstructions, we have obtained structures of MCMV capsid and pp150 at near atomic resolutions and built their atomic models. Surprisingly, the capsid-binding patterns of pp150 differ between HCMV and MCMV despite their highly similar capsid structures. In MCMV, pp150 is absent on triplex Tc and exists as a \"{Lambda}\"-shaped dimer on other triplexes, leading to only 260 groups of two pp150 subunits per capsid in contrast to 320 groups of three pp150 subunits encasing each HCMV capsid. Many more amino acids contribute to pp150-pp150 interactions in MCMV than in HCMV, making MCMV pp150 dimer inflexible thus incompatible to instigate triplex Tc-binding as observed in HCMV. While pp150 is essential in HCMV, pp150-deleted MCMV mutants remained viable though with attenuated infectivity and exhibiting defects in retaining viral genome. These results support targeting capsid proteins, but invalidate targeting pp150, when using MCMV as a model for HCMV pathogenesis and therapeutic studies.\n\nImportanceCMV infection is a leading viral cause of congenital birth defects and often responsible for life-threating complications in immunocompromised individuals like AIDS and post-organ transplantation patients. Absence of effective vaccines and potent drugs against CMV infections has motivated animal-based studies, mostly based on the mouse model with MCMV, both for understanding pathogenesis of CMV infections and for developing therapeutic strategies. Here, we present the first atomic structures of MCMV and show that the organization patterns of capsid-associated tegument protein pp150 between human and mouse CMV are different despite their highly similar capsid structures. Our functional studies demonstrate that deleting pp150 does not eliminate MCMV infection in contrast to pp150s essential role in HCMV infections. These results thus establish the validity to target capsid proteins, but raise concerns to target pp150, when using MCMV as HCMV model for pathogenesis and therapeutic studies.

microbiology↗

bioRxiv2018

Multiple isotopic models using various kinetic fractionation coefficients to estimate δ18O of leaf water

Investigation of{delta} 18O of leaf water may improve our understanding of the evapotranspiration partitioning and material exchange between the inside and outside of leaves. In this study,{delta} 18O of bulk leaf water ({delta}L,b) was estimated by both isotopic-steady-state (ISS) and non-steady-state (NSS) assumptions considering the Peclet effect. Specifically, we carefully modified kinetic fractionation coefficients (k). The results showed that the Peclet effect is required to predict{delta} L,b. On the diel time scale, both NSS assumption + Peclet effect (NSS + P) and ISS assumption + Peclet effect (ISS + P) using modified k (k-modified) for{delta} L,b showed a good agreement with observed{delta} L,b (p > 0.05). When using previously proposed k, however, both NSS + P and ISS + P were not reliable estimators of{delta} L,b (p < 0.05). On a longer time scale (days), estimates of daily mean{delta} L,b from ISS + P outperformed the estimates from NSS + P when using the same k values. Also, the employment of k-modified improved model performance in predicting daily mean{delta} L,b compared to the use of previously proposed k. Clearly, special care must be taken concerning k when using isotopic models to estimate{delta} L,b.\n\nHighlightFor hourly and daily mean data sets, the employment of modified kinetic fractionation coefficients significantly improved model performance for{delta} 18O of bulk leaf water.

ecology↗

bioRxiv2018

Interactions in self-assembled microbial communities saturate with diversity

How the diversity of organisms competing for or sharing resources influences community production is an important question in ecology but has rarely been explored in natural microbial communities. These generally contain large numbers of species making it difficult to disentangle how the effects of different interactions scale with diversity. Here, we show that changing diversity affects measures of community function in relatively simple communities but that increasing richness beyond a threshold has little detectable effect. We generated self-assembled communities with a wide range of diversity by growth of cells from serially diluted seawater on brown algal leachate. We subsequently isolated the most abundant taxa from these communities via dilution-to-extinction in order to compare productivity functions of the entire community to those of individual taxa. To parse the effect of different types of organismal interactions, we developed relative total function (RTF) as an index for positive or negative effects of diversity on community function. Our analysis identified three overall regimes with increasing diversity. At low richness (<12 taxa), potential positive and negative effects of interactions are both weak, while at moderate richness (12-20 taxa), community resource uptake increases but the carbon use efficiency decreases. Finally, beyond 20 taxa, there was no net change in community function indicating a saturation of potential interactions. These data suggest that although more diverse communities had overall greater access to resources, individual taxa within these communities had lower resource availability and reduced carbon use efficiency, indicating that competition due to niche overlap increases with diversity but that these interactions saturate at a specific threshold.

ecology↗

bioRxiv2018

GONST2 transports GDP-Mannose for sphingolipid glycosylation in the Golgi apparatus of Arabidopsis

The Golgi lumen is the site of many different glycosylation events, including cell wall polysaccharide biosynthesis and lipid glycosylation. Transporters are necessary for the import of the substrates required for glycosylation (nucleotide sugars) from the cytosol where they are synthesized. Plants use four GDP-linked sugars to glycosylate macromolecules: GDP-L-Fucose, GDP-D-Mannose, GDP-L-Galactose and GDP-D-Glucose. Of the predicted fifty-one members of the nucleotide sugar transporter/triose phosphate transporter family in Arabidopsis, only four appear to contain the conserved motif needed for the transport of GDP-linked sugars, GOLGI LOCALIZED NUCLEOTIDE SUGAR TRANSPORTER (GONST) 1-4. Previously, we have demonstrated that GONST1 provides GDP-D-Mannose for glycosylation of a class of sphingolipids, the glycosylinositolphosphorylceramides (GIPCs). Here, we characterize its closest homologue, GONST2, and conclude that it also specifically provides substrate for GIPC glycosylation. Expression of GONST2 driven by the GONST1 promoter is able to rescue the severe growth phenotype of gonst1. Loss of GONST2 exacerbates the gonst1 constitutive hypersensitive response, as well as the reduced cell wall cellulose content. The gonst2 mutant grows normally under standard conditions, but has enhanced resistance to the powdery mildew-causing fungus Golovinomyces orontii.

plant biology↗

bioRxiv2018

Defining p53 pioneering capabilities with competitive nucleosome binding assays

Accurate gene expression requires the targeting of transcription factors (TFs) to regulatory sequences often occluded within nucleosomes. The ability to target a transcription factor binding site (TFBS) within a nucleosome has been the defining characteristic for a special class of TFs known as pioneer factors. Recent studies suggest p53 functions as a pioneer factor that can target its TFBS within nucleosomes, but it remains unclear how p53 binds to nucleosomal DNA. To comprehensively examine p53 nucleosome binding we competitively bound p53 to multiple in vitro formed nucleosomes containing a high or low-affinity p53 TFBS located at differing translational and rotational positions within the nucleosome. Stable p53-nucleosome complexes were isolated and quantified using next generation sequencing. Our results demonstrate p53 binding is limited to nucleosome edges with significant binding inhibition occurring within 50-bp of the nucleosome dyad. Binding site affinity only affects p53 binding for TFBS located outside the nucleosome core at the same nucleosomal positions. Furthermore, p53 has strong non-specific nucleosome binding facilitating its interaction with chromatin. Our in vitro findings were confirmed by examining p53 induced binding in a cell line model, showing induced binding at nucleosome edges flanked by a nucleosome free region. Overall, our results suggest that the pioneering capabilities of p53 are driven by non-specific nucleosome binding with specific binding at nucleosome edges.

genomics↗

bioRxiv2018

TP53 Intron Derived Concentrations Implicate p53

Introduction Introduction Background Mechanisms of p53 Regulation... Relative Concentration Dynamics ... Method TP53 intronic half-sites... ID Gene-Transcript-Intron... Conclusion References TP53 is a highly studied gene due to its important regulatory role in DNA, RNA (Marcel, Catez, and Diaz 2015), disease and the progression of cancer. TP53 functions as a tumor suppressor and has been described as the \"Guardian of the Genome\". p53, the protein coded by TP53 predominantly binds regulatory response elements (\"RE\") in introns of multiple target genes. We compared identical subsequences in introns of multiple gene/transcripts including TP53, BRCA1, menl, PELP1, SET, HIF1A, ULBP1/2 and IRF3. Some identical subsequences also contain the ...

bioinformatics↗

bioRxiv2018

Low nutrient levels reduce the fitness cost of MexCD-OprJ efflux pump overexpression in ciprofloxacin-resistant Pseudomonas aeruginosa

The long-term persistence of antibiotic resistance in the environment is a public health concern. Expression of an efflux pump, an important mechanism of resistance to antibiotics, is usually associated with a fitness cost in bacteria. In this study, we aimed to determine why antibiotic resistance conferred by overexpression of an efflux pump persists in environments such as drinking and source water in which antibiotic selective pressure may be very low or even absent. Competition experiments between wild-type Pseudomonas aeruginosa and ciprofloxacin-resistant mutants revealed that the fitness cost of ciprofloxacin resistance (strains cip_1, cip_2, and cip_3) significantly decreased (P < 0.05) under low-nutrient (0.5 mg/l total organic carbon (TOC)) relative to high-nutrient (500 mg/l TOC) conditions. Mechanisms underlying this fitness cost were analyzed. MexD gene expression in resistant bacteria (cip_3 strain) was significantly lower (P < 0.05) in low-nutrient conditions, with 10 mg/l TOC (8.01 {+/-} 0.82-fold), than in high-nutrient conditions, with 500 mg/l TOC (48.89 {+/-} 4.16-fold). Moreover, rpoS gene expression in resistant bacteria (1.36 {+/-} 0.13-fold) was significantly lower (P < 0.05) than that in the wild-type strain (2.78 {+/-} 0.29-fold) under low-nutrient conditions (10 mg/l TOC), suggesting a growth advantage. Furthermore, the difference in metabolic activity between the two competing strains was significantly smaller (P < 0.05) in low-nutrient conditions (5 and 0.5 mg/l TOC). These results suggest that nutrient levels are a key factor in determining the persistence and spread of antibiotic resistance conferred by efflux pumps in the natural environment with trace amounts or no antibiotics.\n\nImportanceThe widespread of antibiotic resistance has led to an increasing concern about the environmental and public health risks. Mechanisms associated with antibiotic resistance including efflux pumps often increase bacterial fitness cost. Our study showed that the fitness cost of ciprofloxacin resistance conferred by overexpression of MexCD-OprJ efflux pump significantly decreased under low-nutrient relative to high-nutrient conditions. The significance of our research is to reveal that nutrient levels are key factor in determining the persistence of antibiotic resistance conferred by efflux pumps under conditions with trace amounts or no antibiotics, which can be mediated by some mechanisms including MexD gene expression, SOURs differences, and rpoS gene regulation.

microbiology↗

bioRxiv2018

Water stress and CO2 concentration interactions affect carbon isotope signatures of leaf and phloem organic matter

Investigation of {delta}13C of leaf and twig phloem water-soluble organic material (WSOM) is a promising approach for analysis of the effects of environmental factors on plant performance. In this study, orthogonal treatments of three CO2 concentrations (Ca) x five soil water contents (SWC) were conducted using Platycladus orientalis saplings to investigate the interaction of water stress and CO2 concentration on {delta}13C of leaf and twig phloem WSOM. Under the lowest SWC, the {delta}13C of leaf and twig phloem WSOM had the most positive values at any Ca and their values decreased as Ca increased. However, at improved soil water conditions, the greatest values of {delta}13C of leaf and twig phloem WSOM were mostly observed at C600. In addition, a more significant relationship between SWC and {delta}13C of twig phloem WSOM than that between SWC and {delta}13C of leaf WSOM demonstrated that {delta}13C of twig phloem WSOM is a more sensitive indicator of SWC. Twig phloem WSOM was generally 13C-depleted compared with leaf WSOM for potential post-photosynthetic fractionation, and the 13C discrimination from leaves to twig phloem was insensitive to the interaction between SWC and Ca. Clearly, interacting effects play a more important role in photosynthetic fractionation than in post-photosynthetic fractionation.\n\nHighlightThe {delta}13C of leaf and twig phloem WSOM exhibited the most positive values at C400x35%-45% FC.\n\nPost-photosynthetic fractionation from leaf to twig was not be impacted by the interacting effects.

ecology↗

bioRxiv2017

Variations in δ13C of different plant organs: implications for post-photosynthetic fractionation

Compared to photosynthetic fractionation, the mechanism of post-photosynthetic carbon isotope fractionation is not well understood. The aim of this study was to investigate post-photosynthetic fractionation in both above and below ground tissues and to evaluate potential hypotheses explaining differences in carbon isotope composition ({delta}13C) among different plant organs, which can provide valuable insights into plant physiology. The results revealed that there is no significant day-night difference in{delta} 13C of twig phloem water soluble organic materials (WSOM), which could be explained by the unrestricted exchange of triose-phosphates between the chloroplast and cytoplasm and a time lag for carbohydrate exportation. Further, we found that{delta} 13C of twig phloem WSOM is more sensitive to plant water status than leaf WSOM. Analysis of{delta} 13C in different plant organs showed that the greatest 13C enrichment was recorded in stem phloem. Divergences in{delta} 13C of phloem WSOM among different plant organs were not likely to be explained by respiratory fractionation or time lag and were ascribed to transport of carbohydrates across organ boundaries and metabolic processes. Our study demonstrated that post-photosynthesis fractionation could not be ascribed to a single, unifying hypotheses; instead, it is the result of multiple processes.\n\nHighlight{delta}13C of twig phloem water soluble organic materials varied no clear diel pattern. In the leaf-twig-stem-root sequence, the greatest 13C enrichment was recorded in stem phloem.

ecology↗

bioRxiv2017

MicroRNA-21 Regulates Metabolic Adaptation of Pathogenic TH17 cells and Controls Autoimmune Inflammation

TH17 cells exhibit great heterogeneity and variable functional states in vivo. However, metabolic reprogramming of TH17 cells in vivo and its regulation during autoimmunity and host defence is unknown. Here we report that TH17 cells derived in vivo show discrete metabolic states. Metabolic states of TH17 cells in vivo were controlled at the epigenetic level, with conserved regulatory region of key metabolic regulators show distinct chromatin accessibility as demonstrated by chromatin landscape profiling. TGF-{beta}1 signaling was further shown to be crucial for remodeling of TH17 cell chromatin states, Ahr and miR-21 were identified as essential metabolic regulators for TH17 cells. Understanding metabolic reprogramming of TH17 cells in vivo may therefore provide more defined therapeutic intervention to TH17 cell mediated autoimmune diseases and insights into TH17 cell mediated host defence.

immunology↗

bioRxiv2017

FGF21 regulates melanogenesis in alpaca melanocytes via ERK1/2-Mediated MITF downregulation

Fibroblast growth factor 21 (FGF21) is known as a metabolic regulator to regulate the metabolism of glucose and lipids. However, the underlying mechanism of FGF21 on melanin synthesis remains unknown. Therefore, the current study investigates the effect of FGF21 on melanogenesis in alpaca melanocytes. We transfected the FGF21 into alpaca melanocytes, then detected the melanin contents, protein and mRNA levels of pigmentation-related genes in order to determine the melanogenesis-regulating pathway of FGF21. The results showed that FGF21 overexpression suppressed melanogenesis and decreased the expression of the major target genes termed microphthalmia-associated transcription factor (MITF) and its downstream genes, including tyrosinase (TYR) and tyrosinase-related protein 2 (TRP2). However FGF21 increased the expression of phospho-extracellular signal-regulated kinase (p-Erk1/2). In contrast, FGF21-siRNA, a small interference RNA mediating FGF21 silencing, abolished the inhibition of melanogenesis. Altogether, FGF21 may decrease melanogenesis in alpaca melanocytes via ERK activation and subsequent MITF downregulation, which is then followed by the suppression of melanogenic enzymes and melanin production.

cell biology↗

bioRxiv2017

Cell type boundaries organize plant development

In plants the dorsoventral boundary of leaves defines an axis of symmetry through the centre of the organ separating the top (dorsal) and bottom (ventral) tissues. Although the positioning of this boundary is critical for leaf morphogenesis, how the boundary is established and how it influences development remains unclear. Using live-imaging and perturbation experiments we show that leaf orientation, morphology and position are pre-patterned by HD-ZIPIII and KAN gene expression in the shoot, leading to a model in which dorsoventral genes coordinate to regulate plant development by localizing auxin response between their expression domains. However we also find that auxin levels feedback on dorsoventral patterning by spatially organizing HD-ZIPIII and KAN expression in the shoot periphery. By demonstrating that the regulation of these genes by auxin also governs their response to wounds, our results also provide a parsimonious explanation for the influence of wounds on leaf dorsoventrality.\n\nOnce sentence summaryCell type boundaries regulate plant development

developmental biology↗

bioRxiv2017

T-bet+ CD11c+ B Cells Are Critical For Anti-Chromatin IgG Production In The Development Of Lupus

A hallmark of systemic lupus erythematosus is high titers of circulating autoantibody. A novel CD11c+ B cell subset has been identified that is critical for the development of autoimmunity. However, the role of CD11c+ B cells in the development of lupus is unclear. Chronic graft-versus-host disease (cGVHD) is a lupus-like syndrome with great autoantibody production. In the present study we investigated the role of CD11c+ B cells in the pathogenesis of lupus in the cGVHD model. Here, we found the percentage and absolute number of CD11c+ B cells and titer of sera anti-chromatin IgG and IgG2a antibody were increased in cGVHD mice. CD11c+ plasma cells from cGVHD mice produced large amounts of anti-chromatin IgG2a upon stimulation. Depletion of CD11c+ B cells reduced anti-chromatin IgG and IgG2a production. T-bet expression was further shown to be upregulated in CD11c+ B cells. Knockout of T-bet in B cells alleviated cGVHD. The percentage of T-bet+ CD11c+ B cells was elevated in lupus patients and positively correlated with serum anti-chromatin levels. Our findings suggest T-bet+ CD11c+ B cells contribute to the pathogenesis of lupus and provides potential target for therapeutic intervention.

immunology↗