BCTCP:A Feedback-Based Congestion Control Method

Delay and throughput are the two network indicators that users most care about.Traditional congestion control methods try to occupy buffer aggressively until packet loss being detected,causing high delay and variation.Using AQM and ECN can highly reduce packet drop rate and delay,however they may also lead to low utilization.Managing queue size of routers properly means a lot to congestion control method.Keeping traffic size varying around bottleneck bandwidth creates some degree of persistent queue in the router,which brings in additional delay into network unwillingly,but a corporation between sender and router can keep it under control.Proper persistent queue not only keeps routers being fully utilized all the time,but also lower the variation of throughput and delay,achieving the balance between delay and utilization.In this paper,we present BCTCP(Buffer Controllable TCP),a congestion control protocol based on explicit feedback from routers.It requires sender,receiver and routers cooperating with each other,in which senders adjust their sending rate according to the multiple bit load factor information from routers.It keeps queue length of bottleneck under control,leading to very good delay and utilization result,making it more applicable to complex network environments.

免疫球蛋白G4相关硬化性胆管炎中RANKL调控髓系源性抑制细胞的免疫生物学特性

在免疫球蛋白G4相关硬化性胆管炎（IgG4-SC）的发病机制领域，免疫细胞及相关细胞因子参与的免疫调控一直是学者关注的研究热点。髓系源性抑制细胞（MDSCs）最初由于介导对T淋巴细胞的显著免疫抑制功能被发现，近年来其在慢性炎症性疾病中的免疫调节功能引起广泛关注。Hepatology杂志于2018年5月在线发表了来自上海交通大学医学院附属仁济医院消化内科、上海市消化疾病研究所马雄教授课题组题为《免疫球蛋白G4相关硬化性胆管炎中RANKL调控髓系源性抑制细胞的免疫生物学特性》的研究论著。该研究通过对IgG4-SC患者肝脏组织及外周血标本的分析，探索IgG4-SC免疫微环境中调控MDSCs的细胞因子及其介导“肝-骨对话”的分子机制。研究结果提示，MDSCs作为骨髓来源的免疫调节细胞，积极参与IgG4-SC免疫微环境中的“肝-骨对话”，扩增活化的MDSCs可促进肝内免疫向Th2型细胞过度活化，加重IgG4-SC纤维化进展。调控IgG4-SC的RANKL诱导bADSCs信号途径具有重要临床意义。

The modulation of co-stimulatory molecules by circulating exosomes in primary biliary cirrhosis

Exosomes are nanoparticles of endocytic origin, secreted by a myriad of cell populations that are attracting increased attention by virtue of their ability to modulate cell-to-cell communications. They are also attracting attention in a variety of immunological issues, including autoimmunity and, in particular, their ability to regulate cytokine and chemokine activation. Primary biliary cirrhosis （PBC） is considered a model autoimmune disease, which has a highly focused cytotoxic response against biliary epithelial cells. We have isolated exosomes from plasma from 29 patients with PBC and 30 healthy controls （HCs）, and studied the effect of these exosomes on co-stimulatory molecule expression and cytokine production in mononuclear cell populations using an ex vivo system. We also identified the microRNA （miRNA） populations in PBC compared to HC exosomes. We report herein that although exosomes do not change cytokine production, they do significantly alter co-stimulatory molecule expression on antigen-presenting populations. Further, we demonstrated that CD86 up-regulated expression on CD14＋ monocytes, whereas CD40 up-regulated on CD11c＋ dendritic cells by exosomes from patients with PBC. In addition, there were differences of miRNA expression of circulating exosomes in patients with PBC. These data have significant importance based on observations that co-stimulatory molecules play a differential role in the regulation of T-cell activation. Our observation indicated that aberrant exosomes from PBC selectively induce expression of co-stimulatory molecules in different subset of antigen-presenting cells. These alterations may involve in pathogenesis of autoimmune liver disease.

Adaptive immunity in the liver

The anatomical architecture of the human liver and the diversity of its immune components endow the liver with its physiological function of immune competence. Adaptive immunity is a major arm of the immune system that is organized in a highly specialized and systematic manner, thus providing long-lasting protection with immunological memory. Adaptive immunity consists of humoral immunity and cellular immunity. Cellular immunity is known to have a crucial role in controlling infection, cancer and autoimmune disorders in the liver. In this article, we will focus on hepatic virus infections, hepatocellular carcinoma and autoimmune disorders as examples to illustrate the current understanding of the contribution of T cells to cellular immunity in these maladies. Cellular immune suppression is primarily responsible for chronic viral infections and cancer. However, an uncontrolled auto-reactive immune response accounts for autoimmunity. Consequently, these immune abnormalities are ascribed to the quantitative and functional changes in adaptive immune cells and their subsets, innate immunocytes, chemokines, cytokines and various surface receptors on immune cells. A greater understanding of the complex orchestration of the hepatic adaptive immune regulators during homeostasis and immune competence are much needed to identify relevant targets for clinical intervention to treat immunological disorders in the liver.

Liver-resident NK cells suppress autoimmune cholangitis and limit the proliferation of CD4^(+) T cells

Liver-resident NK cells are distinct from conventional NK cells and play an important role in the maintenance of liver homeostasis.How liver-resident NK cells participate in autoimmune cholangitis remains unclear.Here,we extensively investigated the impact of NK cells in the pathogenesis of autoimmune cholangitis utilizing the well-established dnTGFβRII cholangitis model,NK cell-deficient(Nfil3−/−)mice,adoptive transfer and in vivo antibody-mediated NK cell depletion.Our data demonstrated that disease progression was associated with a significantly reduced frequency of hepatic NK cells.Depletion of NK cells resulted in exacerbated autoimmune cholangitis in dnTGFβRII mice.We further confirmed that the DX5−CD11c^(hi) liver-resident NK cell subset colocalized with CD4^(+) T cells and inhibited CD4^(+) T cell proliferation.Gene expression microarray analysis demonstrated that liver-resident NK cells had a distinct gene expression pattern consisting of the increased expression of genes involved in negative regulatory functions in the context of the inflammatory microenvironment.

Exosomal microRNA in autoimmunity

Exosomes are small extracellular vesicles that contain a potpourri of nucleic acids,including microRNAs(miRNAs).Importantly,exosomes and these miRNAs are actively secreted from multiple cell populations and play a critical role in intercellular communication.The exosomal miRNA profile reflects the cellular pathophysiological status and modulates multiple biological processes.Accumulating evidence indicates that exosomes and miRNAs are biomarkers for disease diagnosis and may have therapeutic targets.Research studies on exosomal miRNAs have brought new insights into understanding autoimmune diseases.This article summarizes the detection methodologies and updates the potential applications of exosomal miRNAs in autoimmune diseases.

Proteomic analysis reveals distinctive protein profiles involved in CD8^(+) T cell-mediated murine autoimmune cholangitis

Autoimmune cholangitis arises from abnormal innate and adaptive immune responses in the liver,and T cells are critical drivers in this process.However,little is known about the regulation of their functional behavior during disease development.We previously reported that mice with T cell-restricted expression of a dominant negative form of transforming growth factor beta receptor type Ⅱ(dnTGFβ RII)spontaneously develop an autoimmune cholangitis that resembles human primary biliary cholangitis(PBC).Adoptive transfer of CD8^(+) but not CD4^(+) T cells into Rag1^(−/−)mice reproduced the disease,demonstrating a critical role for CD8^(+) T cells in PBC pathogenesis.Herein,we used SOMAscan technology to perform proteomic analysis of serum samples from dnTGFβRII and B6 control mice at different ages.In addition,we analyzed CD8 protein profiles after adoptive transfer of splenic CD8^(+) cells into Rag1^(−/−)recipients.The use of the unique SOMAscan aptamer technology revealed critical and distinct profiles of CD8 cells,which are key to biliary mediation.In total,254 proteins were significantly increased while 216 proteins were significantly decreased in recipient hepatic CD8^(+) cells compared to donor splenic CD8^(+) cells.In contrast to donor splenic CD8^(+) cells,recipient hepatic CD8^(+) cells expressed distinct profiles for proteins involved in chemokine signaling,focal adhesion,T cell receptor and natural killer cell-mediated cytotoxicity pathways.

Long noncoding RNA lncKdm2b: A critical player in the maintenance of group 3 innate lymphoid cells

Innate lymphoid cells(ILCs)represent a heterogeneous population,including both effectors and regulators of innate immunity,inflammation and tissue modeling.1 ILCs are categorized into three subgroups,ILC1s,ILC2s and ILC3s,based on similarities in phenotypic,ontogenetic and functional characteristics.2 ILC3s intrinsically require the transcription factor retinoic acid receptor-related orphan receptorγt(RORγt)for their development and function.3 In response to specific stimuli,ILC3s produce IL-17 and IL-22 and play a critical role in intestinal mucosal protection,inflammation and innate responses 4 accompanied by a series of pathophysiological changes involving large-scale genetic upregulation and downregulation.5,6 However,a key challenge remains in understanding the molecular mechanisms underlying the development and maintenance of ILC3s.

Treatment with a JAK1/2 inhibitor ameliorates murine autoimmune cholangitis induced by IFN overexpression

The interferon(IFN)signaling pathways are major immunological checkpoints with clinical significance in the pathogenesis of autoimmunity.We have generated a unique murine model named ARE-Del,with chronic overexpression of IFNγ,by altering IFNγmetabolism.Importantly,these mice develop an immunologic and clinical profile similar to patients with primary biliary cholangitis,including high titers of autoantibodies and portal inflammation.We hypothesized that the downregulation of IFN signaling pathways with a JAK1/2 inhibitor would inhibit the development and progression of cholangitis.To study this hypothesis,ARE-Del^(+/−)mice were treated with the JAK1/2 inhibitor ruxolitinib and serially studied.JAK inhibition resulted in a significant reduction in portal inflammation and bile duct damage,associated with a significant reduction in splenic and hepatic CD4^(+)T cells and CD8^(+)T cells.Functionally,ruxolitinib inhibited the secretion of the proinflammatory cytokines IFNγand TNF from splenic CD4^(+)T cells.Additionally,ruxolitinib treatment also decreased the frequencies of germinal center B(GC B)cells and T follicular helper(Tfh)cells and led to lower serological AMA levels.Of note,liver and peritoneal macrophages were sharply decreased and polarized from M1 to M2 with a higher level of IRF4 expression after ruxolitinib treatment.Mechanistically,ruxolitinib inhibited the secretion of IL-6,TNF and MCP1 and the expression of STAT1 but promoted the expression of STAT6 in macrophages in vitro,indicating that M1 macrophage polarization to M2 occurred through activation of the STAT6-IRF4 pathway.Our data highlight the significance,both immunologically and clinically,of the JAK/STAT signaling pathway in autoimmune cholangitis.

Recombinant Human Prolactin Protects against Irradiation-Induced Myelosuppression

Prolactin is a multifunctional hormone that exerts many separate functions and acts as an important connection between the endocrine and immune systems. There are increasing researches implicating the role of prolactin in hematopoiesis. Enhanced erythropoiesis in pregnant women and direct erythropoietic effects in vitro of plasma either from pregnant or lactating mice have been reported. Furthermore, regression of erythroblastic leukemia has been observed in a significant number of rats after hypophysectomy. In this study, the effects of recombinant human prolactin （rhPRL） on hematopoiesis were assessed in irradiated mice. Mice were treated with rhPRL for five consecutive days after exposure to a lethal dose or a sub-dose irradiation. Prolonged survival rate and increased erythropoiesis were observed in the irradiation-induced myelosuppressive mice. It was concluded that rhPRL might act on erythropoiesis and could be a potential candidate for the treatment of irradiation-induced myelosuppresion in clinic.