Phosphatidylinositol-4-phosphate-dependent membrane traffic is critical for fungal filamentous growth

The phospholipid phosphatidylinositol-4-phosphate [PI(4)P], generated at the Golgi and plasma membrane, has been implicated in many processes, including membrane traffic, yet its role in cell morphology changes, such as the budding to filamentous growth transition, is unknown. We show that Golgi PI(4)P is required for such a transition in the human pathogenic fungus Candida albicans. Quantitative analyses of membrane traffic revealed that PI(4)P is required for late Golgi and secretory vesicle dynamics and targeting and, as a result, is important for the distribution of a multidrug transporter and hence sensitivity to antifungal drugs. We also observed that plasma membrane PI(4)P, which we show is functionally distinct from Golgi PI(4)P, forms a steep gradient concomitant with filamentous growth, despite uniform plasma membrane PI-4-kinase distribution. Mathematical modeling indicates that local PI(4)P generation and hydrolysis by phosphatases are crucial for this gradient. We conclude that PI(4)P-regulated membrane dynamics are critical for morphology changes.Phosphatidylinositol-4-phosphate [PI(4)P] is a minor constituent of cellular membranes that is essential for polarized growth, membrane traffic, and cytoskeleton organization (1–3). The majority of PI(4)P in budding yeast is generated by two essential PI-4-kinases, Pik1 at the Golgi and Stt4 at the plasma membrane (PM) (4–7). Although we have shown that PM Stt4 and the PI(4)P-5-kinase Mss4 are critical for the human fungal pathogen Candida albicans filamentous growth (8), little is known regarding the importance of Golgi PI(4)P. Perturbation of Golgi PI(4)P levels in Saccharomyces cerevisiae and mammalian cells results in defects in Golgi morphology and secretion (9–13). Furthermore, the Golgi in mammalian cells is important for cell polarity (14). In the filamentous fungus Neurospora crassa, PI(4)P has been observed at the Golgi (15), yet its function is unknown.In a range of fungi, including pathogenic species, a morphological transition between yeast and filamentous forms, triggered by numerous external stimuli, is important for virulence (16, 17). Many proteins localize to the tip of the C. albicans protruding filament and a number of proteins are either secreted or incorporated into the cell wall during the yeast to filamentous morphological transition (17), alluding to the importance of membrane traffic in this process. Here we show that cells with reduced Golgi PI(4)P levels are defective in morphogenesis and that Golgi PI(4)P is critical for two distinct steps in the secretory pathway. Furthermore, we observed a striking gradient of PM PI(4)P along the length of the hyphal filament and mathematical modeling revealed the processes crucial for this distribution.     

TBC1D16 is a Rab4A GTPase activating protein that regulates receptor recycling and EGF receptor signaling

Rab4A is a master regulator of receptor recycling from endocytic compartments to the plasma membrane. The protein TBC1D16 is up-regulated in melanoma, and TBC1D16-overexpressing melanoma cells are dependent on TBC1D16. We show here that TBC1D16 enhances the intrinsic rate of GTP hydrolysis by Rab4A. TBC1D16 is both cytosolic and membrane associated; the membrane-associated pool colocalizes with transferrin and EGF receptors (EGFRs) and early endosome antigen 1, but not with LAMP1 protein. Expression of two TBC1D16 isoforms, but not the inactive R494A mutant, reduces transferrin receptor recycling but has no effect on transferrin receptor internalization. Expression of TBC1D16 alters GFP-Rab4A membrane localization. In HeLa cells, overexpression of TBC1D16 enhances EGF-stimulated EGFR degradation, concomitant with decreased EGFR levels and signaling. Thus, TBC1D16 is a GTPase activating protein for Rab4A that regulates transferrin receptor recycling and EGFR trafficking and signaling.     

Rab8A and Rab13 are activated by insulin and regulate GLUT4 translocation in muscle cells

Skeletal muscle is the primary site of dietary glucose disposal, a function that depends on insulin-mediated exocytosis of GLUT4 vesicles to its cell surface. In skeletal muscle and adipocytes, this response involves Akt signaling to the Rab-GAP (GTPase-activating protein) AS160/TBC1D4. Intriguingly, the AS160-targeted Rabs appear to differ, with Rab8A participating in GLUT4 exocytosis in muscle cells and Rab10 in adipocytes, and their activation by insulin is unknown. Rabs 8A, 10, and 13 belong to the same subfamily of Rab-GTPases. Here we show that insulin promotes GTP loading of Rab13 and Rab8A but not Rab10 in rat L6 muscle cells, Rab8A activation preceding that of Rab13. siRNA-mediated Rab13 knockdown blocked the insulin-induced increase of GLUT4 at the muscle cell surface that was rescued by a Rab13 ortholog but not by Rab8A. Constitutively active AS160 lowered basal and insulin-stimulated levels of surface GLUT4, effects that were reversed by overexpressing Rab8A or Rab13, suggesting that both Rabs are targets of AS160-GAP activity in the context of GLUT4 traffic. Rab13 had a broader intracellular distribution compared with the perinuclear restriction of Rab8A, and insulin promoted Rab13 colocalization with GLUT4 at the cell periphery. We conclude that Rab13 and Rab8A are Rab-GTPases activated by insulin, and that downstream of AS160 they regulate traffic of GLUT4 vesicles, possibly acting at distinct steps and sites. These findings close in on the series of events regulating muscle GLUT4 traffic in response to insulin, crucial for whole-body glucose homeostasis.     

The GTPase Rab3b/3c-positive recycling vesicles are involved in cross-presentation in dendritic cells

Antigen cross-presentation in dendritic cells is a complex intracellular membrane transport process, but the underlying molecular mechanisms remain to be thoroughly investigated. In this study, we examined the effect of siRNA-mediated knockdown of 57 Rab GTPases, the key regulators of membrane trafficking, on antigen cross-presentation. Twelve Rab GTPases were identified to be associated with antigen cross-presentation, and Rab3b/3c was indicated to be colocalized with MHC class I molecules at perinuclear tubular structure. Tracing with fluorescence protein-tagged β₂-microglobulin demonstrated that the MHC class I molecules were internalized from the plasma membrane to Rab3b/3c-positive compartments, which were also colocalized with the internalized transferrin. Moreover, depletion of Rab3b/3c strongly reduced the fast phase recycling rate of transferrin receptors. Furthermore, the Rab3b/3c-positive compartments were colocalized with a fraction of Rab27a at a juxtaposition of phagosomes. Together, these data demonstrate that Rab3b/3c-positive recycling vesicles are involved in and may constitute one of the recycling compartments in exogenous antigen cross-presentation.     

旋毛虫DNA疫苗诱导小鼠免疫应答的研究

目的　观察旋毛虫DNA疫苗在小鼠体内诱导的免疫应答。方法　将旋毛虫肌幼虫编码 31kDa抗原结构基因真核表达质粒pcDNA3-TspE1分别用肌肉注射和基因枪免疫BALB/c小鼠 ,免疫血清用旋毛虫肌幼虫冰冻切片及石蜡切片抗原进行IFAT检测 ,并用旋毛虫肌幼虫可溶性抗原进行Westernblot分析。结果　IFAT表明 pcDNA3-TspE1接种BALB/c小鼠后产生的免疫血清与旋毛虫肌幼虫可产生阳性反应 ,在肌幼虫冰冻及石蜡切片上均显示黄绿色荧光。Westernblot检测结果显示 ,pcDNA3-TspE1接种小鼠后产生的免疫血清只能识别旋毛虫肌幼虫可溶性抗原中的 31kDa抗原组分 ,而 pcDNA3质粒接种小鼠后的血清不能与旋毛虫肌幼虫可溶性抗原发生免疫反应。结论　旋毛虫DNA疫苗 pcDNA3-TspE1能够诱导小鼠产生特异性体液免疫应答。     

Serum antibody response in children with Giardia lamblia infection and identification of an immunodominant 57-kilodalton antigen

Giardia lamblia antigens which react with sera from children with G. lamblia infection were investigated by sodium-dodecyl polyacrylamide gel electrophoresis and immunoblotting. Serum IgG, IgM and IgA response to the antigens were immunochemically characterized. Serum antibodies from all giardiasis patients, but none of the controls, was found to react with a 57-kilodalton antigen. The 57 kDa antigen elicited IgG and IgA but not IgM antibodies. The protein nature of the 57 kDa antigen was demonstrated by loss of antibody recognition after trypsin treatment of G. lamblia trophozoites. Subcellular fractionation of G. lamblia trophozoites followed by SDS-PAGE and immunoblotting showed that the 57 kDa antigen was probably not a component of the cytoskeleton.     

Antibodies to a novel antigen in acute hepatitis C virus infections

BACKGROUND: Conformational viral proteins potentially play an important role in the immunobiology of acute hepatitis C virus (HCV) infection and may enable earlier antibody detection. MATERIALS AND METHODS: HCV RNA was detected using nucleic acid testing. Early antibody production was evaluated using three enzyme immunoassays (EIAs) containing antigenic proteins not present in licensed EIAs. Respectively, these contained: (1) multiple-epitope fusion antigen (MEFA) 7.1-NS3/4a, (2) F and Core, and (3) E1/E2 proteins. NS3/4a is a conformational antigen retaining protease and helicase enzymatic activities. MEFA 7.1 contains the linear epitopes used in licenced EIAs, including the latest EIA-3.0, in combination with genotype 1-3 specific epitopes. Forty-two RNA positive, EIA-3.0 negative samples, including two persistently serosilent cases, were used to evaluate these research EIAs. As controls, 54 EIA-3.0 negative/RNA negative and three HCV RNA+/antibody positive specimens were included. RESULTS: Only the MEFA 7.1-NS3/4a EIA was positive in seven (17%) of the 42 HCV RNA + specimens, in all three EIA-3.0 positive controls but in none of 54 EIA-3.0 negative/HCV RNA negative controls. Notably, six of the seven (86%) specimens had evidence of active hepatitis (ALT > 210 IU/l). The two serosilent cases were research EIA negative. CONCLUSION: A novel EIA with conformational and linear epitopes detected HCV antibodies in 17% of viraemic specimens missed by the standard reference EIA-3.0. Our research EIA appears to detect HCV antibodies closer to the initiation of acute hepatitis. Given that the average RNA-positive, antibody-negative window period is 56.4 days, this 17% yield would translate into a 10-day earlier detection of antibodies.     

Semaphorin 6D regulates the late phase of CD4+ T cell primary immune responses

The semaphorin and plexin family of ligand and receptor proteins provides important axon guidance cues required for development. Recent studies have expanded the role of semaphorins and plexins in the regulation of cardiac, circulatory and immune system function. Within the immune system, semaphorins and plexins regulate cell–cell interactions through a complex network of receptor and ligand pairs. Immune cells at different stages of development often express multiple semaphorins and plexins, leading to multivariate interactions, involving more than one ligand and receptor within each functional group. Because of this complexity, the significance of semaphorin and plexin regulation on individual immune cell types has yet to be fully appreciated. In this work, we examined the regulation of T cells by semaphorin 6D. Both in vitro and in vivo T cell stimulation enhanced semaphorin 6D expression. However, semaphorin 6D was only expressed by a majority of T cells during the late phases of activation. Consequently, the targeted disruption of semaphorin 6D receptor–ligand interactions inhibited T cell proliferation at late but not early phases of activation. This proliferation defect was associated with reduced linker of activated T cells protein phosphorylation, which may reflect semaphorin 6D regulation of c-Abl kinase activity. Semaphorin 6D disruption also inhibited expression of CD127, which is required during the multiphase antigen-presenting cell and T cell interactions leading to selection of long-lived lymphocytes. This work reveals a role for semaphorin 6D as a regulator of the late phase of primary immune responses.     

Response to HBV vaccination in patients with severe liver disease

HLA antigen profiles have been used to identify individuals who are likely not to respond to HBV vaccination. The majority of these reports have included either normal individuals or individuals with severe abnormalities of their immune system. The present investigation assessed the rate of HBV vaccination seroconversion in 132 individuals with chronic advanced liver disease who were referred for possible liver transplantation. Each was vaccinated using a serum-derived vaccine administered intramuscularly at three consecutive monthly clinic visits. As part of their transplant evaluation, each subject also underwent HLA typing for class I and class II antigens. Of the 132 subjects vaccinated, only 47% seroconverted and became HB_sAb positive. There was no difference between types of liver disease. As expected, individuals older than 55 years of age responded less well than those younger than this cutoff age. No difference between seroconverters and nonresponders was evident for gender or any individual or combination of HLA antigens. In conclusion, individuals with advanced chronic liver disease seroconvert less often in response to HBV vaccination than do normal individuals. Moreover, unlike normals and the experience with other disease groups, no difference in conversion rates was evident for gender. Similarly, no difference in seroconversion rates was evident for the two major pathophysiologic types of chronic liver disease. Age greater than 55 years was associated with a reduced rate of seroconversion.This work was supported in part by grants from the NIDDK AM32556 and the NIAAA AA06772.     

Genetic control of the immune response to a synthetic vaccine against Plasmodium falciparum

Two independent vaccination trials using a hybrid synthetic polypeptide containing epitopes from four proteins of Plasmodium falciparum were performed. In the first trial 63 and in the second 122 volunteers were vaccinated, using different immunization schedules. The analysis of the humoral response to the vaccine, measured by IgG antibody titres to the polypeptide showed a bimodal distribution in both cases suggesting genetic control of the immune response to this protein. There was a small group of low or non-responders and a large group of good responders. HLA phenotyping of the two groups disclosed an association of the low responders to HLA-DR4 antigens with chi-square P value of 0.00039 when compared with the good responders group. These findings provide evidence for the genetic control of the immune response to the synthetic vaccine by the association of this response with particular alleles of the HLA class II antigens; such findings may lead to an explanation of the mechanism involved in disease susceptibility and need to be used in the design of a totally effective vaccine.     

Interferon-β regulates proresolving lipids to promote the resolution of acute airway inflammation

Aberrant immune responses, including hyperresponsiveness to Toll-like receptor (TLR) ligands, underlie acute respiratory distress syndrome (ARDS). Type I interferons confer antiviral activities and could also regulate the inflammatory response, whereas little is known about their actions to resolve aberrant inflammation. Here we report that interferon-β (IFN-β) exerts partially overlapping, but also cooperative actions with aspirin-triggered 15-epi-lipoxin A₄ (15-epi-LXA₄) and 17-epi-resolvin D1 to counter TLR9-generated cues to regulate neutrophil apoptosis and phagocytosis in human neutrophils. In mice, TLR9 activation impairs bacterial clearance, prolongs Escherichia coli–evoked lung injury, and suppresses production of IFN-β and the proresolving lipid mediators 15-epi-LXA₄ and resolvin D1 (RvD1) in the lung. Neutralization of endogenous IFN-β delays pulmonary clearance of E. coli and aggravates mucosal injury. Conversely, treatment of mice with IFN-β accelerates clearance of bacteria, restores neutrophil phagocytosis, promotes neutrophil apoptosis and efferocytosis, and accelerates resolution of airway inflammation with concomitant increases in 15-epi-LXA₄ and RvD1 production in the lungs. Pharmacological blockade of the lipoxin receptor ALX/FPR2 partially prevents IFN-β–mediated resolution. These findings point to a pivotal role of IFN-β in orchestrating timely resolution of neutrophil and TLR9 activation–driven airway inflammation and uncover an IFN-β–initiated resolution program, activation of an ALX/FPR2-centered, proresolving lipids-mediated circuit, for ARDS.

Acute respiratory distress syndrome (ARDS) is a common syndrome associated with high mortality in patients admitted to intensive care units (1). ARDS is characterized by diffuse alveolar damage that develops in patients with known risk factors, most commonly pneumonia, sepsis, or trauma (2, 3). The initial alveolar damage leads to recruitment of neutrophils and monocytes, which further aggravate injury (3). Treatment of the underlying cause and lung-protective ventilation are the main elements of supportive therapy (4, 5). Importantly, no therapies are available to resolve the aberrant immune responses underlying ARDS.Type I interferons, IFN-α and IFN-β, are well established to confer antiviral activities to host cells and could also regulate the inflammatory response. A delayed type I interferon response triggers the generation of proinflammatory cytokines and facilitates the recruitment of monocytes to the lung, resulting in lethal pneumonia in mice infected with SARS-CoV-1 (6) or SARS-CoV-2 (7). Type I interferons break TNF-induced tolerance to Toll-like receptor (TLR) signals on monocytes/macrophages, rendering them hyperresponsive to additional TLR signals concurrent with inflammatory activation (8). For instance, bacterial DNA (CpG DNA) or mitochondrial DNA through TLR9 impairs neutrophil phagocytosis, delays neutrophil apoptosis, and perpetuates inflammation (9, 10). In contrast, IFN-β protects against lethal polymicrobial sepsis through inhibiting IL-1 production and/or induction of IL-10 (11–13). IFN-β produced by macrophages during resolution of bacterial pneumonia facilitates removal of neutrophils from inflamed tissues and reprograms macrophages to a proresolving phenotype, thereby driving inflammatory resolution in mice (14). However, the underlying mechanisms are incompletely understood; albeit these would be essential for implementing precision treatment with IFN-β.Resolution of inflammation is an active process governed by specialized proresolving lipid and protein mediators (SPMs) (15–19). These mediators converge on select receptors, including the pleiotropic lipoxin A₄ receptor/formyl peptide receptor 2 (ALX/FPR2) (20). ALX/FPR2 plays critical roles in host defense and orchestrating inflammatory resolution (20–23). ALX/FPR2 binds multiple lipid ligands, including aspirin-triggered 15-epi-lipoxin A₄ (15-epi-LXA₄) and 17-epi-resolvin D1 (17-epi-RvD1), generated within the inflammatory microenvironment (17, 18). SPMs inhibit neutrophil recruitment, promote neutrophil apoptosis and efferocytosis, and facilitate tissue repair and return to homeostasis (17, 18, 24). Activation of ALX/FPR2 with 15-epi-LXA₄ or 17-epi-RvD1 counters TLR9-generated cues, restores impaired neutrophil function, and enhances timely resolution of airway bacterial infections (9). Since resolution of inflammation is skewed toward a proresolving lipid profile (18, 25, 26), we investigated whether IFN-β can modulate ALX/FPR2-based resolution mechanisms. Here, we report that IFN-β exerts partially overlapping, but also cooperative actions with 17-epi-RvD1 to counter TLR9-generated signals to regulate neutrophil phagocytosis and apoptosis in vitro. In mice, IFN-β facilitates clearance of bacteria, neutrophil apoptosis and efferocytosis, and promotes the resolution of acute airway inflammation, in part, by stimulating generation of proresolving lipids and activation of ALX/FPR2-centered proresolving circuits. Our results uncover a hitherto unrecognized effector mechanism by which IFN-β may facilitate resolution of ARDS.     

Colonize,evade, flourish

Helicobacter pylori is an adapted gastric pathogen that colonizes the human stomach, causing severe gastritis and gastric cancer. A hallmark of infection is the ability of this organism to evade detection by the human immune system. H. pylori has evolved a number of features to achieve this, many of which involve glyco-conjugates including the lipopolysaccharide, peptidoglycan layer, glycoproteins, and glucosylated cholesterol. These major bacterial components possess unique features from those of other gram-negative organisms, including differences in structure, assembly, and modification. These defining characteristics of H. pylori glycobiology help the pathogen establish a long-lived infection by providing camouflage, modulating the host immune response, and promoting virulence mechanisms. In this way, glyco-conjugates are essential for H. pylori pathogenicity and survival, allowing it to carve out a niche in the formidable environment of the human stomach.     

参连合用对代谢综合征患者“肠道菌群-免疫反应”的影响

目的 观察参连联合常规西药治疗对代谢综合征(metabolic syndrome,MS)患者糖脂代谢及肠道菌群-免疫反应的影响.方法 选取2019年1月—2020年8月上海交通大学医学院附属同仁医院收治的54例湿热中阻兼气虚型的MS患者作为研究对象,按照随机数字表法分为对照组(常规西药治疗)与治疗组(常规西药+参连联合治疗),每组各27例.观察2组治疗前后的血糖、血脂、CRP、IL-6、IL-10水平;采用荧光定量PCR法测定肠道细菌DNA,定量分析肠道主要菌群结构变化.结果 与治疗前相比,2组治疗后肠杆菌含量及空腹血糖、TC、TG、LDL-C、CRP、IL-6水平均下降,乳酸杆菌含量、双歧杆菌含量、HDL-C、IL-10水平均升高,其中2组TG、IL-6水平下降及IL-10水平上升差异均有统计学意义,治疗组乳酸杆菌含量升高差异有统计学意义(P均<0.05);治疗组IL-10上升幅度及IL-6下降幅度均大于对照组(P均<0.05).结论 参连联合常规西药治疗MS患者可提高其外周血免疫炎性因子IL-10水平,降低IL-6水平,明显升高肠道乳酸杆菌含量,对于探索参连联合常规西医治疗的MS患者"肠道菌群-免疫反应"机制研究具有重要意义.     

Characterization of Serum and Mucosal SARS-CoV-2-Antibodies in HIV-1-Infected Subjects after BNT162b2 mRNA Vaccination or SARS-CoV-2 Infection

Only limited data are available regarding the immunogenicity of the BNT162b2 mRNA vaccine in HIV-1⁺ patients. Therefore, we investigated the humoral immune response after BNT162b2-mRNA vaccination or SARS-CoV-2 infection in HIV-1⁺ patients on antiretroviral therapy compared to HIV-1-uninfected subjects. Serum and saliva samples were analysed by SARS-CoV-2 spike-specific IgG and IgA ELISAs and a surrogate neutralization assay. While all subjects developed anti-spike IgG and IgA and neutralizing antibodies in serum after two doses of BNT162b2 mRNA vaccine, the HIV-1⁺ subjects displayed significantly lower neutralizing capacity and anti-spike IgA in serum compared to HIV-1-uninfected subjects. Serum levels of anti-spike IgG and neutralizing activity were significantly higher in vaccinees compared to SARS-CoV-2 convalescents irrespective of HIV-1 status. Among SARS-CoV-2 convalescents, there was no significant difference in spike-specific antibody response between HIV-1⁺ and uninfected subjects. In saliva, anti-spike IgG and IgA antibodies were detected both in vaccinees and convalescents, albeit at lower frequencies compared to the serum and only rarely with detectable neutralizing activity. In summary, our study demonstrates that the BNT162b2 mRNA vaccine induces SARS-CoV-2-specific antibodies in HIV-1-infected patients on antiretroviral therapy, however, lower vaccine induced neutralization activity indicates a lower functionality of the humoral vaccine response in HIV-1⁺ patients.     

Interleukin-13 mucosal production in Helicobacter pylori-related gastric diseases

A shift from Th1 (IFN-gamma) towards Th2 (IL-4)-type immune response was found in patients with gastric cancer and dysplasia. Recently, IL-13 has been described as a central mediator of Th2-dominant immune response in different inflammatory diseases. AIM AND METHODS: to analyse, by Enzyme-Linked-Immuno-SPOT (ELISPOT) assay and immunohistochemistry, the IL-13 production of mononuclear cells obtained from gastric biopsies of 19 H. pylori-negative subjects and 23 H. pylori-positive patients. RESULTS: By ELISPOT, we did not find any significant variation of the spot range number of IL-13, IL-4 and IFN-gamma secreting cells, irrespective of H. pylori status. After antigenic exposition, the spot range for IL-13, IL-4 and IFN-gamma significantly increased (p<.0001) only in H. pylori-positive patients. A prevalent Th1 (IFN-gamma) immunoresponse was observed in 2/23 cases with active gastritis, while a prevalent Th2 (IL-13 and IL-4) was detected in 5/23 cases all with atrophic chronic gastritis of whom two with intestinal metaplasia. By immunohistochemistry, IL-13, IL-4 and IFN-gamma were detectable in all cases directly related to the inflammatory infiltrate. In the two cases with intestinal metaplasia, IL-13 and IL-4 were localised in both inflammatory and epithelial cells. This immunopattern was confirmed in selected additional 10 cases of H. pylori-positive chronic atrophic gastritis with intestinal metaplasia and 10 cases of intestinal type gastric cancer. CONCLUSION: These preliminary results suggest that IL-13 could be implicated in the different outcome of H. pylori infection.     

Effect of recombinant human transforming growth factor β1 on immune responses in patients with chronic hepatitis B

ABSTRACT— Studies were undertaken to examine the effect of recombinant human transforming growth factor beta 1 (rTGF-β1) on cellular and humoral immune responses of peripheral blood mononuclear cells (PBMC) from patients with chronic hepatitis B. The addition of TGF-β1 caused a significant dose-dependent inhibition of hepatitis B (HB) core Ag-stimulated interferon-γ and antibody to HB core Ag production and proliferation of PBMC from chronic hepatitis patients and HB-immune donors. TGF-β1 also induced a significant reduction in pokeweed mitogen-stimulated IgG and IgM production, as well as phytohemagglutinin p-stimulated proliferative response of PBMC. The degree of inhibition of TGF-β1 did not differ between antigen-specific and -nonspecific cellular and humoral immune responses, and between control individuals and patients. Pretreatment study with TGF-β1 showed that the activities of T cells, B cells and monocytes were similarly inhibited. Further, TGF-β1 inhibited activities of HLA class I antigen-matched cytotoxic T cells from patients with chronic hepatitis B for HBV DNA-transfected HepG2 cells in a ⁵¹Cr release assay. The results suggest that TGF-β1 may play a role in the regulation of antigen-dependent and -independent immune responses in patients with chronic hepatitis B.     

CXCL13/CXCR6信号通路在HBV感染中的研究进展及临床意义

[摘要]?HBV感染是人类面临的重大公共卫生问题,尽管有效的抗病毒治疗可延缓疾病进展,但仍很难实现“临床治愈”的目标。机体的适应性免疫应答在控制和清除病毒的过程中发挥关键作用。新近研究发现,趋化因子配体13（chemokine ligand 13, CXCL13）/趋化因子受体5（chemokine receptor 5, CXCR5）信号通路在调节HBV特异性体液免疫和细胞免疫应答中均发挥重要作用,这或是探索慢性乙型肝炎“临床治愈”的重要靶点。本文就CXCL13/CXCR5信号通路的生物学特点及其在HBV感染中的临床研究进展及意义进行综述。