病毒复制能力,血源扩散的抗原可用性以及T_(FH):T_(FR)的比率驱动诱导有效中和抗体应答

<正>病毒活疫苗可引起长期保护性的体液免疫,但其潜在机制尚未完全阐明。亲和成熟的发生、长效的保护性抗体应答的产生涉及T滤泡辅助细胞,生发中心,B细胞和T滤泡调节细胞之间的密切相互作用。作者假设通过血源途径传播的复制病毒或活疫苗引起的抗原浓度升高对于诱导和维持长期保护性抗体应答是必要的。使用复制或很少复制或不复制的甲型流感病毒,发现TFH细胞、GC B细胞和中和抗体反应的大小与病毒的复制能力直接相关。此外,还发现,在GC反应峰值期间,淋巴和循环     

抗体多样化及相关免疫系统疾病研究进展

在应对复杂生存环境内各种病原体入侵过程中,人体获得性免疫系统能够产生多样化的抗原识别分子,特异地识别与有选择地清除外来病原体。在B细胞介导的体液免疫应答中,抗体基因需经历一系列的程序性DNA断裂、重排和突变等过程,从而编码抗原特异性的抗体分子。抗体类型转换是抗体多样化中的重要一环。其中,B细胞特异性胞苷去氨酶AID(activation-induced deaminase)起始了抗体类型转换过程,而DNA损伤修复系统则最终完成了DNA重排,使B细胞表达其他类型的抗体。这一过程的缺陷将导致原发性免疫缺陷疾病,而失调又可能导致B细胞淋巴瘤的发生。该文将介绍抗体多样化过程,着重讨论抗体类型转换的分子机制以及各个水平的精细调控,并针对相关免疫系统疾病展望可能的诊断和治疗手段。     

靶向疫苗诱导的B细胞分化的滤泡外传导途径提高对狂犬病暴露后的预防

<正>疫苗诱导的B细胞沿着两条途径分化。滤泡通路产生可能需要几周才能完全发育的生发中心(GCs)。滤泡外途径产生短寿命的浆细胞(PC),它们能在疫苗接种的数天内快速分泌保护性抗体。狂犬病毒(RABV)暴露后的预防(PEP)需要疫苗快速诱导的保护性体液免疫。因此,作者假设以激活滤泡外B细胞应答为靶标,应会提高RABV PEP的速度和幅度。为了验证这个假设,     

滤泡辅助性T细胞与病毒感染性疾病研究进展

滤泡辅助性T细胞(follicular helper T cells,Tfh)作为一种新发现的CD4+T细胞亚群,其主要功能是辅助B细胞增殖、分化、产生抗体,参与体液免疫应答。由于Tfh细胞在体液免疫应答中的重要作用,近年来成为研究的热点。现将概述Tfh细胞的发现、分化过程、相关的调控分子,及其在病毒感染性疾病中的研究进展。     

协同刺激分子配体ICOSL参与高亲和力抗体筛选生成的新机制

生发中心(germinal center,GC)支持B细胞竞争与亲和力成熟的过程。滤泡辅助T细胞通过与B细胞长时程互作来传递辅助信号并促进生发中心形成。然而,当生发中心形成以后,T细胞如何调控B细胞间的竞争及选择尚不明确。借助骨髓嵌合体和活体成像研究发现,GC里T-B互作短暂而重复,由ICOS-ICOSL分子以一种正反馈的方式调控,而这种正反馈对于迅速、有效地筛选出高亲和力抗体至关重要。这些结果使我们更进一步理解了生发中心亲和力选择的机制。     

滤泡辅助性T细胞分化和功能的研究进展

滤泡辅助性T细胞(follicular helper CD4 T cell,T_(FH))是一类专门为B细胞提供帮助的CD4 T细胞。T_(FH)的分化依赖主要调控因子Bcl6的表达,细胞表面高表达趋化因子受体CXCR5,并能分泌细胞因子IL-21。T_(FH)对生发中心(germinal center,GC)的形成很重要,并调控B细胞亲和力成熟、抗体同型转换、浆细胞分化和记忆B细胞产生等重要生物过程,因此,对机体产生抗体的保护性免疫十分重要。现主要总结了目前对T_(FH)分化过程的认识、T_(FH)中起重要调控作用的分子,并讨论了T_(FH)在体液免疫中的功能。     

基因免疫

基因免疫吴青（中山大学生物工程中心,广州５１０２７５）关键词基因免疫１．前言免疫反应主要包括由抗体介导的体液免疫和由致敏Ｔ淋巴细胞介导的细胞免疫。部分被病原体激活的淋巴细胞能产生免疫记忆,当机体再次受同种病原体入侵时可迅速分化增殖,产生免疫应答以清除...     

茯苓多糖PCP-Ⅰ增强抗原特异性体液免疫反应的机制研究

目的:以炭疽芽孢杆菌保护性抗原(PA)为模式抗原,对茯苓多糖PCP-Ⅰ作为疫苗佐剂增强抗原特异性体液免疫反应的机制进行研究。方法:PCP-Ⅰ混合PA免疫BALB/c小鼠,分别采用ELISA和毒素中和实验,检测免疫后小鼠血清中PA特异性(anti-PA)抗体和炭疽毒素中和抗体;采用流式细胞术检测树突状细胞(DC)经PCP-Ⅰ体外刺激后的成熟情况,及二免后7 d小鼠脾脏中生发中心(GC)B细胞和滤泡状辅助T细胞(Tfh)的频率。结果:相对于单独PA免疫组,200μg PCP-Ⅰ能够显著提高二免后2周小鼠血清中anti-PA抗体和毒素中和抗体的水平(5.38×10~3vs 6.48×10~1,8.7×10~1vs 1.54×10~1)。PCP-Ⅰ与PA混合刺激培养DC,CD80和MHC-Ⅱ分子阳性细胞频率(82.2%,74.9%)显著高于PA刺激组(51.7%,46.8%)。二免后7 d,PA+PCP-Ⅰ组小鼠脾脏中Tfh细胞频率略高于PA组(4.97%vs 4.20%),GC B细胞频率显著高于PA组(7.73%vs 6.30%)。结论:PCP-Ⅰ可通过促进DC成熟和增强生发中心反应来增强抗原特异性体液免疫反应。     

生发中心B淋巴细胞活化机制研究进展

B淋巴细胞介导的体液免疫作为机体抵御外界病原微生物的防御机制之一,在维持机体免疫稳态中发挥重要作用。其中,生发中心是体液免疫发生的重要部位,B淋巴细胞在此处的活化受多种因素调控。T细胞的辅助参与、免疫球蛋白的多样性以及充足的能量供应都会影响B淋巴细胞产生特异性抗体的过程以及发挥免疫效应的功能。此外,一些免疫相关疾病也与生发中心B淋巴细胞活化密切相关。本文就B淋巴细胞在生发中心活化的相关机制及其活化异常所导致的相关疾病进行综述。     

滤泡辅助性T细胞分化和功能的研究进展

滤泡辅助性T细胞(Tfollicular helper cells,TFH细胞)是新近发现的一种CD4+辅助性T细胞亚群,具有不同于其他亚群的独特功能:迁移到B淋巴滤泡并辅助B淋巴细胞产生抗体。在短短的几年里面,已有大量针对滤泡辅助性T细胞分化与功能的研究。该文将对滤泡辅助性T细胞的最新研究进展作一综述。     

Immunotoxicity of phosphamidon following subchronic exposure in albino rats

Effect of subchronic doses of phosphamidon exposure on humoral and cell mediated immune (CMI) responses were studied in male albino rats using SRBC, ovalbumin and KLH as antigens. Humoral immune responses were assessed by estimating antibody titre against antigen and splenic plaque forming cells (PFC) assay. CMI responses were studied by using leucocyte migration inhibition (LMI), macrophage migration inhibition (MMI) and delayed type hypersensitivity (DTH) response. Results obtained in the present study revealed marked suppression of humoral and CMI responses in a dose dependent pattern. Hence, suppression of immune responses by phosphamidon even at subchronic doses is clearly an important aspect for its safety evaluation.     

Experimental Mycoplasma pulmonis infection of rats suppresses humoral but not cellular immune response

Humoral antibody response to sheep red blood cells and cellular immune response to bovine serum albumin were studied in Mycoplasma pulmonis infected, adult, male Sprague-Dawley rats. The hemagglutinating antibody response to sheep red blood cells was evaluated at 0, 3, 5, 7, 14, 21 and 28 days postinfection. Antibody titers during all days postinfection were depressed significantly (p less than 0.05) in infected rats as compared to noninfected controls. Cellular immune responses were evaluated by a delayed hypersensitivity response. Rats were sensitized at 0, 3, 5, 7, 14, 21 or 28 days postinfection with bovine serum albumin and challenged with heat aggregated bovine serum albumin 7 days later. Cell-mediated immune responses in infected rats were not significantly different at any point from controls. These results indicate that M. pulmonis infection in rats suppresses the humoral antibody response to sheep red blood cells, but not the cellular immune response to bovine serum albumin.     

Bill colour and immunocompetence in the European blackbird

The level of expression of secondary sexual characters has been suggested to signal male ability to resist parasitic infestations. To test this idea, several studies have examined the link between sexual signals and immunocompetence in birds. However, most of them have used only a single aspect of immune response to evaluate immunocompetence. We investigated the relation between bill colour and immunocompetence in captive male European blackbirds, Turdus merula, during the breeding season by assessing both cell-mediated and humoral components of the immune system. The blackbird is a sexually dimorphic species with bill colour varying from yellow to orange in males. Humoral immunity was assessed by measuring both primary and secondary responses to sheep red blood cell inoculation. Cell-mediated immunity was estimated with a delayed cutaneous hypersensitivity response to an injection of a mitogen (phytohaemagglutinin). No relation was found between male bill colour and the primary humoral response. However, males with orange bills showed a lower secondary humoral response but a higher cell-mediated immune response than males with yellow bills. Thus, the relation between immunocompetence and a secondary sexual trait may differ markedly depending on which component of the immune system is under consideration. We discuss our results in relation to mechanisms involved in sexual selection. Copyright 2003 Published by Elsevier Science Ltd on behalf of The Association for the Study of Animal Behaviour      

Plexin-D1 is a novel regulator of germinal centers and humoral immune responses

Long-lived humoral immune responses depend upon the generation of memory B cells and long-lived plasma cells during the germinal center (GC) reaction. These memory compartments, characterized by class-switched IgG and high-affinity Abs, are the basis for successful vaccination. We report that a new member of the plexin family of molecules, plexin-D1, controls the GC reaction and is required for secondary humoral immune responses. Plexin-D1 was not required for B cell maturation, marginal zone precursor development, dark and light zone formation, Igλ(+) and Igκ(+) B cell skewing, B1/B2 development, and the initial extrafollicular response. Plexin-D1 expression was increased following B cell activation, and PlxnD1(-/-) mice exhibited defective GC reactions during T-dependent immune activation. PlxnD1(-/-) B cells showed a defect in migration toward the GC chemokines, CXCL12, CXCL13, and CCL19. Accordingly, PlxnD1(-/-) mice exhibited defective production of IgG1 and IgG2b, but not IgG3 serum Ab, accompanied by reductions in long-lived bone marrow plasmacytes and recall humoral memory responses. These data show a new role for immune plexins in the GC reaction and generation of immunologic memory.     

Estrogen induces normal murine CD5+ B cells to produce autoantibodies

Females have better humoral immune responses and are more susceptible to autoimmune diseases than males. Normal female mice (C57BL/6J, C3H/HeJ, and NZW) have significantly increased spontaneous autoimmune plaque-forming cells (APFC) to mouse erythrocytes pretreated with bromelain (Br-ME) in spleen, peritoneal exudate cell, and bone marrow compared to their male counterparts. A minor subpopulation of B cells, CD5+ B, is thought to produce this autoantibody. As determined by dual color flow cytometry, increased APFC to Br-ME in females is not due to quantitative increase of CD5+ B cells. Rather, it is due to increased numbers or percentages) of CD5+ B cells producing these autoantibodies, because CD5+ B cells from females produced greater numbers of APFC to Br-ME than equal numbers of cells derived from males. The increased autoantibody production in females can be attributed to the effect of estrogen on the immune response because this hormone markedly augments APFC to Br-ME in intact or orchidectomized males. Male hormone had little effect. Importantly, estrogen did not increase the numbers of B or CD5+ B cells but augmented the ability of B cells to produce this response. This was verified when a T cell-depleted B cell fraction or fluorescence-activated cell sorter purified CD5+ B cells from estrogen-treated mice proved more efficient in the production of APFC to Br-ME. These results suggest that the number of CD5+ B cells committed to produce autoantibodies to Br-ME is increased under the influence of estrogen. This is the first demonstration that estrogen can augment the production of natural autoantibodies in normal mice. The overall augmented humoral immune responses in females and the B cell hyperactivity in female predominant autoimmune diseases appears to be due to estrogen.     

Sex steroid regulation of autoimmunity

The immune response of males and females is not identical but instead has been shown to be dimorphic in its nature, with females generally demonstrating a greater overall response than males. This dimorphism extends to both the humoral and cell mediated systems and appears to be mechanistically based on the differences in type and concentration of sex steroids in males vs females. Furthermore, growth hormone and prolactin secretions which are different in males and females may also be partly responsible for the observed dimorphism. Because autoimmune disease results from a pathological perturbation of normal immune function, it follows that expression of these disease will also demonstrate a dimorphic pattern. Examples of this autoimmune dimorphism include (but are not limited to) lupus, rheumatoid arthritis and multiple sclerosis with the two former more prevalent in females than males and the latter more severe during pregnancy. To explain autoimmune dimorphism it therefore becomes necessary firstly to describe the cellular and hormonal interactions found in normal immune regulation and thereafter extrapolate these to autoimmune phenomena.     

CCL2 regulation of MST1-mTOR-STAT1 signaling axis controls BCR signaling and B-cell differentiation

Chemokines are important regulators of the immune system, inducing specific cellular responses by binding to receptors on immune cells. In SLE patients, decreased expression of CCL2 on mesenchymal stem cells (MSC) prevents inhibition of B-cell proliferation, causing the characteristic autoimmune phenotype. Nevertheless, the intrinsic role of CCL2 on B-cell autoimmunity is unknown. In this study using Ccl2 KO mice, we found that CCL2 deficiency enhanced BCR signaling by upregulating the phosphorylation of the MST1-mTORC1-STAT1 axis, which led to reduced marginal zone (MZ) B cells and increased germinal center (GC) B cells. The abnormal differentiation of MZ and GC B cells were rescued by in vivo inhibition of mTORC1. Additionally, the inhibition of MST1-mTORC1-STAT1 with specific inhibitors in vitro also rescued the BCR signaling upon antigenic stimulation. The deficiency of CCL2 also enhanced the early activation of B cells including B-cell spreading, clustering and signalosome recruitment by upregulating the DOCK8-WASP-actin axis. Our study has revealed the intrinsic role and underlying molecular mechanism of CCL2 in BCR signaling, B-cell differentiation, and humoral response.Subject terms: B cells, Signal transduction     

Depression of Humoral Antibody Formation in the Chicken by Thymectomy and Antilymphocyte Serum

STUDIES on the chicken¹ established that transplantation immunity and humoral antibody formation were two independent systems of immune reactivity which were under the developmental control of two distinct primary lymphoid organs—the thymus and the bursa of Fabricius. Although a clear distinction of the two primary lymphoid organs has not been made in mammals, a division between thymus-dependent (T cells) and thymus independent (B cells) lymphocyte functions is now well documented^2,3. In the mouse, T cells are involved in cell mediated immune responses and are also necessary for the full expression of the humoral antibody response to many antigens.     

Mycoplasma pulmonis depresses humoral and cell-mediated responses in mice

Humoral and cell-mediated immune responses to sheep red blood cells (SRBC) were studied in mice infected experimentally with Mycoplasma pulmonis. The hemagglutinating (HA) antibody against SRBC was evaluated at 0, 3, 5, 7, 14, 21 and 28 days postinfection (PI). Antibody tiers during all days PI were depressed significantly (p less than 0.05) in infected mice as compared to noninfected controls. The HA antibody, which is of the IgM class, peaks at day 5 PI. There is no shift in the kinetics of the humoral response in M. pulmonis infected mice. Cellular immune responses were evaluated by a delayed-type hypersensitivity (DTH) reaction and the lymphocyte transformation technique. Mice were sensitized at 0,3,5,7,14, 21 and 28 days PI with SRBC and challenged by footpad injection of SRBC 7 days later. The DTH reaction measured at 24 hours after challenge was depressed significantly (p less than 0.05) in all infected animals. After a transient enhancement on day 3 PI, the DTH responses remained depressed through day 28 PI. The lymphocyte transformation test showed a significantly (p less than 0.05) depressed response except on days 5 and 7 PI. These results indicate that M. pulmonis infection in mice suppresses the humoral antibody and cell-mediated immune responses.     

B-cell targeted therapeutics in clinical development

B lymphocytes are the source of humoral immunity and are thus a critical component of the adaptive immune system. However, B cells can also be pathogenic and the origin of disease. Deregulated B-cell function has been implicated in several autoimmune diseases, including systemic lupus erythematosus, rheumatoid arthritis, and multiple sclerosis. B cells contribute to pathological immune responses through the secretion of cytokines, costimulation of T cells, antigen presentation, and the production of autoantibodies. DNA-and RNA-containing immune complexes can also induce the production of type I interferons, which further promotes the inflammatory response. B-cell depletion with the CD20 antibody rituximab has provided clinical proof of concept that targeting B cells and the humoral response can result in significant benefit to patients. Consequently, the interest in B-cell targeted therapies has greatly increased in recent years and a number of new biologics exploiting various mechanisms are now in clinical development. This review provides an overview on current developments in the area of B-cell targeted therapies by describing molecules and subpopulations that currently offer themselves as therapeutic targets, the different strategies to target B cells currently under investigation as well as an update on the status of novel therapeutics in clinical development. Emerging data from clinical trials are providing critical insight regarding the role of B cells and autoantibodies in various autoimmune conditions and will guide the development of more efficacious therapeutics and better patient selection.