记忆性B细胞体外扩增影响因素的研究进展

正记忆性B细胞(Memory B cells)是成熟的初始B细胞被抗原激活分化为具有记忆功能并持续存在于宿主的一类细胞。当再次遇到相同抗原时,该细胞可迅速增殖分化为浆细胞,产生高亲和力的抗原特异性抗体,介导体液免疫应答,从而保护机体免受再次入侵的抗原感染~([1,2])。     

B细胞在胸腺依赖抗原免疫应答中的活化、增殖和分化

Ｂ细胞在胸腺依赖抗原免疫应答中所经历的活化、增殖和分化是一个极为复杂的生物学过程。本文在总结近年来该领域进展和假说的基础上，对这一过程中包括Ｂ细胞的活化部位、机制和途径，Ｂ细胞的增殖、生发中心的形成、免疫球蛋白编码基因的超突变和抗体亲和力的筛选、免疫球蛋白重链转型、浆细胞和记忆Ｂ细胞的分化形成以及免疫记忆的维持等方面作了较为系统全面的介绍。     

167B细胞在胸腺依赖抗原免疫应答中的活化,增殖和分化

Ｂ细胞在胸腺依赖抗原免疫应答中所经历的活化、增殖和分化是一个级为复杂的生物学过程。本文在总结近年来该领域进展和假说的基础上，对这一过程中包括Ｂ细胞的活化部位、机制和途径，Ｂ细胞的增殖、生发中心的形成、免疫球蛋白编码基因的超突变和抗体亲和力的筛选、免疫球蛋白重链转型，浆细胞和记忆Ｂ细胞的分化形成以及免疫记忆的维持等方面作了较为系统全面的介绍。     

记忆B细胞与血清记忆

记忆B细胞被认为是记忆干细胞,通过抗原依赖和非抗原依赖的方式,能转化为浆细胞而产生抗体.B细胞的记忆形成涉及静止记忆B细胞和长寿命浆细胞.尽管已知这些细胞来源于生发中心,但刺激生发中心B细胞进入并维持记忆池所需的信号和环境尚不清楚.且它们是怎样从生发中心迁出,哪些因素决定其长期存活,记忆B细胞池与浆细胞池的组成和容量是多少等都还不十分清楚.这些问题的解决对免疫调控,防治自身免疫性疾病有重要的价值.     

T细胞在记忆B细胞发生中的作用

注射抗原可产生原发性体液免疫应答及记忆细胞的发生。已知对许多抗原来说,初次免疫应答中抗原特异性B细胞转化为抗体形成细胞需T淋巴细胞参与。然而,在记忆细胞发生过程中是否需T细胞辅助尚无定论。本文描述切除胸腺并予以致死量照射的鼠,在补入胎鼠肝细胞、给予不同量的T细胞并用胸腺依赖性抗原免疫后,通过细胞转移方法检测记忆B细胞的发生,同时检测初次和二次抗体应答的量及亲和力。     

生发中心的研究进展

生发中心在Ｔ细胞依赖性抗体应答中起了不可忽视的作用，它与Ｂ细胞的克隆扩增、体细胞高度突变、亲和力成熟、凋亡选择以及记忆Ｂ细胞的形成都有着密切的关系，这其中还涉及多种细胞和分子之间的相互作用，因而对生发中心作深入的研究，将使我们更能清晰的了解体液免疫应答的全过程。     

生发中心的研究进展

生发中心在Ｔ细胞依赖性抗体应答中起了不可忽视的作用，它与Ｂ细胞的克隆扩增、体细胞高度突变、亲和力成熟、凋亡选择以记忆Ｂ细胞的形成都有着密切的关系，这其中还涉及多咎细胞和分子之间的相互作用，因而对生发中心作深入的研究，将使我们更能的了解体液免疫应答的全过程。     

滤泡辅助T细胞的分化和功能及其在疾病中的作用

CD4~+辅助T(Th)细胞在抗原的刺激下会分化为不同的效应T细胞亚群。体液免疫应答具有很好的持久性,持久性的维持依赖于一群特殊的CD4~+T细胞提供辅助,即滤泡辅助性T(Tfh)细胞。树突状细胞(DC)提呈抗原并促进活化的Tfh前体细胞迁移到B细胞滤泡区域分化为成熟的Tfh细胞,辅助生发中心(GC)形成以及浆细胞和记忆性B细胞的分化,从而形成完整的体液免疫应答。Tfh细胞分化和功能上的失调均会导致多种疾病的发生。本文主要从Tfh细胞分化、功能以及在疾病中的作用三个方面对Tfh细胞的研究进展进行阐述。     

可溶性免疫复合物在临床免疫学中的地位

对于免疫复合物的生理病理学意义已经一致公认,相比之下,它们的检出对于疾病描述和治疗的实用性却存在明显的争议.免疫复合物的形成是浆细胞大规模合成抗体的合理结果.免疫复合物将抗原提呈给吞噬细胞清除;也可将抗原送到淋巴样组织的生发中心,从而引起更强的抗体应答.如果抗原是外来的,上述过程对机体有利;如果是自身抗原,这种由免疫复合物介导的清除将是有害的.     

调节性B 细胞与人类系统性红斑狼疮研究进展

正一般来说,B淋巴细胞具有对体液免疫应答具有正向调节作用,因为它们最终能分化为浆细胞并产生抗原特异性抗体。然而,有一群特异的B细胞能够负向调节免疫应答,被命名为调节性B细胞~([1])。有证据表明调节性B细胞在许多炎症和自身免疫小鼠模型中扮演重要角色~([1,2])。尽管调节性     

How do follicular dendritic cells interact intimately with B cells in the germinal centre?

The germinal centre is a dynamic microenvironment where antigen-activated B cells rapidly expand and differentiate, generating plasma cells and memory B cells. These cellular events are accompanied by dramatic changes in the antibody molecules that undergo somatic hypermutation and isotype switching. Follicular dendritic cells (FDCs) are the stromal cells located in the germinal centre. Although the capacity of FDCs to present antigen to B cells through antigen-antibody complexes has been recognized for many years, additional critical functions of FDCs have only recently been recognized. FDCs prevent apoptosis of germinal centre B cells and stimulate cellular interaction and proliferation. Here, we review the FDC signalling molecules that have recently been identified, some of which offer potential therapeutic targets for autoimmune diseases and B-cell lymphomas.     

The germinal center response

The germinal center reaction is the foundation of T-cell-dependent humoral responses. Antigen-specific B cells recruited into germinal centers undergo a complex cellular program that allows for extensive expansion, isotype switching, somatic hypermutation, and differentiation into antibody-forming cells and memory cells. Importantly, the germinal center environment filters the repertoire of differentiating B cells such that high affinity variants are preferentially selected while low affinity or self-reactive clones are eliminated by apoptosis. The present article reviews the many processes that govern germinal center B-cell differentiation, as well as the cellular and molecular elements necessary to initiate and sustain a germinal center response. The major histologic features of the germinal center are also discussed, as well as the current dominant models of the germinal center reaction in humans and mice. Finally, a new model of murine B-cell differentiation is described on the basis of a multiparameter flow cytometric kinetic analysis of germinal center B cells.     

Expression of CD137 (4-1BB) on human follicular dendritic cells

Follicular dendritic cells (FDCs) are the antigen (Ag)-trapping accessory cells of the germinal centres (GCs), essential for the development of humoral immune responses and memory. FDCs reside in the microenvironment of secondary lymphoid tissue where Ag-activated B cells expand, and undergo isotype switching and affinity maturation prior to becoming memory B cells. In addition to delivering Ag, FDCs also provide potent nonspecific accessory signals to the B cells, which are important for the GC reaction. In this report, we show that human tonsilar FDCs express the costimulatory molecule CD137. Surface expression of CD137 on FDCs was confirmed by immunofluorescent labelling and fluorescence-activated cell sorter analysis. CD137 was also highly expressed by the human cell line HK, which displays many characteristics of in vivo FDCs. The interaction between B cells and FDCs is essential for the GC reactions, and our finding suggests that CD137 plays a role in FDC-regulated B-cell responses.     

Protection of germinal centres from complement attack: Decay-accelerating factor (DAF) is a constitutive protein on follicular dendritic cells. A study in reactive and neoplastic follicles

The development of B-cell memory is linked to the presence of germinal centres. This process is dependent on the presence of antigen, usually in the form of immune complexes with antibody, on the surface of the follicular dendritic cells (FDCs) that form a network in the germinal centre. The presence of immune complexes poses a constant danger of activating complement. Decay accelerating factor (DAF, CD55) and the membrane attack complex (MAC) inhibitor (CD59) are two cell proteins whose sole function is to protect cells from the action of complement, the former affecting the earlier components of the complement cascade, and the latter the terminal ones; both are bound to the cell surface via a glycosylphosphatidylinositol link. DAF but not CD59 could be demonstrated on FDCs. DAF is also present on the FDCs in follicular lymphomas despite the absence of complement (C3) in neoplastic follicles. This indicates that DAF is constitutive to FDCs but does not preclude the possibility that its expression is increased when immune complexes are deposited.     

Follicular dendritic cells and T cells: nurses and executioners in the germinal centre reaction.

The humoral immune response constitutes an efficient system to protect the organism against diseases caused by invading pathogens. To guarantee a highly efficient defence, the humoral immune system has to be tightly regulated. Two cell subsets in particular, T cells and follicular dendritic cells (FDCs), contribute to the success of these regulation processes. Whereas the particular role of T cells is the elimination of autoreactive clones, the main role of FDCs is to present unprocessed antigen and check B-cell clones for higher affinity. B-cell clones unsuited for improved humoral immune response will be specifically killed. Involvement of Fas-mediated apoptosis might be an additional tool not only in T-cell-mediated regulation, but also in FDC-B cell interaction in the germinal centre.     

Correction of age-associated deficiency in germinal center response by immunization with immune complexes

In aging, both primary and secondary antibody responses are impaired. One of the most notable changes in age-associated immune deficiency is the diminished germinal center (GC) reaction. This impaired GC response reduces antibody affinity maturation, decreases memory B cell development, and prevents the establishment of long-term antibody-forming cells in the bone marrow. It is of great importance to explore novel strategy in improving GC response in the elderly. In this study, the efficacy of immunization with immune complexes in overcoming age-associated deficiency in GC response was investigated. We show that the depressed GC response in aged mice can be significantly elevated by immunization with immune complexes. Importantly, there is a significant improvement of B cell memory response and long-lived plasma cells. Our results demonstrate that immune complex immunization may represent a novel strategy to elicit functional GC response in aging, and possibly, to overcome age-related immune deficiency in general.     

T cells and follicular dendritic cells in germinal center B-cell formation and selection

Summary: Germinal centers (GCs) are specialized microenvironments formed after infection where activated B cells can mutate their B-cell receptors to undergo affinity maturation. A stringent process of selection allows high affinity, non-self-reactive B cells to become long-lived memory B cells and plasma cells. While the precise mechanism of selection is still poorly understood, the last decade has advanced our understanding of the role of T cells and follicular dendritic cells (FDCs) in GC B-cell formation and selection. T cells and non-T-cell-derived CD40 ligands on FDCs are essential for T-dependent (TD) and T-independent GC formation, respectively. TD-GC formation requires Bcl-6-expressing T cells capable of signaling through SAP, which promotes formation of stable T:B conjugates. By contrast, differentiation of B blasts along the extrafollicular pathway is less dependent on SAP. T-follicular helper (Tfh) cell-derived CD40L, interleukin-21, and interleukin-4 play important roles in GC B-cell proliferation, survival, and affinity maturation. A role for FDC-derived integrin signals has also emerged: GC B cells capable of forming an immune synapse with FDCs have a survival advantage. This emerges as a powerful mechanism to ensure death of B cells that bind self-reactive antigen, which would not normally be presented on FDCs.     

Germinal centre formation and follicular antigen trapping in the spleen of lethally X-irradiated and reconstituted rats.

In this study, the relationship between germinal centre formation and the follicular trapping of immune complexes in the rat spleen was investigated. Lethally (9 Gy) X-irradiated rats were reconstituted with thoracic duct lymphocytes and subsequently challenged with sheep red blood cells to induce germinal centre formation. Rats were killed at daily intervals from 1 to 8 days after reconstitution and antigenic stimulation. Antigen trapping capacity during this interval was assessed by intravenous injection of HRP-anti-HRP immune complexes, 24 hr before killing of the animals. Germinal centre formation could be observed from Day 4 onwards. The follicular trapping capacity, which had been abolished by the X-irradiation, however, returned 2 days later (i.e. by Day 6). Apparently, in these experiments, early germinal centre formation could occur without an intact follicular trapping mechanism. It was, therefore, concluded that in this transfer system follicular immune complex trapping is not a prerequisite for the induction of de novo germinal centre formation. Previous studies have shown that both follicular dendritic cells and marginal zone B cells may play a role in the follicular antigen trapping mechanism. FDCs, as detectable with mAB MRC OX 2 in immunoperoxidase-stained frozen sections, were present in spleens at any time after irradiation and reconstitution; the impaired follicular trapping of HRP-anti-HRP immune complexes was therefore not due to an absence of FDCs. Marginal zone B cells, however, were almost absent until 5 days after reconstitution, as observed by immunohistochemical staining with anti-B cell mABs (HIS 14 and HIS 22) and a polyclonal anti-IgD antiserum. Our data suggest that regeneration of follicular antigen trapping capacity is dependent on the presence of marginal zone B cells.     

Follicular dendritic cells in aging, a "bottle-neck" in the humoral immune response

Senescence leads to the appearance of atrophic follicular dendritic cells (FDCs) that trap and retain little immune complexes (IC), generate few memory B cells, and induce a reduced number of germinal centers (GC). Deficiencies in antibody responses to T cell dependent exogenous antigens such as pneumonia and influenza vaccines may reflect intrinsic FDC defects or altered FDC-B cell interactions. We recently studied antigen handling capacity and co-stimulatory activity of old FDCs and determined age-related changes in the expression or function of FcgammaRII or CR1 and 2 on FDCs. Here, we present an overview of FDC function in recall responses with known deficiencies in FDCs and GC development. Then, we review our recent work on aged FDCs and discuss age-related changes in molecular interactions between FDCs and B cells. We also discuss the causes underlying the impaired humoral immune response with respect to age-related molecular changes in FDC and B cell interactions. In vitro evidence suggests that FcgammaRII on aged FDCs is regulated abnormally and this in turn might cause the development of a defective FDC-network (reticulum) that retains few ICs, promotes ITIM signaling, prevents B cell proliferation and GC formation, and antibody production.