Dysfunction of Monocytes and Dendritic Cells in Patients With Premature Ovarian Failure

PROBLEM: Due to the presence of ovarian antibodies it has been suggested that premature ovarian failure (POF) belongs to the autoimmune endocrinopathies. Monocytes and the monocyte-derived dendritic cells play a prominent role in the initial stages of endocrine autoimmune reactions: the accumulation of monocytes/dendritic cells and the clustering of dendritic cells in endocrine organs is one of the first phenomena of an autoimmune endocrinopathy. METHOD: This report describes a study on (1) the chemotactic responsiveness of blood monocytes, and (2) the cluster capability of blood dendritic cells in POF patients. The monocyte chemotaxis was determined using the cell's capability to polarize (changes in shape determined by light microscopy) under the influence of the chemoattractant, N-formyl-methionylleucyl-phenylalanine (fMLP). The cluster capability of dendritic cells was tested by allowing the dendritic cells to form aggregates with allogenic lymphocytes in vitro. RESULTS: The blood monocytes of 46% of a total of 28 POF patients showed a decreased fMLP induced monocyte polarization in comparison to healthy control values. None of the young female controls (N = 28) and postmenopausal women (N= 17), showed such a defective monocyte polarization. The blood dendritic cells of 36% of the POF patients showed a decreased cluster capability. Defects in monocyte polarization and dendritic cell clustering were not affected by therapies aimed at changes in the estrogen levels or gonadotropin levels of the patients [using estrogen substitution therapy, gonadotropin-releasing hormone (GnRH) analog, follicle-stimulating hormone (FSH)]. CONCLUSIONS: A redistribution of active monocytes and of active dendritic cells from the peripheral blood to the ovaries may be the cause of the described abnormalities. Since similar abnormalities in monocyte function and dendritic cell function have been described in Graves' disease and type I diabetes, the data strengthen the view that POF is one of the endocrine autoimmune diseases.     

Early cellular responses to Salmonella infection: dendritic cells,monocytes, and more

Summary: Dendritic cells (DCs), monocytes, macrophages, and neutrophils are myeloid-derived phagocytes critical to controlling bacterial infections, and these cells have complementary functions to ensure host survival. Recent data have shed light on the dynamics and function of myeloid cells at the early stage of infection. In particular, murine infection models with Salmonella enterica serovar Typhimurium have been useful for understanding the host response required to develop immunity to systemic salmonellosis. This review summarizes the early cellular responses in the intestinal lymphoid tissues to Salmonella and discusses Peyer's patch-dependent and -independent penetration of bacteria through the intestinal epithelium. Once Salmonella accesses host tissue, phagocytes respond by recruitment, redistribution, and activation in intestinal tissues. Recruited monocytes are specialized in controlling bacterial replication by producing anti-microbial molecules but are poor antigen-presenting cells. In contrast, DCs undergo maturation by direct (bacteria-mediated) and indirect (cytokine-mediated) pathways in vivo to optimize their antigen presentation capacity, and directly matured DCs have unique mechanisms to ensure T-cell stimulation. Toll-like receptor signaling is critical to DC maturation and myeloid cell recruitment during Salmonella infection, and the role of myeloid differentiation factor 88 (MyD88)-dependent and MyD88-independent pathways as well as proinflammatory cytokines and type 1 interferons in these processes are discussed.     

Dendritic Cells: A Link Between Innate and Adaptive Immunity

Dendritic cells (DC) constitute a unique system of cells able to induce primary immune responses. As a component of the innate immune system, DC organize and transfer information from the outside world to the cells of the adaptive immune system. DC can induce such contrasting states as active immune responsiveness or immunological tolerance. Recent years have brought a wealth of information regarding DC biology and pathophysiology, that shows the complexity of this cell system. Although our understanding of DC biology is still in its infancy, we are now in a position to use DC-based immunotherapy protocols to treat cancer and infectious diseases.     

The Plasticity of γδT Cells: Innate Immunity, Antigen Presentation and New Immunotherapy

Several signals influence dendritic cell (DC) functions and consequent the immune responses to infectious pathogens. Our recent findings provide a new model of intervention on DCs implicating human γδ T cell stimuli. Vγ9Vδ2 T cells represent the major subset of circulating human γδ T cells and can be activated by non-peptidic molecules derived from different microorganisms or abnormal metabolic routes. With activated-Vγ9Vδ2 T cell co-culture, immature DCs acquire features of mature DCs, such as increasing the migratory activity, up-regulating the chemokine receptors, and triggering the Thl immune response. Similar to the NK-derived signals, DC activation is mediated by soluble factors as well as cell-to-cell contact. Many non-peptidic molecules including nitrogen- containing bisphosphonates and pyrophosphomonoester drugs, can stimulate the activity of Vγ9Vδ2 T cells in vitro and in vivo. The relatively low in vivo toxicity of many of these drugs makes possible novel vaccine and immune-based strategies against infectious diseases. Cellular & Molecular Immunology. 2008;5(3):161-170.     

Non-Pathogenic <Emphasis Type="Italic">Mycobacterium smegmatis</Emphasis> Induces the Differentiation of Human Monocytes Directly into Fully Mature Dendritic Cells

Mycobacterium smegmatis infects human monocytes that can be precursors of dendritic cells. We tested whether the interaction of M. smegmatis with monocytes modulated their differentiation into dendritic cells. We found that M. smegmatis-infected monocytes differentiated into CD1a⁻CCR7⁺ dendritic cells in the presence of GM-CSF and IL-4 and acquired a mature phenotype since they expressed CD83 molecules in the absence of maturation stimuli. Dendritic cells derived from M. smegmatis-infected monocytes stimulated with bacterial products, produced IL-10 and still retained the capacity to produce IL-12. Consequently, they polarized naïve T lymphocytes towards a mixed Th1/Th2 immune response inducing both IFN-γ and IL-4 production. These findings suggest that the exposure to environmental mycobacteria could modulate the differentiation of dendritic cells making them able to migrate into secondary lymphoid organs and modulate the adaptive immune response. This could explain one of the mechanisms by which environmental mycobacteria can influence the immune response to pathogenic species.     

杀伤性树突状细胞的研究进展

目的：探讨杀伤性树突状细胞在人体免疫功能中的作用。方法：在Pubmed上查阅杀伤性树突状细胞的相关文献,对其在啮齿类动物和人类体内的免疫作用进行归纳总结。结果：啮齿类和人类体内均有杀伤性树突状细胞,它可以直接连接固有免疫和适应性免疫,并具有杀伤肿瘤细胞的功能。结论：杀伤性树突状细胞可以为临床肿瘤免疫疗法提供一条新思路。     

Dendritic cells modulated by innate immunity improve collagen-induced arthritis and induce regulatory T cells in vivo

Dendritic cells (DCs) mediate interactions between innate and specific immunity and may induce regulatory mechanisms. We investigated the effects of modulated DCs in mice with collagen-induced arthritis (CIA) and tested the responses of cells to induced naturally occurring regulatory T cells. DCs were stimulated or not with DNA or lipopolysaccharide (LPS) for 24 hr. DC maturation was assayed, and then modulated DCs were intraperitoneally injected on day 14 into DBA/1 mice to treat CIA. In addition to arthritis scores and type 2 collagen (CII) response, the induction of CD4(+) CD25(+) T cells was analysed by flow cytometry in peripheral blood and the expression of Foxp3, transforming growth factor (TGF)-beta, interleukin (IL)-10 and cytotoxic T-lymphocyte antigen (CTLA)-4 was quantified. Finally, the expression of indoleamine-2,3-dioxygenase (IDO) was assayed in DCs. In comparison with LPS-stimulated DCs, plasmid-stimulated DCs expressed lower levels of major histocompatibility complex (MHC) class II, CD40, CD80 and CD86 molecules and secreted less IL-12p70, interferon (IFN)-gamma, IL-10 and TNF-alpha, displaying a semi-mature phenotype. Compared with non-stimulated DCs, stimulated DCs improved arthritis scores when injected after immunization, without modifying the T helper type 1 (Th1)/Th2 balance of the immune response against collagen. Stimulated DCs induced markers for regulatory T cells (Foxp3, TGF-beta1 and CTLA-4) in vivo. Only LPS-stimulated DCs expressed IDO, which may explain their better therapeutic efficacy. Regulatory mechanisms were induced using DCs modulated by innate immunity stimulators. Innate immunity mechanisms do not require the presence of the disease-causing antigen, even in T- and B-cell specific diseases. Our results have implications for the treatment of rheumatoid arthritis, an autoimmune disease whose triggering antigen has not been identified, and substantially clarify the role of regulatory T cells in CIA.     

Dendritic cell maturation and cross-presentation: timing matters!

As a population, dendritic cells (DCs) appear to be the best cross-presenters of internalized antigens on major histocompatibility complex class I molecules in the mouse. To do this, DCs have developed a number of unique and dedicated means to control their endocytic and phagocytic pathways: among them, the capacity to limit acidification of their phagosomes, to prevent proteolytic degradation, to delay fusion of phagosomes to lysosomes, to recruit ER proteins to phagosomes, and to export phagocytosed antigens to the cytosol. The regulation of phagocytic functions, and thereby of antigen processing and presentation by innate signaling, represents a critical level of integration of adaptive and innate immune responses. Understanding how innate signals control antigen cross-presentation is critical to define effective vaccination strategies for CD8⁺ T-cell responses.     

A Subset of Type I Conventional Dendritic Cells Controls Cutaneous Bacterial Infections through VEGFα-Mediated Recruitment of Neutrophils

1. Download high-res image (235KB)
2. Download full-size image

     

Plasmacytoid dendritic cells act as the most competent cell type in linking antiviral innate and adaptive immune responses

Appropriate in vivo control of plasmacytoid dendritic cell （pDC） recruitment and activation is a fundamental requirement for defense against viral infection. During this process, a pivotal event that influences the outcome of viral infection is the production of high levels of type I interferon by pDCs. In particular, recent research findings showed that pDCs not only shape the nature of innate resistance, but are also responsible for the successful transition from innate to adaptive immunity for viral resistance. In addition, pDCs can differentiate into antigen presenting cells that may regulate tolerance to a given pathogen. Importantly, in a series of recent clinical studies, pDCs appeared to be defective in number and function in conditions of chronic viral diseases such as infected with HIV-1, HBV or HCV. pDC-associated clinical antiviral therapy is also emerging. This review describes research findings exatnining the functional and antiviral properties of in vivo pDC plasticity. Cellular ＆ Molecular Immunology. 2005;2（6）：411- 417.     

树突状细胞与特异性细胞免疫

树突状细胞是目前发现的递呈功能最强的抗原递呈细胞,它在抗原摄取与递呈方面的独特作用越来越引起人们的重视;同时,它通过提供双信号刺激、细胞辅助作用、细胞因子等直接和间接地启动特异性细胞免疫。在免疫应答中发挥着极其重要的作用。     

The Plasticity of γδ T Cells： Innate Immunity,Antigen Presentation and New Immunotherapy

Several signals influence dendritic cell （DC） functions and consequent the immune responses to infectious pathogens. Our recent findings provide a new model of intervention on DCs implicating human γδ T cell stimuli. Vγ/9Vδ2 T cells represent the major subset of circulating human γδ T cells and can be activated by non-peptidic molecules derived from different microorganisms or abnormal metabolic routes. With activated-Vγ/9Vδ2 T cell co-culture, immature DCs acquire features of mature DCs, such as increasing the migratory activity, up-regulating the chemokine receptors, and triggering the Thl immune response. Similar to the NK-derived signals, DC activation is mediated by soluble factors as well as cell-to-cell contact. Many non-peptidic molecules including nitrogen- containing bisphosphonates and pyrophosphomonoester drugs, can stimulate the activity of Vγ/9Vδ2 T cells in vitro and in vivo. The relatively low in vivo toxicity of many of these drugs makes possible novel vaccine and immune-based strategies against infectious diseases.     

The Role of Plasmacytoid and Myeloid Dendritic Cells in Induction of Asthma in a Mouse Model and the Effect of a TLR9 Agonist on Dendritic Cells

Purpose

To determine the role of plasmacytoid dendritic cells (pDC) and myeloid dendritic cells (mDC) in priming effector T cells to induce allergy, and to evaluate the effect of immunostimulatory sequences (ISS, TLR9 agonist) on dendritic cells.

Methods

Cultured mDC and pDC with/without ISS were injected intratracheally into sensitized Balb/C mice. Mice were sacrificed, and then pulmonary function tests, bronchoalveolar lavage (BAL), cell counts, and cytokine levels were evaluated. Migration of dendritic cells was also evaluated after ISS administration.

Results

In mice injected with mDC, airway hyperresponsiveness, eosinophil counts, and Th2 cytokine levels in BAL increased with increasing numbers of mDC injected. However, in mice injected with pDC, none of these changed, suggesting poor priming of T cells by pDC. In addition, mDC pulsed with ISS inhibited asthmatic reactions, and ISS administration inhibited migration of DC to the lung.

Conclusions

We suggest that pDC played a limited role in priming T cells in this asthma model and that mDC played a major role in inducing asthma. In addition, ISS inhibited migration of DC to the lung.     

Thymic Dendritic Cells: Phenotype and Function

Interdigitating (IDC) cells of the thymus have been characterized in situ by their ultrastructure and phenotype. Thymic dendritic cells (DC), thought to represent their in vitro correlate, resemble splenic DC in their ability to initiate peripheral T cell responses. In vivo, however, DC of the thymus have been implicated in tolerance induction, although at one time they were thought to impart MHC-restriction on developing T cells. Our present understanding of these areas is reviewed here.

An in vitro model has been developed to address directly the function of DC in the thymus. Mature DC and immature thymocytes migrate into deoxyguanosine-treated thymus lobes where they adopt a reciprocal distribution, DC homing primarily to the medulla while the thymocytes remain in the cortex. These observations support the close relationship between thymic DC and IDC and provide a powerful tool to examine the role of DC in thymocyte ontogeny.     

细胞因子诱导不同来源的贴壁细胞分化为树突状细胞的研究

通过贴壁的方法分离胚肝、脐带血、造血动员后的外周血及正常人外周血中的树突状细胞 (DC )的前体细胞 ,体外采用细胞因子诱导 ,并对其进行形态学观察和细胞表型分析 ;同时比较了不同来源DC的增殖、分泌IL 12的能力及激发同种异体T细胞和脐带血幼稚型T细胞 (naiveTcell)的作用。实验结果表明 ,经过造血动员后的外周血细胞产生的DC数量和纯度均较高 ,而且能经体外细胞因子诱导为功能性DC ,是较理想的DC来源     

抗大鼠树突状细胞单克隆抗体的研制及初步鉴定

树突状细胞是一种重要的抗原提呈细胞,在移植排斥反应中发挥重要作用。为了进一步研究该细胞的功能和寻找抗移植排斥反应的更有效途径,我们在分离大鼠树突状细胞获得成功的基础上,应用杂交瘤技术制备出5株抗树突状细胞单克隆抗体,分别命名为WZD1～5。杂交瘤细胞培养上清或腹水对新鲜分离的大鼠树突状细胞均显示不同程度的细胞毒性作用,且与腹腔Mφ及淋巴细胞无明显交叉反应。经间接免疫荧光染色测定,腹水中单抗的效价为2×10~(-2)。     

Subset of Vascular Dendritic Cells Transforming into Foam Cells in Human Atherosclerotic Lesions

It has been previously demonstrated that S-100 positive vascular dendritic cells are involved in human atherosclerosis and they usually show a low level of accumulation of lipids in their cytoplasm, even though they located among foam cells and cellular debris in atherosclerotic lesions. During ongoing immunohistochemical investigations, however, we have found that a few S-100 positive cells exhibited a foam cell appearance. Therefore, we undertook an electronmicroscopic examination to see if any foam cells exhibit the distinctive features of vascular dendritic cells such as the presence of dense granules and a tubulovesicular system uniquely found in well differentiated dendritic cells. Foam cells exhibiting the typical characteristics of vascular dendritic cells were indeed found. Their cytoplasm contained a large number of lipid vacuoles and cisterns of the tubulovesicular system as well as dense granules which, in contrast to lysosomes present in macrophages, did not transform into phagolysosomes. The formation of a central lamina inside cisterns of the tubulovesicular system was also detected. These pentalaminal structures, comprised of two parallel limiting membranes and a central lamina, are similar to the Birbeck granules present in human epidermal Langerhans cells. From our present observations we speculate that the defense mechanisms against extensive lipid accumulation may be broken in some vascular dendritic cells, causing them to transform into foam cells.     

Crosstalk between components of the innate immune system: promoting anti-microbial defenses and avoiding immunopathologies

Summary:  Because it reaches full functional efficacy rapidly upon encounter with a pathogen, the innate immune system is considered as the first line of defense against infections. The sensing of microbes or of transformed or infected cells, through innate immune recognition receptors (referred to as activating I2R2), initiates pro-inflammatory responses and innate immune effector functions. Other I2R2 with inhibitory properties bind self-ligands constitutively expressed in host. However, this dichotomy in the recognition of foreign or induced self versus constitutive self by I2R2 is not always respected in certain non-infectious conditions reminiscent of immunopathologies. In this review, we discuss that immune mechanisms have evolved to avoid inappropriate inflammatory disorders in individuals. Molecular crossregulation exists between components of I2R2 signaling pathways, and intricate interactions between cells from both innate and adaptive immune systems set the bases of controlled immune responses. We also pinpoint that, like T or B cells, some cells of the innate immune system must go through education processes to prevent autoreactivity. In addition, we illustrate how gene expression profiling of immune cell types is a useful tool to find functional homologies between cell subsets of different species and to speculate about unidentified functions of these cells in the responses to pathogen infections.     

Dendritic Cells Transduced with SOCS1 Gene Exhibit Regulatory DC Properties and Prolong Allograft Survival

SOCS1 is a key regulator of cytokine signaling and is important for maintaining balance in the immune system. It is thought to participate in negative feedback loops in cytokine signaling and may be an important signal for the regulation of dendritic cell （DC） maturation. However, it remains unclear whether DCs transduced with SOCS1 exhibit characteristics of regulatory DCs and induce allogeneic T-cell hyporesponsiveness. In this study, we constructed adenovirai vector coding SOCS1 （Ad-SOCS1） that can efficiently increase SOCS1 gene expression in bone marrow-derived dendritic cells. DCs transduced with Ad-SOCS1 （DC-SOCS1） expressed low levels of costimulatory and MHC molecules, were resistant to maturation and activation stimulation, induced allogeneic T-cell hyporesponsiveness, and promoted the generation of regulatory-like T cells in vitro. DC-SOCS1 pretreatment significantly prolonged the survival of ailografts and led to a substantial increase in the generation of regulatory T cells. Our data suggest that SOCS1 inhibits DC maturation and induces regulatory DC generation, therefore possessing therapeutic potential to prevent rejection in organ transplantation.