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1.
Intravenous immunoglobulins (IVIgs) exert a variety of immunomodulating activities and are therefore increasingly being used for the treatment of immune-mediated as well as autoimmune diseases. Although the exact mode of action is still poorly understood, the efficacy of IVIg in several diseases, such as thrombocytopenic pupura and Kawasaki disease, has been proven in clinical trials. According to some uncontrolled clinical studies and many case reports there is evidence for a high efficacy of IVIg in the treatment of skin diseases such as autoimmune blistering diseases, lupus erythematosus, dermatomyositis, scleroderma, toxic epidermal necrolysis, atopic dermatitis, chronic autoimmune urticaria and others. In contrast to other commonly used immunomodulating therapeutic strategies, the safety profile of IVIg treatment is significantly better. This update aims to give a current view on the efficacy and safety of IVIg treatment for dermatological diseases.  相似文献   

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Allergic contact dermatitis is induced by chemicals or metal ions. A hallmark of this T cell mediated skin disease is the activation of the innate immune system by contact allergens. This immune response results in inflammation and is a prerequisite for the activation of the adaptive immune system with tissue-specific migration of effector and regulatory T cells. Recent studies have begun to address in detail the innate immune cells as well as the innate receptors on these cells and the associated signaling pathways which lead to skin inflammation. We review here recent findings regarding innate and adaptive immune responses and immune regulation of contact dermatitis and other skin diseases as well as recent developments towards an in vitro assessment of the allergenic potential of chemicals. The elucidation of the innate inflammatory pathways, cellular components and mediators will help to identify new drug targets for more efficient treatment of allergic contact dermatitis and hopefully also for its prevention.  相似文献   

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Sepsis results in the concurrent activation of inflammatory and procoagulant pathways. Bacterial products and proinflammatory cytokines trigger the coagulation system primarily via induction of tissue factor. During sepsis, activation of coagulation is accompanied by impaired function of major anticoagulant mechanisms, including antithrombin, the protein C system and fibrinolysis. Protease activated receptors (PARs) form the molecular connection between coagulation and inflammation, and especially PAR1 seems to play an eminent role in sepsis pathogenesis. Activated protein C (APC) can cleave PAR1 when associated with either the endothelial protein C receptor (EPCR) or CD11b/CD18, resulting in broad cytoprotective effects mediated by sphingosine 1 phosphate (S1P) receptor 1 (S1P1). In contrast, activation of PAR1 by high dose thrombin results in barrier disruptive effects in endothelial cells via an S1P3 dependent mechanism. Recombinant APC protects against mortality in experimental endotoxemia and sepsis by effects that can be mediated by either EPCR - PAR1 dependent (endothelial cells, dendritic cells) or CD11b/CD18 - PAR1 dependent (macrophages) mechanisms. These protective APC effects do not rely on the anticoagulant properties of this protein. APC mutants that lack anticoagulant properties but retain the capacity to activate PAR1 are promising new drugs for sepsis treatment.  相似文献   

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Apart from cancer chronic (auto)immune-mediated diseases are a major threat for patients and a challenge for physicians. These conditions include classic autoimmune diseases like systemic lupus erythematosus, systemic sclerosis and dermatomyositis and also immune-mediated inflammatory diseases such as rheumatoid arthritis and psoriasis. Traditional therapies for these conditions include unspecific immunosuppressants including steroids and cyclophosphamide, more specific compounds such as ciclosporin or other drugs which are thought to act as immunomodulators (fumarates and intravenous immunoglobulins). With increasing knowledge about the underlying pathomechanisms of the diseases, targeted biologic therapies mainly consisting of anti-cytokine or anti-cytokine receptor agents have been developed. The latter have led to a substantial improvement of the induction of long term remission but drug costs are high and are not affordable in all countries. In China an extract of the herb Tripterygium wilfordii Hook F. (TwHF) is frequently used to treat autoimmune and/or inflammatory diseases due to its favourable cost-benefit ratio. Triptolide has turned out to be the active substance of TwHF extracts and has been shown to exert potent anti-inflammatory and immunosuppressive effects in vitro and in vivo. There is increasing evidence for an immunomodulatory and partly immunosuppressive mechanism of action of triptolide. Thus, compounds such as triptolide or triptolide derivatives may have the potential to be developed as a new class of drugs for these diseases. In this review we summarize the published knowledge regarding clinical use, pharmacokinetics and the possible mode of action of triptolide in the treatment of inflammatory diseases with a particular focus on psoriasis.  相似文献   

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Transcription factors in autoimmune diseases   总被引:4,自引:0,他引:4  
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Peptide-mediated immunotherapy has been studied in a number of experimental models of autoimmune diseases and has also been tested in human patients to a certain extent. Copolymer 1 is a synthetic amino acid copolymer that has been demonstrated to suppress experimental autoimmune encephalomyelitis (a model for multiple sclerosis) when administered parenterally. Some study results indicate that mucosal tolerance induced by appropriate recombinant peptide fragments of human AChR is effective in suppressing experimental autoimmune myasthenia gravis and might be considered as a therapeutic modality for patients with MG. A peptide of the heat-shock protein 60 molecule, designated peptide p277, was shown to be a target of T cells in autoimmune diabetes in NOD mice, and intraperitoneal injections of glutamic acid decarboxylase (GAD) peptide 524-543 delayed the onset of diabetes and significantly reduced its incidence. Experimental evidence has revealed that CDR-based peptides may be potential candidates for the therapy of systemic lupus erythematosus. The use of synthetic peptides that focus on neutralization of pathogenic anti-beta 2GPI antibodies represents a possible new therapeutic approach to antiphospholipid syndrome. Studies in both acute and chronic-relapsing experimental autoimmune uveoretinitis have indicated that oral administration of S-Ag, S-Ag-derived peptides, inter-photoreceptor retinoid binding protein or HLA-derived peptides before immunization can protect animals from the disease.  相似文献   

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A sexual dysmorphism in the immune response has been described and females display an increased incidence of autoimmune diseases. Experimental data show that sex steroids influence immune cell development and have immunomodulatory effects. The distribution, the action (genomic and nongenomic), the sex and tissue-depending expression pattern of estrogen, progesterone and androgen receptors and their functional disruptions in corresponding receptor knockout animals will be discussed, pointing out the difference among sex steroid hormones. Recent advances indicate an immunomodulatory role of sex steroids in the pathogenesis of systemic lupus erythematosus, multiple sclerosis and rheumatoid arthritis. The outcomes of the clinical trials will help to find the best use of sex steroids in combination with current therapeutic drugs in autoimmune diseases. Sex steroid receptor modulating drugs will provide new therapeutic approaches in these pathologies.  相似文献   

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There are a large number of diseases involving inappropriate activation of the immune system. This review focuses on one such disease, rheumatoid arthritis (RA). Over recent years there has been a dramatic shift in the treatment of RA, in which biological agents, such as monoclonal antibodies and immuno-fusion proteins, have offered the potential to enhance or replace conventional immunosuppressive therapies. This review covers some of the novel biological molecules currently under investigation as potential therapeutic targets in RA. In addition, it covers the genomic and proteomic strategies being used to identify potential new molecular targets for future therapies. Selectively blocking the immune response, in a combination approach blocking not only inflammation but also the adaptive memory response and tissue destruction, holds great promise for the treatment of RA and many other immune-mediated diseases.  相似文献   

12.
Thrombomodulin (TM) is a type 1 membrane bound glycoprotein that has a C-type lectin domain at its Nterminus, 6 copies of the epidermal growth factor-like (EGF) motif and serine/threonine rich domain carrying a glycosoaminoglycan external to the membrane. TM binds thrombin changing thrombin's substrate specificity from procoagulant and pro-inflammatory to anti-coagulant and anti-inflammatory because of the activation of protein C (PC) and thrombin-activatable fibrinolysis inhibitor (TAFI). Thrombin's anion binding site 1 binds to TM's EGF domains 5 and 6. EGF4 is required for PC activation and EGF3 and 4 for TAFI activation in addition to EGF56. The X-ray structure of thrombin bound to TM has been solved and shows few major alterations in the active site of thrombin. The lectin domain can bind high mobility group box protein 1 (HMGB1) and a sugar, Lewisy. TM's lectin domain behaves as an antagonist to HMGB1 endowing it with intrinsic anti-inflammatory activity. Treatment of dendritic cells with TM converts them from immunogenic to tolerogenic. TM is necessary for maintenance of pregnancy as well as prevention of coagulation throughout life. Soluble TM has been developed as an anticoagulant possessing favorable pharmacokinetics that has been approved for treatment of disseminated intravascular coagulation in Japan.  相似文献   

13.
There are a large number of diseases involving inappropriate activation of the immune system. This review focuses on one such disease, rheumatoid arthritis (RA). Over recent years there has been a dramatic shift in the treatment of RA, in which biological agents, such as monoclonal antibodies and immuno-fusion proteins, have offered the potential to enhance or replace conventional immunosuppressive therapies. This review covers some of the novel biological molecules currently under investigation as potential therapeutic targets in RA. In addition, it covers the genomic and proteomic strategies being used to identify potential new molecular targets for future therapies. Selectively blocking the immune response, in a combination approach blocking not only inflammation but also the adaptive memory response and tissue destruction, holds great promise for the treatment of RA and many other immune-mediated diseases.  相似文献   

14.
自身免疫性疾病是一种病因复杂的疾病,然而最近对多种自身免疫性疾病的研究表明IL-17可能作为一种重要的因素并与其他因子共同作用导致疾病的发生。IL-17可由多种免疫细胞分泌,是一种重要的免疫调节物质,具有很强的中性粒细胞募集作用,同时也具有信号转导作用,另外还具有促进自身免疫性疾病发生的作用。本文就其产生、作用以及与类风湿性关节炎(RA)、多发性硬化病(MS)、系统性红斑狼疮(SLE)、哮喘4种自身免疫性疾病的关系进行研究。  相似文献   

15.
Lipopolysaccharide (LPS) is a toxic component of the outer membrane of gram-negative bacteria that can activate the blood coagulation system, leading to disseminated intravascular coagulation (DIC). DIC is a syndrome characterized by thromboembolism and multiple organ failure. Herein, the beneficial effect of paeoniflorin (PF) on the alleviation of LPS-induced DIC was investigated with an experimental DIC mouse model. Briefly, mice were randomly divided into the following six groups: (1) control; (2) LPS; (3) heparin; (4) low-PF treatment; (5) medium-PF treatment; and (6) high-PF treatment. The histological morphology of the liver and kidney was observed, and the coagulation indicators (such as prothrombin time), function indicators (such as alanine transferase), and inflammatory factors (such as TNF-α) were detected. Additionally, an in vitro cell inflammation model using RAW 264.7 murine macrophages was established. Activation of the nuclear factor kappa B (NF-κB) signaling pathway and tumor necrosis factor-α (TNF-α) were determined by western blotting. Based on our findings, PF could significantly improve the histological morphology of the liver and kidney, indicating that PF protects the liver and kidney against damage induced by LPS. Additionally, PF improved the function and coagulation indicators and reduced the production of inflammatory factors. In vitro, PF inhibited the expression of TNF-α by suppressing NF-κB signaling pathway activation. Collectively, our findings support the hypothesis that PF has anti-inflammatory and anticoagulation effects for the alleviation of LPS-induced DIC. PF is thus a potential co-treatment option for DIC.  相似文献   

16.
 CD200是一种I型跨膜糖蛋白,在人体内分布十分广泛,但其受体主要分布于髓系细胞。大量研究发现,CD200介导的通路在调节免疫应答中起重要作用,对该通路的调节可影响自身免疫病的发生发展。此文就CD200的结构、表达、功能及其对自身免疫病的影响进行综述。  相似文献   

17.
There is increasing appreciation of the critical pathogenic role of IL-17 in inflammation and autoimmune diseases, which could be produced from both adaptive Th17 cells and innate γδ T cells. Existing evidences suggest that IL-2 is important for in vivo accumulation of IL-17+ γδ T cells, leaving the mechanisms still elusive. Herein, using lupus-prone MRL/lpr mice, we demonstrated that splenic γδ T cells were potent IL-17 producers at the onset of lupus, which could be diminished by in vivo IL-2 neutralization. Additional in vivo results showed that neutralization of IL-2 also significantly deleted the IL-17-producing γδ T cells in ovalbumin (OVA) /CFA-immunized B6 mice. Using splenic γδ T cells from OVA/CFA-immunized B6 mice, we further demonstrated that IL-2 could induce IL-17 production alone or together with IL-1β or IL-23 or anti-TCRγδ. Mechanism studies demonstrated that IL-2 could support the survival of γδ T cells, rather than induce the proliferation. Through specific pharmacologic inhibitor, we demonstrated that IL-2 could maintain that RORγt expression of γδ T cells in a STAT5-dependent manner. Collectively, this study suggested that the interplay between IL and 2 and other pro-inflammatory cytokines could trigger the rapid IL-17 production from innate γδ T cells, thus to orchestrate an inflammatory response before the development of adaptive Th17 cells.  相似文献   

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Autoimmune diseases are pathologic conditions defined by abnormal autoimmune responses and characterized by immune system reactivity in the form of autoantibodies and T cell responses to self-structures. Here we review the limited but growing epidemiologic and experimental literature pertaining to the association between autoimmune diseases and occupational exposure to silica, solvents, pesticides, and ultraviolet radiation. The strongest associations (i.e., relative risks of 3.0 and higher) have been documented in investigations of silica dust and rheumatoid arthritis, lupus, scleroderma and glomerulonephritis. Weaker associations are seen, however, for solvent exposures (in scleroderma, undifferentiated connective tissue disease, and multiple sclerosis) and for farming or pesticide exposures (in rheumatoid arthritis). Experimental studies suggest two different effects of these exposures: an enhanced proinflammatory (TH1) response (e.g., TNF-alpha and IL-1 cytokine production with T cell activation), and increased apoptosis of lymphocytes leading to exposure to or modification of endogenous proteins and subsequent autoantibody formation. The former is a general mechanism that may be relevant across a spectrum of autoimmune diseases, whereas the latter may be a mechanism more specific to particular diseases (e.g., ultraviolet radiation, Ro autoantibodies, and lupus). Occupational exposures are important risk factors for some autoimmune diseases, but improved exposure assessment methods and better coordination between experimental/animal models and epidemiologic studies are needed to define these risks more precisely.  相似文献   

20.
Autoimmune diseases affect about 3% of the world population, more frequently women than men, and their incidence is attributed to an immune response of a genetically predisposed individual to an environmental pathogen, under the influence of inadequate immuno-regulatory mechanisms. Advances in understanding the cellular activity pathways and cytokine expression profiles have led to new therapeutic regiments, like soluble receptors, monoclonal antibodies and molecular mimetics that have been employed to enhance or replace conventional immunosuppressive therapies. Among new biologicals that have been developed to target defined pathways of the adaptive immune response are TNF-alpha inhibitors. TNF-alpha is a proinflammatory cytokine elevated in many autoimmune lesions, and its deregulation characterizes many autoimmune diseases. TNF-alpha seems to exhibit an immunoregulatory role that can alter the balance of T regulatory cells and orchestrate acute immunological responses. More than half a million autoimmune patients have received therapy with anti-TNF-alpha antibodies, usually because they were refractory to conventional treatments. This review offers an update on TNF-alpha-targeted therapies used in patients suffering from various autoimmune diseases, based on the current knowledge of disease pathogenesis, with emphasis on the efficacy and safety that clinical trials have shown until now.  相似文献   

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