TLR9 responses of B cells are repressed by intravenous immunoglobulin through the recruitment of phosphatase

One way for intravenous Ig (IVIg) to affect responses of the B cells might be to operate through their TLR7 and TLR9. We confirm the ability of TLR agonists to induce CD25 expression in B cells. For this to occur, sialylated Fc-gamma of IgG included in the IVIg preparation are required. As a result, IVIg suppresses TLR-induced production of the proinflammatory IL-6, but not that of the anti-inflammatory IL-10. That is, IVIg mimics the effects of the MyD88 inhibitor. Finally, as we previously showed that IVIg induces CD22 to recruit the inhibitory SHP-1, we established that this enzyme was also involved in IVIg-induced inhibition of TLR9 signaling. This is the first report to demonstrate such a mechanism underlying the negative impact of IVIg on B lymphocytes.     

Intravenous immunoglobulin therapy for autoimmune diseases

Therapeutic approaches for autoimmune diseases are primarily based on suppressive measures that down regulate an over productive immune system. The increasing availability of modern biological therapies has advanced the ability to target and to neutralize essential components of the immune response without experiencing the hazardous adverse effects caused by the traditional immunosuppressants. One of the noticeable examples of this approach is the increasing use of high-dose intravenous immunoglobulin (IVIg). IVIg mechanisms include modulating function of Fc receptors, interference with complement activation and cytokine network, provision of anti-idiotypic antibodies, regulation of cell growth, and effects on of T and B cells. In this review we gather existing information regarding IVIg mechanisms of action, clinical applications and its effects on various conditions.     

The steroid-sparing effect of intravenous immunoglobulin in patients with autoimmune diseases

This review covers the major advances in the therapeutic potential of intravenous immunoglobulin (IVIg) as a steroid-sparing agent in autoimmune diseases utilizing a structured search of Medline (1992–2007). IVIg is a potent biological drug, utilized routinely for idiopathic thrombocytopenic purpura, Kawasaki’s diseases, Guillain–Barre syndrome and dermatomyositis. In addition, however, IVIg is an adjunct second-line therapy in neuroimmunologic, infectious, dermatologic, hematologic, obstetric, autoimmune, inflammatory and idiopathic disorders. Compared with immunosuppressive agents administered routinely for systemic autoimmune diseases, IVIg is advantageous, owing to its few and transient minor adverse effects. Hence, it is logical to deliver IVIg with steroids as a sparing agent. All the published material on IVIg and its steroid-sparing effect was reviewed. Currently, there is insufficient evidence to confirm that IVIg has a significant steroid-sparing effect. Based on the available information, IVIg has the potential to act as a steroid-sparing agent in systemic lupus erythematosus and autoimmune blistering diseases, but its effect in other autoimmune diseases remains uncertain. Further investigation is warranted where this issue will be addressed as a primary endpoint and in controlled trials.     

Suppression of immunoglobulin production of lymphocytes by intravenous immunoglobulin

The proliferative responses and the immunoglobulin production of peripheral blood mononuclear cells to pokeweed mitogen were dose-dependently suppressed by sulfonated intravenous immunoglobulin (IVIG), polyethylene glycol-treated IVIG, pH 4-treated IVIG, or human -globulin, but they were not or only slightly suppressed by human serum albumin or pepsin-treated IVIG. Moreover, the suppression of immunoglobulin production by sulfonated IVIG, polyethylene glycol-treated IVIG, or pH 4-treated IVIG was seen in the cases in which B cells preincubated with IVIGs were cocultured with T cells and monocytes preincubated with or without IVIGs and in the cases in which monocytes preincubated with IVIGs were cocultured with T cells and B cells preincubated with or without IVIGs. However, in the cases in which only T cells were preincubated with IVIGs, immunoglobulin production was not suppressed. The suppression of the monocyte function by IVIGs tended to be less than the suppression of the B-cell function by IVIGs. Moreover, the suppression by IVIGs was blocked by antihuman IgG Fc. Our results suggest that IVIGs suppress the immunoglobulin production of lymphocytes through suppression of the B-cell function and the antigen presenting-cell function by attachment of IVIGs to Fc receptors of B-cell membranes and antigen presenting-cell membranes.     

巨噬细胞活化与自身免疫病

巨噬细胞“活化”在免疫反应、机体自稳、疾病的发生发展与预后中发挥重要作用,与多种自身免疫病的发生发展密切相关.但目前对其活化的定义、分类、鉴定等尚未有统一的标准,因此研究巨噬细胞活化的定义、分类、表面标记的改变、更清楚地了解巨噬细胞活化在自身免疫病中发挥的重要作用很有必要.     

Th9细胞与自身免疫性疾病

Th1、Th2、Th17和调节性T细胞（Treg）亚群是CD4＋T细胞亚群中的重要成员,其参与了人类及动物自身免疫性疾病的发病过程.既往认为,IL-9是由CD4＋Th2细胞分泌的细胞因子,是机体免疫应答中重要的调节因子.最近研究表明,机体内可能存在着一群新型的具有分泌IL-9和IL-10能力的CD4＋Th细胞亚群,称之为＂Th9＂细胞.该细胞亚群与自身免疫性疾病的相关性尚不清楚.     

Modulation of immunoglobulin production and cytokine mRNA expression in peripheral blood mononuclear cells by intravenous immunoglobulin

Intravenous immunoglobulin (IVIG) has the potential to regulate Ig production, but the mechanism(s) responsible for this effect is unknown. In experiments reported here, we examined the ability of IVIG to regulate Ig production in human peripheral blood mononuclear cells (PBMCs) stimulated with pokeweed mitogen (PWM). IVIG (2–10 mg/ml) showed a potent (80–85%) inhibition of PWM-stimulated IgG, IgM, and IgA production. To determine more precisely how IVIG mediated the inhibition of Ig production, we studied Ig promoting cytokine gene expression after PWM stimulation with or without IVIG (2 and 10 mg/ml) using dot-blot techniques. RNA was isolated from PBMCs at predetermined time points and probed with cDNAs specific for human cytokines (IL-1-, IL-2, IL-2R, IL-4, IL-5, IL-6, -IFN, and TNF-). IL-6 mRNA accumulation was maximal at 4.5 hr post-PWM stimulation and was inhibited 64–75% when IVIG (10 mg/ml) was present. -IFN mRNA levels peaked at 72 hr poststimulation and were also 68–75% inhibited by IVIG. IL-2 mRNA levels peaked at 4.5 hr and were 23–46% inhibited by IVIG. The inhibitory effect of IVIG on production of these cytokines (IL-6 and -IFN) was also observed at the protein level in sonicated PBMCs after incubation with PWM and IVIG. The mRNA levels for other cytokines were not or only minimally inhibited by IVIG. Addition of IL-6, -IFN, or IL-2 partially restored Ig production in IVIG-treated PWM-stimulated cultures, suggesting that inhibition of other cytokines or another mechanism(s) independent of cytokine inhibition might also be involved, although inhibition of IL-6, -IFN, and IL-2 may be one of the critical factors in the suppression of Ig production by IVIG.     

Immunomodulation of autoimmune diseases by high-dose intravenous immunoglobulins

Conclusion  IVIG represents a promising immunoregulatory agent which has the ability to control autoimmune disorders without subsequent predisposition to infectious complications. However, it is extremely expensive: the approximate average wholesale price is U.S. $1,800 per dose for a 70-kg patient. Further studies and controlled clinical trials will be necessary to prove the efficacy of this therapy for specific autoimmune disorders.     

Intravenous immunoglobulin (IVIG) for the therapy of autoimmune disorders

The weight of evidence from numerous clinical studies supports the use of IVIG, particularly at higher doses, in the treatment of a wide range of autoimmune disorders. Extensive experience has documented the safety of IVIG therapy but its present relatively high cost necessitates firmly establishing its efficacy. There is an acute need to define those disease states where IVIG is indicated and effective. Large-scale, possibly multicentered, clinical trials employing rigorous controls will resolve these questions. Concurrent fundamental immunologic studies will elucidate the mechanisms underlying the clinical effects. We are experiencing an exciting new era of effective immunotherapies and intravenous gamma-globulin preparations have already secured an important place in the therapeutic armamentarium. While one must guard against unsubstantiated applications, critical exploration of new uses for this unique product is warranted.     

Mechanisms of action of intravenous immunoglobulin in autoimmune and inflammatory diseases.

Therapeutic polyclonal intravenous immunoglobulin (IVIg) consists of normal IgG obtained from the pools of plasma of several thousand healthy blood donors. IVIg is used as substitutive treatment of primary and secondary immunodeficiences. Since the first study of Paul Imbach who demonstrated the beneficial effect in idiopathic thrombocytopenic purpura, IVIg is also used in a number of autoimmune and inflammatory diseases. The immunoregulatory effects of IVIg in autoimmune diseases depend on the interaction of Fc portion of immunoglobulins with Fc receptors and on the selection of lymphocyte repertoires of patients through variable regions of infused immunoglobulins. IVIg modulates the activation and effector functions of B and T lymphocytes, neutralizes pathogenic autoantibodies, interferes with antigen presentation and has a strong anti-inflammatory effect which depends on its interaction with the complement system, cytokines and endothelial cells. The immunomodulatory potential of IVIg in patients is thus a result of a variety of complex mechanisms that act in a synergy.     

Drug nanocarriers to treat autoimmunity and chronic inflammatory diseases

Nanoparticles represent a new generation of drug delivery systems that can be engineered to harness optimal target selectivity for specific cells and tissues and high drug loading capacity, allowing for improved pharmacokinetics and enhanced bioavailability of therapeutics. The spontaneous propensity of both organic and colloidal nanoparticles to be captured by the cells of the reticuloendothelial system encouraged their utilization as passive targeting systems that can be preferentially directed to innate immune cells, such as macrophages, dendritic cells and neutrophils. The natural affinity for phagocytic cells suggests the possible implementation of nanoparticles as an immunotherapeutic platform for inflammatory diseases and autoimmune disorders. Here we discuss the recent advances in the application of nanotechnology to induce antigen-specific tolerance in autoimmunity and the use of nanoparticles for anti-inflammatory therapies, including treatment of inflammatory bowel diseases, psoriasis and rheumatoid arthritis.     

白细胞介素-37与自身免疫性疾病

白细胞介素(interleukin,IL)-37是新近发现的IL-1家族细胞因子,对固有免疫和适应性免疫均有抑制作用.IL-37主要表达于中性粒细胞、淋巴细胞、巨噬细胞、单核细胞、组织上皮细胞、角质形成细胞和树突状细胞.最近大量研究显示,IL-37在许多自身免疫性疾病患者或动物模型中表达异常并发挥关键作用,如系统性红斑狼疮、炎症性肠病、强直性脊柱炎、支气管哮喘、银屑病、Graves病以及类风湿性关节炎等.深入研究IL-37的生物学功能、信号转导途径及作用机制将为IL-37在自身免疫性疾病的治疗提供新思路和靶点.     

Immunomodulation by statins: mechanisms and potential impact on autoimmune diseases

Statins are inhibitors of the enzyme 3-hydroxy-3methylglutaryl coenzyme A (HMG-CoA) and they are the most effective agents for lowering cholesterol in clinical practice for the treatment of cardiovascular diseases. However, it has become clear that statins also have pleiotropic immunomodulatory effects in addition to their lipid-lowering properties. As a result, much attention has been focused on their potential as therapeutic agents for the treatment of inflammatory autoimmune diseases. In this review the effect of statins on the expression and function of a variety of immune-relevant molecules will be discussed alongside the underlying mechanisms that contribute to the immunomodulatory effects of statins.     

口服耐受机制和对自身免疫性疾病治疗的研究进展

ｅｌｌｓ等 ( 1 91 1 ) [1 ] 首次描述了口服耐受现象 ,他们发现预先给豚鼠口服鸡蛋白可防止后来对该蛋白的全身性过敏反应。Ｃｈａｓｅ( 1 946) [2 ] 发现预先给豚鼠口服接触性致敏原二硝基氯苯 (ｄｉｎｉｔｒｏｃｈｌｏｒｏ-ｂｅｎｚｅｎｅ) ,可使动物减少对其皮肤接触性过敏反应。Ｎａｇｌｅｒ-Ａｎｄｅｒｓｏｎ等[3] 和Ｔｈｏｍｐｓｏｎ等[4] ( 1 986)首次将口服耐受用于自身免疫性疾病的实验研究。针对自身抗原的免疫无反应状态称为自然耐受 (ｎａｔｕｒａｌｔｏｌｅｒａｎｃｅ)或自身耐受 (ｓｅｌｆ-ｔｏｌｅｒａｎｃｅ) ;针对外源性…     

Polyvalent immunoglobulin for intravenous use interferes with cell proliferationin vitro

Intravenous immunoglobulin is used to an increasing extent in various immune-mediated diseases, but its mechanism(s) of actionin vivo is incompletely understood. Previous studies have shown that intravenous immunoglobulin may interfere with autoantibodies and their production by B cells and also inhibit Fc-mediated antibody-dependent cytotoxicity. Here we describe a novel effect of intravenous immunoglobulin on proliferation ofin vitro activated peripheral blood lymphocytes and autonomously growing cell lines of various origin. Independently of whether proliferation was autonomous or induced by antigen-specific or antigen-nonspecific reagents, proliferation was inhibited in a dose-dependent fashion, as measured by reduced³H-thymidine and BrdU uptake and cell counting. The effect was not due to cytotoxic effects of intravenous immunoglobulin and was reversible after removing the intravenous immunoglobulin by washing. The IgG levels required for this inhibition of proliferation are supraphysiological but are reachedin vivo during treatment with intravenous immunoglobulin.     

感染因素与自身免疫性疾病发病相关性的研究进展

自身免疫病(AID)是指自身免疫出现异常,自身抗体和/或自身反应性淋巴细胞攻击表达靶抗原的细胞和组织,导致组织器官损伤和功能障碍所引起的一大类疾病.自身免疫病的发病机制是目前研究的热点之一.最近的研究表明感染因素与自身免疫病的发生密切相关,细菌或病毒等通过诱发自身免疫而致病.自身免疫病的种类很多,发病机制亦相当复杂,确切病因尚不十分清楚,国内外研究者做了多方面深入研究提出了包括分子模拟、自身抗原或表位扩展的提呈、病毒或细菌的超抗原、旁路激活和淋巴细胞感染等多种机制.文中就感染因素致自身免疫病的机制及两者的相关性进行综述.     

小檗碱在自身免疫性疾病治疗中的研究进展

小檗碱在临床上主要用于治疗肠道感染,是我国传统药物.近年来研究发现小檗碱可通过抑制Th1、Th17细胞分化,调节Th1/Th2平衡,抑制T细胞增殖,诱导树突状细胞、巨噬细胞凋亡,抑制促炎性因子和抗体生成,保护上皮屏障功能等机制发挥免疫调节作用.通过以上机制,小檗碱在多发性硬化、类风湿性关节炎、1型糖尿病、肾小管间质性肾炎、结肠炎等自身免疫性疾病中发挥治疗作用.     

Common mechanisms of autoimmune diseases (the autoimmune tautology)

The fact that autoimmune diseases share subphenotypes, physiopathological mechanisms and genetic factors has been called autoimmune tautology, and indicates that they have a common origin. The autoimmune phenotypes vary depending on the target cell and the affected organ, gender, ancestry, trigger factors and age at onset. Ten shared characteristics supporting this logical theory are herein reviewed.