免疫吸附治疗自身免疫疾病的研究进展

自身免疫疾病治疗的常规方法(如免疫抑制剂和血浆置换等)缺乏足够的安全性和有效性,因此,寻找新的治疗方法十分必要。免疫吸附(immunoadsorption,IA)是一种通过选择性或非选择性去除自身致病抗体,从而实现对自身免疫疾病治疗的方法。本文介绍了免疫吸附在扩张型心肌病、特发性膜性肾病、系统性红斑狼疮、重症肌无力4种自身免疫疾病中的研究和临床应用,讨论了该治疗方法的有效性和安全性;同时指出,免疫吸附要在更多的疾病中实现临床应用,还需要在可信度、地域性、样本量等方面做更加深入的临床前试验。     

免疫吸附治疗自身免疫疾病的研究进展

自身免疫疾病治疗的常规方法(如免疫抑制剂和血浆置换等)缺乏足够的安全性和有效性,因此,寻找新的治疗方法十分必要。免疫吸附(immunoadsorption,IA)是一种通过选择性或非选择性去除自身致病抗体,从而实现对自身免疫疾病治疗的方法。本文介绍了免疫吸附在扩张型心肌病、特发性膜性肾病、系统性红斑狼疮、重症肌无力4种自身免疫疾病中的研究和临床应用,讨论了该治疗方法的有效性和安全性;同时指出,免疫吸附要在更多的疾病中实现临床应用,还需要在可信度、地域性、样本量等方面做更加深入的临床前试验。     

自身免疫性疾病治疗性疫苗研究进展

自身免疫性疾病的发生与体内自身反应性T／B细胞的异常活化有关。病理性自身免疫应答是多发性硬化、重症肌无力等自身免疫性疾病的主要致病原因。针对已感染致病原的无症状携带者或发病的患者的自身免疫性疾病治疗性疫苗能特异性地调节异常的免疫应答,具有重要的理论价值和应用前景。     

多发性硬化生物标记物的研究进展

多发性硬化(MS)是主要以中枢神经系统(CNS)白质脱髓鞘病变为主要特点的自身免疫性疾病。生物标记物是中枢神经系统自身免疫性疾病病因、诊断和预后的重要参考因素,因为他们可能反映遗传以及环境变化所引起的某些免疫反应的存在,性质和强度。因此生物标记有助于MS的早期诊断和鉴别诊断,指导治疗方案,推断MS疾病活动性,以及判断疗效。本文概述了多发性硬化领域当前的生物标记物研究状况及其相关的临床实践,并通过对三种具有较大潜力的生物标记物与病理的特异性、灵敏度、可靠性和临床实用工具进行分析,以确定最优化的治疗以防止致残,同时还可以对疾病修饰药物的有效性进行测试。     

细胞因子TNFSF13B的结构与功能及其在相关疾病发生中的作用

TNFSF13B是于1999年发现并克隆的一种重要的细胞因子,它广泛参与了T、B淋巴细胞的增殖及功能调节。该介绍TNFSF13B的结构及功能特点、TNFSF1B在相关疾病(如免疫功能低下、某些自身免疫性疾病及某些肿瘤等)发生中的作用以及TNFSF13B在相关疾病治疗中的应用前景等。     

白细胞介素-18在部分自身免疫性疾病中的作用

白细胞介素-18(interleukin-18,IL-18)是一个多肽片段,具有促进T细胞增殖、增强细胞毒性T细胞和自然杀伤细胞活性等功能。自身免疫性疾病是指机体对自身抗原发生免疫反应而导致自身组织损害所引起的疾病。IL-18在免疫调节中有着高效、广泛的作用,部分自身免疫性疾病发病与免疫系统的异常会伴随IL-18的高表达,且不同病程IL-18表达量会有规律性变化,因此IL-18可作为一种自身免疫性疾病较敏感的标志物。现对IL-18在常见自身免疫性疾病如系统性红斑狼疮、成人Still病、自身免疫性心肌炎和类风湿关节炎中的作用作一综述。     

自身免疫调节因子(AIRE)的研究进展

自身免疫调节因子(autoimmune regulator,AIRE)是一种具有转录活化潜能的DNA结合蛋白。由于AIRE基因的突变可导致自身免疫病APECED(autoimmune polyendocrinopathy—candidiasis-ectodermal dystrophy,APECED),又称自身免疫性多腺体综合征I(autoimmune polyglandular syndrome typeI,APSI)。因此,这一基因在正常生理状态下很可能对维持自身免疫耐受、控制自身免疫起着重要作用。对自身免疫耐受产生机制的揭示将为自身免疫病、超敏反应、移植排斥及肿瘤的治疗提供新的策略。本文对AIRE的基因鉴定、分子结构和生化功能、亚细胞定位、组织分布及其在自身耐受产生中的作用作一综述性介绍。     

TLR/MyD88信号通路与自身免疫性疾病

Toll样受体(Toll-like receptor,TLR)是近年来发现的一类模式识别受体,通过识别病原相关分子模式(pathogen-associated molecular pattern,PAMP),激活天然免疫.TLR信号还通过上调抗原提呈细胞(antigen presenting cells,APC)表面共刺激分子及APC分泌的炎症细胞因子调节获得性免疫.TLR/MyD88信号在自身免疫性疾病的发病过程中起重要作用.本文介绍了TLR/MYD88信号通路及其在自身免疫病如实验性自身免疫脑脊髓膜炎、类风湿性关节炎、实验性自身免疫性葡萄膜炎、实验性自身免疫性心肌炎和自身免疫性肾小球肾炎等发生发展中的作用.     

粘膜耐受在预防和治疗自身免疫病中的作用

粘膜应用自身抗原诱导外周免疫耐受状态 ,依赖应用抗原剂量 ,诱导产生两种粘膜耐受机制 :高剂量偏向产生T细胞克隆无能 /排除 ,低剂量偏向产生分泌抑制性细胞因子(TGF β ,IL 4,IL 10 )的T细胞克隆扩增。大量研究表明鼻内或口服应用抗原诱导粘膜耐受可有效预防几种实验性自身免疫病 (EAE ,EAMG ,EAN ,EAU ,IDDM和CIA) ,在同等剂量鼻内应用比口服诱导粘膜耐受更有效。基于动物实验结果 ,对人类自身免疫病MS、RA和葡萄膜炎的临床试验正在进行。耐受原与CTB偶联可拓宽粘膜耐受的有效性 ,加强对临床疾病的抑制。然而 ,粘膜免疫与抗原应用途径、种类和疾病发病时间有关 ,可能表现为双重作用 ,尤其在发展中的自身免疫病 ,粘膜应用抗原可能加重病情。     

Concomitant reduction of disease activity and IL-10 secreting peripheral blood mononuclear cells during immunoadsorption in patients with active systenic lupus erythematosus.

In patients with systemic lupus erythematosus (SLE) increased secretion of interleukin 10 (IL-10) by peripheral blood mononuclear cells (PBMC) is associated with overproduction of pathogenic autoantibodies. Herein we report the effect of immunoadsorption (IA) on the number of IL-10 secreting PBMC in patients with active SLE. Three courses of IA were performed in 9 patients with active SLE (SLAM 15,9+/-2,9). Each course consisted of 3 treatments on consecutive days. ELISPOT assay using IL-10 specific monoclonal antibodies was used to determine the number of IL- 10 secreting PBMC before and after each treatment. Eleven healthy, age and sex matched volunteers served as controls. Anti-ds-DNA autoantibodies were reduced to 67+/-14% after the treatment period. Before therapy patients showed significantly more spontaneously IL-10 secreting PBMC than controls (p<0.01). After the first course a significant reduction of the IL-10 secreting cells to normal levels was observed which paralleled the development of disease activity (p<0.01). Our results demonstrate a concomitant reduction of disease activity, anti-ds-DNA antibodies and the number of IL-10 secreting PBMC. The production of anti-ds-DNA antibodies and IL-10 are interdependent. Thus we conclude that IA is beneficial in SLE by depletion of these pathogenic antibodies which may lead to a reduced IL-10 secretion in vivo.     

Removal of autoantibodies by 4-mercaptoethylpyridine-based adsorbent

Extracorporeal immunoadsorption (ECI) therapy using Staphylococcal Protein A columns has proven effective for removing autoantibodies and circulating immune complexes from patients selectively, providing a promising treatment for autoimmune diseases. However, due to the drawbacks of Protein A in terms of cost and stability, the widespread use of Protein A based ECI is limited. In this study, we investigated the feasibility of 4-mercaptoethylpyridine (MEP, MW 139 Da), a simple and inexpensive synthetic compound, as an alternative to Protein A for autoantibody removal therapy. MEP-based adsorbents were prepared by coupling MEP to Sepharose CL-6B. We found that ligand density was an adjustable parameter for the synthesis of adsorbents aiming at different pathogenic factors, depending on the class of antibody. MEP-Sepharose with a ligand density of 98.8 μmol/ml could remove 80% of the anti-double-stranded DNA antibodies from human serum, whereas a ligand density of 64.5 μmol/ml was enough to remove 96% of the rheumatoid factor (RF) in the serum. Moreover, MEP-based adsorbents showed a lower degree of individual differences compared to Protein A-Sepharose. RF removal of 90% was achieved for all 12 serum samples from different individuals. Among the 14 serum samples derived from systemic lupus erythematosus patients, 11 samples had markedly reduced antinuclear antibody titers. In addition, non-specific adsorption of plasma components to MEP-Sepharose was limited, and the binding capacity of the absorbent for IgG was still about 20 mg/ml of gel after 10 cycles. The results indicated that MEP-based adsorbent could offer a new type of adsorber for the treatment of autoimmune diseases.     

On the role of IgG4 in inflammatory conditions: lessons for IgG4-related disease

The pathophysiology of immunoglobulin G4-related disease (IgG4-RD) and its most common manifestations, IgG4-associated (sclerosing) cholangitis and autoimmune pancreatitis, remains largely unknown, but IgG4 is presumably involved. IgG4 is a promiscuous antibody, which could be directly pathogenic, fulfill a protective role, or could just be a fortuitous marker of an aberrant inflammatory response. IgG4 antibodies possess exclusive structural and functional characteristics suggesting anti-inflammatory and tolerance-inducing effects. By studying the role of IgG4 in other inflammatory conditions, namely hypersensitivity and allergies, autoimmune and immune-mediated diseases, infections and malignancies, new insights can be obtained increasing our understanding of the role of IgG4 antibodies in IgG4-RD. Beekeepers, animal laboratory workers and individuals undergoing allergen immunotherapy possess high serum levels of allergen-specific IgG4, which exhibit immunosuppressive functions, protecting the individual from anaphylactic reactions. In autoimmune/immune-mediated diseases, such as pemphigus vulgaris, pemphigus foliaceus and MuSK-myasthenia gravis, IgG4 autoantibodies are pathogenic. Regarding malignancies such as melanoma and cholangiocarcinoma or helminthic infections, IgG4 antibodies inhibit clearance of tumor cells or the invader, respectively. Translating these findings to IgG4-RD, IgG4 alone can implement pathogenic effects and structural damage, but may also function as a protective antibody dampening the more harmful effects of IgG1 when directed against the same epitopes. This article is part of a Special Issue entitled: Cholangiocytes in Health and Disease edited by Jesus Banales, Marco Marzioni, Nicholas LaRusso and Peter Jansen.     

Clearance of feline leukemia virus from persistently infected pet cats treated by extracorporeal immunoadsorption is correlated with an enhanced antibody response to FeLV gp 70

Six persistently feline leukemia virus (FeLV)-infected pet cats were treated by extracorporeal immunoadsorption with Staphylococcus aureus Cowan I (SAC) to remove circulating immune complexes and immunoglobulin G (IgG) from plasma. In three of these cats, the FeLV infection was eliminated, whereas in the other three cats the infection persisted. The amounts of peripheral blood leukocyte (PBL)-associated FeLV, soluble FeLV envelope glycoprotein (gp70) antigens in serum, and FeLV-gp70-specific antibodies were determined in all six cats at different times during treatment. In all of the cats, there were fluctuations in the amounts of FeLV-positive PBL and of serum antigen related to FeLV gp70. The one serologic parameter that always correlated with complete clearance of FeLV in the responder cats was the development of free antibodies to gp70. These results suggest that extracorporeal immunoadsorption treatment stimulates an existing low level antibody response to FeLV in some cats, and that these antibodies mediate the clearance of FeLV. The results also suggest that determination of antibody titer to FeLV is of value in predicting the outcome of extracorporeal immunoadsorption treatments as well as when treatment may be terminated.     

Human and animal spongiform encephalopathies are the result of chronic autoimmune attack in the CNS: a novel medical theory supported by overwhelming experimental evidence

Spongiform encephalopathies, also called "prion diseases", are fatal degenerative diseases of the central nervous system which can occur in animals (such as the "mad cow disease" in cattle) and also in humans. This paper presents a novel medical theory concerning the pathogenic mechanisms for various human and animal spongiform encephalopathies. It is hypothesized that various forms of prion diseases are essentially autoimmune diseases, resulting from chronic autoimmune attack of the central nervous system. A key step in the pathogenic process leading towards the development of spongiform encephalopathies involves the production of specific autoimmune antibodies against the disease-causing prion protein (PrPsc) and possibly other immunogenic macromolecules present in the brain. As precisely explained in this paper, the autoimmune antibodies produced against PrPsc are responsible for the conversion of the normal cellular prion protein (PrPc) to PrPsc, for the accumulation of PrPsc in the brain and other peripheral tissues, and also for the initiation of an antibody-mediated chronic autoimmune attack of the central nervous system neurons, which would contribute to the development of characteristic pathological changes and clinical symptoms associated with spongiform encephalopathies. The validity and correctness of the proposed theory is supported by an overwhelming body of experimental observations that are scattered in the biomedical literature. In addition, the theory also offers practical new strategies for early diagnosis, treatment, and prevention of various human and animal prion diseases.     

Characterization of the expressed immunoglobulin IGHV repertoire in the New World marmoset Callithrix jacchus

The common marmoset (Callithrix jacchus jacchus) is a member of the Callithrichinae, a family of outbred New World primates with limited MHC polymorphisms and a propensity to develop spontaneous or experimentally induced autoimmunity. C. jacchus marmosets are susceptible to experimental allergic encephalomyelitis (EAE), and spontaneously develop autoimmune colitis and thyroiditis. Such disease models approximate the complexity of human autoimmune disorders, and allow an investigation of the respective roles of T-cell and antibody responses to self-antigens in outbred species. A key issue for further definition of the pathogenic antibody responses in human autoimmunity is to understand the diversity of the immunoglobulin repertoire in primate models. Here, we characterized the expressed immunoglobulin IGHV repertoire of the C. jacchus marmoset. Six IGHV subgroups were identified which show a high degree of sequence similarity to their human IGHV counterparts (IGHV1, IGHV3, IGHV4, IGHV5, IGHV6, and IGHV7). As in the expressed human IGHV repertoire, the framework regions are more conserved when compared to the complementarity-determining regions (CDRs), with the greatest degree of variability located in CDR3. Predicted structural features are highly conserved between C. jacchus and human IGHV. This information now provides a framework for studies of the antigen-specific repertoire of pathogenic antibodies in EAE and other immune-mediated diseases.     

Haplotype-specific suppression of experimental allergic encephalomyelitis with anti-IA antibodies

Treatment with monoclonal antibodies directed against the IA antigens of the MHC is known to alter the course and prevent a number of experimental autoimmune diseases. To determine whether the treatment in vivo with anti-IA antibodies is haplotype-specific, we studied the development of EAE in F1 (SJL/J X BALB/c) mice following anti-IA antibody therapy. We report that treatment of animals with monoclonal antibody directed against the high responder allele product, I-As, was successful in preventing disease when therapy was begun either at the time of immunization with antigen, or following passive transfer of MBP-sensitized T cells. Therapy with antibody directed to the low responder allele product (I-Ad), while effective when used at the time of immunization with antigen, was ineffective following passive transfer of MBP-sensitized lymphocytes.     

Peptide-based immunoadsorbents: Molecular grafting of IgG–Fc-binding epitopes of Protein A onto a de novo-designed helix-loop-helix peptide

The development of immunoadsorbents that have high specificity for immunoglobulin and no immunogenicity is essential for immunoadsorption treatment of autoimmune diseases. In this study, we designed peptide immunoadsorbents by molecular grafting of the IgG–Fc binding epitopes of Protein A onto a de novo-designed helix-loop-helix peptide. Linear (linG7A5) and cyclic (cyG7A5) grafted peptides were synthesized to test their binding affinity and specificity. Peptide cyG7A5 demonstrated high specificity for human IgG–Fc, with a K_D of 19 μM, and demonstrated no affinity to other plasma proteins, human serum albumin, or fibrinogen. To evaluate their immunoadsorbance efficiency, the grafted peptides and Protein A were conjugated to polyvinyl acetate resin and tested in a batch-wise process for adsorption removal of IgG from human plasma. The IgG capture capacities of the peptides correlated well with their binding affinities. Interestingly, cyG7A5 showed a higher binding specificity for IgG than did Protein A.