BXSB小鼠的免疫学及免疫病理学研究

几种小鼠自发性系统性红斑狼疮(SLE)模型的研究,对于探讨人类SLE的病因与发病机制有重要的参考意义。BXSB小鼠是从美国Jackson实验室引进的好发SLE的纯系鼠,其发病受Y染色体连锁的基因影响,雄鼠发病早,雌鼠发病晚。我们将     

SLE的淋巴细胞异常

系统性红斑狼疮(SLE)的淋巴细胞异常,表现为B细胞功能亢进和T细胞缺陷。但引起这些异常的原因以及哪种异常发生在先都尚未明确。本文就SLE动物模型及SLE患者的淋巴细胞异常,怎样参与发病过程加以说明。作为SLE模型动物,有NZB、(NZB×NZW)F_1,MRL/L、BXSB、SWan、M-otheaten等小鼠以及与人类SLE更近似的狗模型,这些都为SLE的研究作出了贡献。各种同系交配小鼠的临床表现和血清学所见,虽然与SLE很相似,但不同系鼠间所表现出     

系统性红斑狼疮合并动脉粥样硬化的小鼠模型建立和评价

目的动脉粥样硬化(AS)相关心血管病变是系统性红斑狼疮(SLE)患者最主要的致病和死亡因素,但是其具体机制不明。本研究旨在建立SLE合并AS的小鼠模型并进行评估,为研究SLE合并AS的机制和治疗奠定基础。方法将SLE模型(Fasl~(-/-))和动脉粥样硬化模型(apoE~(-/-))小鼠进行杂交纯化;采用PCR方法鉴定小鼠的基因型;检测小鼠血清中肾功能和血脂等生化指标;分析肾脏和心脏等病理改变。结果 PCR结果显示SLE和AS杂合小鼠为Fasl和apo E基因纯合突变;小鼠血清肌酐增高,血清中出现抗ds-DNA抗体。血清中总胆固醇、甘油三酯和低密度脂蛋白增加,高密度脂蛋白降低;小鼠肾脏出现狼疮性肾炎病理改变,心脏有明显动脉粥样斑块沉积。结论 SLE和AS模型小鼠杂合纯化的小鼠,同时表现出SLE和AS样病变,成功建立了SLE合并AS的小鼠模型,为后续研究奠定了基础。     

狼疮性肾炎发病机理的研究进展

系统性红斑狼疮 (SLE)是一种累及多脏器的自身免疫性炎症性结缔组织病 ,病因复杂 ,受遗传、免疫、神经内分泌、环境等多因素影响。狼疮性肾炎(LN)是SLE最常见而严重的临床表现 ,已成为国内外风湿病学界研究的热点 ,本文将其发病机理的研究近况作一综述。1　遗传因素小鼠狼疮性肾炎 (LN)模型的遗传分析及人类SLE家系研究表明 ,遗传因素确实促进SLE发病 ,具有复杂的多基因遗传的特点 ,LN相关的易感基因不断被揭示。 (SWR×NewZealandBlack(NZB) )F(1)(或SNF(1) )鼠有倾向发展成LN ,虽然NZB鼠狼疮的几个易感遗传位点已被证实 ,S…     

小鼠SLE模型研究概况

至今已有三种不同品系的小鼠系统性红斑狼疮(SLE)模型,它们既有类似人类SLE共同的临床及免疫病理学表现,又有各自在遗传学标志、性别和胸腺对早发病的影响、免疫细胞异常等方面的不同.这提示SLE为一种发病原因和条件有各种不同但有某些共同的临床和免疫病理学表现的综合征,不象一个独立的疾病.SLE的病因与发病机制还不完全清楚,近年来研究的兴趣转向了对这些模型的各种免疫分子的分子生物学与分子遗传学研究,取得很大进展.     

Yaa基因与狼疮性BXSB小鼠

:BXSB小鼠是系统性红斑狼疮小鼠 (SLE)模型之一。由于Y染色体上存在Yaa(Ychromosome linkedautoimmuneacceleration ,Yaa)基因能够加速自身免疫反应 ,使得雄性鼠早发病 (earlyonsetofdisease)。但是 ,Yaa基因的作用依赖于狼疮性遗传背景基因的存在 ,并由此导致B细胞和T细胞的表型或功能的变化 ,继而引起致病性自身抗体的产生 ,从而形成BXSB小鼠SLE发病的细胞学基础     

系统性红斑狼疮合并动脉粥样硬化动物模型及其发病机制研究进展

系统性红斑狼疮(SLE)合并动脉粥样硬化(AS)是影响SLE患者生存率的重要因素,其发病机制目前尚不明确.因此,建立合适的动物模型对于探索SLE合并AS的病因、发病机制及治疗均有重要意义.本文就目前常用的几种SLE合并AS的动物模型做一简要综述.     

Pristane诱导小鼠系统性红班狼疮动物模型的研究

目的:建立pristane诱导的系统性红斑狼疮(SLE)小鼠模型,并对该小鼠模型的发病机制进行初步的探讨。方法:6-8周龄雌性BALB/c小鼠单次腹腔注射pristane0.5mL,对照组单次腹腔注射PBS0.5mL,注射前及注射后每2周行流式细胞术(FCM)检测外周血中IFN-α分泌细胞(CD11b+Ly6Chigh)的比例及细胞活化状态B220+Aβ1dhigh),ELISA检测血清中自身抗体(anti-dsDNA,anti-smRNP,anti-ribosomalP0)的含量。至6个月处死动物,FCM检测腹腔细胞中IFN-α分泌细胞(CD11b+Ly6Chigh)的比例和脾脏中细胞的活化(B220,Aβ1d),采用直接免疫荧光法标记小鼠肾脏免疫球蛋白复合物及H&E染色评估小鼠肾脏免疫复合物的沉积及损伤情况。结果:小鼠腹腔注射pristane第2个月开始血清总IgG升高,第3个月起出现自身抗体阳性,到个6月时达到最高,并维持高水平至被处死;Pristane处理6个月后,Pristane处理组小鼠出现关节炎症状,肾脏免疫复合物的大量沉积和明显肾脏损伤。Pristane注射2周起,小鼠外周血中IFN-α分泌细胞(CD11b+Ly6Chigh)的比例明显高于PBS注射组,小鼠腹腔细胞中IFN-α分泌细胞的比例也明显升高;同时外周血和脾细胞中B细胞表面MHCII分子Aβ1d的平均荧光强度(MFI)均高于对照组,表明pristane处理组小鼠中B细胞发生了显著活化。结论:BALB/c小鼠腹腔注射pristane可诱导构建小鼠SLE模型,其SLE的发病可能与IFN-α的持续分泌导致B细胞的异常活化有关。该模型的建立为进一步研究SLE的发病机制提供了良好的动物模型。     

滤泡辅助T(Tfh)细胞在系统性红斑狼疮发病机制中的作用

系统性红斑狼疮(SLE)是一种慢性自身免疫性疾病,其特异性B细胞功能亢进而产生的抗核抗体似乎是发病机制的基础。因此,控制SLE患者自身抗体的异常分泌可能成为治疗SLE的关键步骤,一些可以影响B细胞分泌抗体的分子和细胞因子可作为新的治疗靶点。滤泡辅助性T(Tfh)细胞是近些年描述的辅助性T(Th)细胞新亚群。Tfh细胞是生发中心和长期血清学记忆生成所必需的,并在B细胞分化为浆细胞分泌免疫球蛋白过程中发挥关键作用。无论是在SLE小鼠模型中,还是SLE患者体内,都可以观察到Tfh细胞的异常扩增。以Tfh细胞为新的治疗靶点可能成为治疗包括SLE在内的自身免疫性疾病的重要方法。因此,我们总结了SLE动物模型以及SLE患者方面Tfh细胞与SLE之间的相关关系,并强调了Tfh细胞作为新靶点在SLE治疗上的巨大潜力。     

系统性红斑狼疮兔模型的研究进展

系统性红斑狼疮(Systemic lupus erythematosus,SLE)是自身免疫介导的、以免疫性炎症为突出表现的弥漫性结缔组织病.SLE发病机制复杂,临床上治疗效果不尽人意,使得对该病的研究成为当今热点.在过去一个多世纪中,已经建立了各种用于研究的动物模型,如鼠、猫及犬类的模型等,其中,多种品系的自发性狼疮鼠模型由于某些基因缺陷位点与人类相似,在病程中出现B细胞高反应性、产生自身抗体及免疫复合物、补体异常等免疫学表现与临床上有一定程度的相似性,使自发性狼疮鼠模型成为研究SLE发病机制及治疗的重要手段.但自发性狼疮鼠模型的发病完全由基因调控,发病率、死亡率极高,可控性差,而且由于鼠自身体积小,所提供的组织少等缺陷,远远不能满足研究的需要,而猫和犬类由于价格昂贵和饲养难度等问题不能广泛应用于研究,因此近年来逐渐尝试以家兔作为SLE动物模型,本文就SLE兔模型研究进展作一综述.     

Lupus manifestations in severe combined immunodeficient (SCID) mice and in human/mouse radiation chimeras

The objective of this study was to develop a human lupus model. To this end we have established and compared two models: (1) severe combined immunodeficient (SCID) mice reconstituted with peripheral blood lymphocytes (PBL) of either systemic lupus erythematosus (SLE) patients or healthy controls and (2) lethally irradiated BALB/c mice radioprotected with bone marrow of SCID mice, to which human PBL were transferred (human/mouse chimera). Engraftment was successful in most (78.4%) recipient mice as determined by the levels of human IgG measured. In about 50% of either SCID mice or human/mouse chimeras that were successfully engrafted with PBL of SLE patients, significant anti-dsDNA autoantibodies, mostly of the IgG1 and IgG2 isotypes, were determined. Interestingly, in a significant number (84.5%) of recipients of PBL of the healthy controls, anti-dsDNA antibodies were observed as well, suggesting that PBL of at least some of the healthy controls have the potential to develop SLE-associated autoantibodies under the appropriate stimulatory conditions. Glomerular immune deposits (human IgG, mouse C3) were detected in 70–80% of SCID mice with human DNA specific antibodies and in a third of the human/ mouse chimeras. Thus, SLE serology and glomerular pathology were reproducibly demonstrated in two models of human SLE. These models should allow the evaluation of potential therapies for the treatment of lupus patients.     

Anti-interleukin-6 monoclonal antibody inhibits autoimmune responses in a murine model of systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is an autoimmune disease resulting from dysregulation of the immune system. Interleukin-6 (IL-6) is a multifunctional cytokine produced by macrophages, monocytes and T and B cells. It stimulates B-cell differentiation/maturation, immunoglobulin secretion, and T-cell functions. Elevated levels of IL-6 in serum, urine and renal glomeruli were detected in patients with active SLE and in murine models of SLE. Our study investigated the role of IL-6 in an SLE-like disease in New Zealand Black/White (NZB/W) F1 mice by administration of an anti-murine IL-6 monoclonal antibody (mAb). Intraperitoneal administration of the anti-IL-6 mAb suppressed the production of anti-dsDNA autoantibody. B-cell proliferation induced by anti-IgM and anti-CD40 was lower in the anti-IL-6 mAb-treated mice, ex vivo studies demonstrated that anti-IL-6 mAb treatment inhibited anti-dsDNA production. Anti-CD3-induced T-cell proliferation and mixed lymphocyte reactions were inhibited by anti-IL-6 mAb treatment, indicating a partial down-regulation of T cells. Histological analysis showed that treatment with anti-IL-6 mAb prevented the development of severe kidney disease. These results suggest that treatment with anti-IL-6 mAb has a beneficial effect on autoimmunity in murine SLE and that autoreactive B cells may be the primary target for anti-IL-6 mAb treatment; its effect on autoreactive T cells is also indicated.     

IgM Antibodies Against dsDNA in SLE

IgG antibodies against dsDNA are involved in the pathogenesis of systemic lupus erythematosus (SLE) glomerulonephritis. In contrast, glomerulonephritis is rare in SLE patients with IgM antibodies against dsDNA. Therefore, a possible protective effect of IgM antibodies has been studied in more detail. In murine models of SLE, the lack of secreted IgM was associated with more severe glomerulonephritis. In more recent studies, the treatment of lupus-prone mice with a murine IgM monoclonal antibody against dsDNA prevented renal damage. Furthermore, the clearance of pathogenic immune complexes may be improved by IgM. Therefore, IgM antibodies against dsDNA are indeed protective and may be a new treatment modality of lupus nephritis in humans.     

Neuropsychiatric systemic lupus erythematosus and cognitive dysfunction: The MRL-lpr mouse strain as a model

Mouse models of autoimmunity, such as (NZB × NZW)F1, MRL/MpJ-Faslpr (MRL-lpr) and BXSB mice, spontaneously develop systemic lupus erythematosus (SLE)-like syndromes with heterogeneity and complexity that characterize human SLE. Despite their inherent limitations, such models have highly contributed to our current understanding of the pathogenesis of SLE as they provide powerful tools to approach the human disease at the genetic, cellular, molecular and environmental levels. They also allow novel treatment strategies to be evaluated in a complex integrated system, a favorable context knowing that very few murine models that adequately mimic human autoimmune diseases exist. As we move forward with more efficient medications to treat lupus patients, certain forms of the disease that requires to be better understood at the mechanistic level emerge. This is the case of neuropsychiatric (NP) events that affect 50–60% at SLE onset or within the first year after SLE diagnosis. Intense research performed at deciphering NP features in lupus mouse models has been undertaken. It is central to develop the first lead molecules aimed at specifically treating NPSLE. Here we discuss how mouse models, and most particularly MRL-lpr female mice, can be used for studying the pathogenesis of NPSLE in an animal setting, what are the NP symptoms that develop, and how they compare with human SLE, and, with a critical view, what are the neurobehavioral tests that are pertinent for evaluating the degree of altered functions and the progresses resulting from potentially active therapeutics.     

Methotrexate treatment in murine experimental systemic lupus erythematosus (SLE); clinical benefits associated with cytokine manipulation.

The objective of this study was to determine the effects of Methotrexate (MTX) on the development and the course of experimental murine SLE, as well as on the cytokine profile involved in the disease. SLE was induced in naive BALB/c female mice by injection of the human anti-DNA MoAb bearing a common idiotype (16/6 Id). Six weeks following immunization, when high levels of autoantibodies were demonstrated, the mice were treated with MTX (2 mg/kg once a week) for a period of 10 months. MTX treatment had no effect on 16/6 Id-induced autoantibody production. However, MTX treatment had beneficial effects on the clinical manifestations of the experimental disease (i.e. leucocyte counts, levels of protein in the urine and immune complex deposits in the kidneys). Thus, only 20% of 16/6 Id-immunized BALB/c mice that were treated with MTX had immune complex deposits in their kidneys compared with 100% of SLE-afflicted BALB/c mice that were not treated. We have observed a significant elevation in IL-1, tumour necrosis factor (TNF) and IL-10 secretion in BALB/c mice afflicted with experimental SLE. IL-2, IL-4, IL-6 and interferon-gamma (INF-gamma) levels were decreased in these mice compared with the levels detected in healthy controls. Treatment with MTX reversed the levels of all the above cytokines to normal levels observed in control mice. These studies demonstrate therapeutic effects of MTX on murine experimental SLE. The normal cytokine profile observed following treatment with MTX is suggested to play a role in the amelioration of the clinical manifestations of experimental SLE.     

BXSB小鼠外周B淋巴细胞异常增生的研究

系统性红斑狼疮（ＳＬＥ）突出的免疫学异常表现是Ｂ淋巴细胞的异常增生与活化，其发生机制至今不明，本文以遗传性自发性ＳＬＥ模型ＢＸＳＢ小鼠为对象，采用体内ＢｒｄＵ标记法及ＨＵ增殖细胞删除法研究了ＢＸＳＢ小鼠脾脏Ｂ细胞的增殖动力学。结果表明，与正常对照相比，ＢＸＳＢ小鼠脾脏Ｂ细胞更新速率明显增高。提示Ｂ细胞更新加速可能是ＢＸＳＢ小鼠外周Ｂ细胞异常增生的原因。     

Estrogen Modulates Bone Marrow-Derived DCs in SLE Murine Model-(NZB × NZW) F1 Female Mice

Dendritic cells (DCs) in the patient and animal models of systemic lupus erythematosus (SLE) are abnormal, but the detailed mechanism is unclear. Estrogen can modulate DCs in biological condition and estrogen consentration is related to the onset and development of SLE. So the control of estrogen on DCs might lead to the disorder of DCs. To prove the hypothesis, we detected the effects of 17β-estradiol (E2) on bone marrow (BM)-derived DCs in SLE murine model-(NZB × NZW) F1 (NZB/w F1) female mice before and after the disease onset. We found that E2 mainly enhanced the expression of surface molecule CD40, MHCII and the stimulation activity of immature DCs, but weakened the activity of mature DCs. E2 decreased the production of cytokines IL-6, IL-10, IL-12 and TNFα of DCs in young mice, but increased them in old mice. Tamoxifen could antagonize the E2 effect. E2 changed the expression of estrogen receptor-α (ERα) in DCs. The level of ERα in DCs of various old mice and the differentiation states varied. The results suggest that E2 can modulate the functions of BM-derived DCs in SLE pathology. The modulation is achieved by binding ER. The effects of E2 on DCs are different depending on the progression of SLE and cell differentiation status. This might be due to the difference of ER expression.     

Amelioration of SLE-like manifestations in (NZBxNZW)F1 mice following treatment with a peptide based on the complementarity determining region 1 of an autoantibody is associated with a down-regulation of apoptosis and of the pro-apoptotic factor JNK kinase

Treatment with peptides based on the complementarity determining regions (CDR) of murine and human monoclonal anti-DNA antibodies that bear the common idiotype, 16/6 Id, ameliorates disease manifestations of mice with either induced or spontaneous SLE. Aberrant expression and function of the p21Ras/MAP kinase pathway are associated with active SLE. Therefore, we examined the effect of treatment with a CDR1-based peptide of a human autoantibody (hCDR1) on the p21Ras pathway and SLE manifestations of SLE-prone (NZBxNZW)F1 mice. Untreated SLE-afflicted mice demonstrated increased expression of p21Ras and the phosphorylated active form of its down-stream element JNK kinase in conjunction with reduced hSOS and unchanged p120GAP, as compared to healthy controls. Amelioration of SLE manifestations following treatment with hCDR1 was associated with a diminished expression of phosphorylated JNK kinase, mainly in the T cell population that also exhibited reduced rates of apoptosis. Thus, hCDR1 therapy ameliorates SLE, at least in part, via down-regulation of the activity of the pro-apoptotic JNK kinase.     

A role for the B-cell CD74/macrophage migration inhibitory factor pathway in the immunomodulation of systemic lupus erythematosus by a therapeutic tolerogenic peptide

Systemic lupus erythematosus (SLE) is an autoimmune disease that involves dysregulation of B and T cells. A tolerogenic peptide, designated hCDR1, ameliorates disease manifestations in SLE‐afflicted mice. In the present study, the effect of treatment with hCDR1 on the CD74/macrophage migration inhibitory factor (MIF) pathway was studied. We report here that B lymphocytes from SLE‐afflicted mice express relatively elevated levels of CD74, compared with B cells from healthy mice. CD74 is a receptor found in complex with CD44, and it binds the pro‐inflammatory cytokine MIF. The latter components were also up‐regulated in B cells from the diseased mice, and treatment with hCDR1 resulted in their down‐regulation and in reduced B‐cell survival. Furthermore, up‐regulation of CD74 and CD44 expression was detected in brain hippocampi and kidneys, two target organs in SLE. Treatment with hCDR1 diminished the expression of those molecules to the levels determined for young healthy mice. These results suggest that the CD74/MIF pathway plays an important role in lupus pathology.     

The effect of the immunomodulator agent AS101 on interleukin-2 production in systemic lupus erythematosus (SLE) induced in mice by a pathogenic anti-DNA antibody.

The role of the synthetic immunomodulator AS101 on the production of interleukin-2 (IL-2) by spleen cells of mice with SLE was investigated. BALB/c female mice, in which SLE was induced by immunization with the pathogenic idiotype of anti-DNA antibody 16/6 Id were treated with AS101 for 7 weeks 2 and 4 months after induction of the disease. The ability of the splenocytes of the mice with SLE to produce IL-2 was restored after administration of AS101. This effect was particularly impressive when the 7-week AS101 treatment was initiated 4 months after immunization. Despite its beneficial effect on IL-2 production, AS101 exerted no influence on the titres of autoantibodies in the sera of the mice. It also had no effect on clinical parameters of SLE, such as the increased sedimentation rate, proteinuria and low white blood cell counts. Our data indicate that defective IL-2 production in SLE is probably secondary to other disease processes and is not necessarily associated with the production of autoantibodies in this disorder.