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Cytokine production pattern of CD4+ T cells and its relation to anti-DNA antibody production in patients with systemic lupus erythematosus

系统性红斑狼疮患者 CD4 T 细胞的细胞因子产生模式及其与抗 DNA 抗体产生的关系

基本信息

批准号：
02454563
负责人：
SAKANE Tsuyoshi
金额：
$ 1.28万
依托单位：
St. Marianna University School of Medicine (1991)Shimane Medical University (1990)
依托单位国家：
日本
项目类别：
Grant-in-Aid for General Scientific Research (B)
财政年份：
1990
资助国家：
日本
起止时间：
1990 至 1991
项目状态：
已结题

项目摘要

The intracellular accumulation of a series of cytokines in freshly- isolated CD4+ T cells in individual patients with systemic lupus erythematosus (SLE) has been studied to determine what factors may be produced by these cells in vivo. The cytokine-producing cells were identified at a single cell level using by cytokine-specific antibodies and an indirect immunofluorescence technique with flow microfluorometry. CD4+ T cells from patients with SLE, but not normal subjects, were shown to spontaneously produce interleukin (IL)-2, IL-4, IL-6, interferon-gamma, and tumor necrosis factor-alpha. By performing two-color immunofluorescence studies, we observed a variegated production pattern with cells making no, one or several cytokines simultaneously. The results indicate that CD4+ T cells in patients with SLE may reactivated polyclonally in vivo, and thus that the expanded population of these polyclonally activated CD4+ T cells spontaneously produces several cytokines which may. cause sustai … More ned activation of immunological effector cells such as B cells. This may have important roles in both the development and maintenance of human SLE.In the course of our studies of the cytokine production pattern, we found overexpression of cell adhesion molecules such as LFA-1 and ICAM-+L on peripheral blood lymphocytes (PBL) of SLE patients. Moreover, there existed a novel CD4+ T lymphocyte subset, which expressed CD45RA and ICAM-1 simultaneously in the blood of patients with SLE. Introduction of anti-LFA-1 or anti-ICAM-1 monoclonal antibodies (mabsi into the in vitro cultures of freshly isolated SLE PBL resulted in inhibition of both the spontaneous polyclonal IgG production and spontaneous IgG anti-DNA antibody production. Thus, overexpression of LFA-1 and ICAM-1 molecules of SLE lymphocytes facilitates T-B cell communication, thereby causing them to produce excessive antibodies. This finding may be offer a possible strategy for therapeutic immune intervention by mabs.Extensive studies in the murine model of lupus nephritis have shown that cationic anti-DNA autoantibodies have nephritogenic potential. We have also investigated whether cationic anti-DNA antibodies of IgG class are also produced in vivo in patients with active lupus nephritis, and analyzed the mechanism by which such antibodies are produced. The highly cationic anti-DNA antibodies of IgG class were prominent in the isoelectric focusing-immunoblots of serum antibodies from the patients with lupus nephritis. Decreased proteinuria after successful treatment with preunisolone was associated with disappearance of the cationic anti-DNA antibodies in the circulation. Moreover, the cationic anti-DNA antibodies were produced through numerous point mutations in the genes, including substitution of neutral amino acids of germline sequences for cationic amino acids. The results indicate that these antibodies may be produced by antigen-driven manner. Less

已经研究了系统性红斑狼疮（SLE）个体患者中新鲜分离的CD 4 + T细胞中一系列细胞因子的细胞内积累，以确定这些细胞在体内可能产生哪些因子。在单细胞水平上，通过使用精氨酸特异性抗体和间接免疫荧光技术与流动显微荧光测定法来鉴定精氨酸产生细胞。来自SLE患者的CD 4 + T细胞，而不是正常受试者，显示自发产生白细胞介素（IL）-2，IL-4，IL-6，干扰素-γ和肿瘤坏死因子-α。通过进行双色免疫荧光研究，我们观察到细胞不产生、同时产生一种或几种细胞因子的杂色生产模式。结果表明，SLE患者的CD 4 + T细胞可以在体内多克隆地再活化，因此这些多克隆活化的CD 4 + T细胞的扩增群体自发地产生几种细胞因子，这些细胞因子可以在体内多克隆地活化。原因维持 ...更多信息免疫效应细胞如B细胞的诱导活化。在研究SLE患者细胞因子产生模式的过程中，我们发现SLE患者外周血淋巴细胞（PBL）上存在LFA-1和ICAM-+L等细胞粘附分子的过度表达。此外，SLE患者外周血中还存在一种新的同时表达CD 45 RA和ICAM-1的CD 4 + T淋巴细胞亚群。将抗-LFA-1或抗-ICAM-1单克隆抗体（mabsi）引入新鲜分离的SLE PBL的体外培养物中导致自发多克隆IgG产生和自发IgG抗-DNA抗体产生的抑制。因此，SLE淋巴细胞的LFA-1和ICAM-1分子的过表达促进了T-B细胞通讯，从而导致它们产生过量的抗体。这一发现可能为单克隆抗体的免疫干预治疗提供了一种可能的策略。在狼疮性肾炎小鼠模型中的广泛研究表明，阳离子抗DNA自身抗体具有致肾炎的潜力。我们还研究了活动性狼疮肾炎患者体内是否也产生IgG类阳离子抗DNA抗体，并分析了产生这种抗体的机制。狼疮性肾炎患者血清抗体的等电聚焦免疫印迹以IgG类的高阳离子抗DNA抗体为主。在成功地用Preunisolone治疗后，蛋白尿减少与循环中阳离子抗DNA抗体的消失有关。此外，阳离子抗DNA抗体是通过基因中的许多点突变产生的，包括阳离子氨基酸取代种系序列的中性氨基酸。结果表明，这些抗体可能是通过抗原驱动的方式产生的。少