狼疮肾炎患者Th1/Th2细胞因子失平衡状况的研究

目的探讨不同病理类型、不同病程狼疮肾炎(LN)患者的Th1和Th2失衡情况。方法采用酶联免疫吸附试验(ELISA)法测定16名正常人及18例LN患者外周血浆白细胞介素(IL)-18及IL-13水平,同时应用免疫组织化学检测6名正常人肾组织和18例LN患者肾组织IL-18及IL-13的表达量。结果无论在肾组织或外周血,LN患者IL-18水平及IL-13水平均较正常对照组显著上升(P均<0.001),Ⅳ型LN患者血浆IL-18/IL-13较正常对照组显著增高(P<0.05),V型LN患者较正常对照组有降低趋势,但未达统计学意义(P>0.05),而Ⅱ型LN患者其比率数值与正常对照组极其接近;在肾组织局部,不同病理类型LN患者之间IL-18/IL-13比率差异无显著性(P>0.05);血浆IL-18/IL-13比率与肾组织狼疮活动指数(AI)呈正相关(P<0.05),肾组织IL-18/IL-13比率与AI无相关关系(P>0.05)。结论LN患者免疫紊乱状态似乎不能简单的按Th1优势/Th2优势进行二分法分类,其免疫紊乱状态远较此复杂,不同活动状态,不同部位及不同病理类型的狼疮的免疫紊乱状态是不同的。     

狼疮性肾炎患者外周血Th1／Th2淋巴细胞平衡的研究

目的：通过检测狼疮性肾炎患者外周血中CD4^ 淋巴细胞分泌细胞子的情况,探讨了Th1/Th2细胞类型与狼疮性肾炎的发病关系。方法：采用流式细胞分析法对29例狼疮性肾炎患者和15名健康志愿者外周血中淋巴细胞的胞内细胞因子（INF－γ、IL-4）和表面抗原（CD4）进行分析。结果：狼疮性肾炎患者Th1细胞数和Th1/Th2比值与正常对照组比较,差异有非常显著性（P＜0．01）。活动期与缓解期Th1数和Th1/Th2比值比较,增加趋势,但差异无显著性（P＞0．05）。患者Th1和Th2细胞数与Th1/Th2比值与疾病活动指数SIEDAI、ANA和C3补体之间没有相关性（P＞0．05）。结论“狼疮性肾炎有强的Th1优势。     

Th1/Th2失衡在初发系统性红斑狼疮患者中的研究

目的：利用三荧光标记法流式细胞术检测细胞内细胞因子，从单细胞水平研究初发系统性红斑狼疮（SLE）患者Th1/Th2平衡。方法：全血培养后使用荧光标记的抗细胞表面抗原单抗标记表面抗原，抗细胞因子单抗进行细胞内染色，检测出CD4^ 干扰素（IFN）-γ^4白细胞介素（IL）-4^-及CD4^ IFN-γ^-IL-4^ 细胞作为Th1及Th2细胞，从单细胞水平研究初发SLE患者Th1/Th2平衡。结果：未用药治疗的SLE病人其Th1细胞明显低于正常对照组（P=0.02）。35例SLE患者按Th1/Th2可分成两组，Th1/Th2降低组与Th1/Th2升高组。Th1/Th2降低组其Th1细胞的降低十分明显。Th1/Th2升高组中Th1细胞仅轻度下降。Th1/Th2降低组体现了更高的颊部红斑发生率（P=0.036）。结论：Th1型反应与Th2型反应均参与了SLE的发病。不同患者可能免疫系统的异常并不同。Th1细胞的降低可能与颊部红斑发生有关。     

肺结核患者的Th1/Th2细胞因子失衡

目的　探讨肺结核患者是否存在Th1/Th2反应失衡 ,以及与病情严重程度和治疗反应的关系。方法　对 10 0名健康对照和 12 4例未经治疗的菌阳肺结核患者检测血清IgE、IL 4和IFN γ ,比较两组间差异并分析其与病情严重程度、治疗后痰菌阴转情况及初复治的关系。结果　肺结核组血清IgE(1.0 4 8± 0 .4 96 )、IL 4 (0 .4 39± 0 .16 0 )显著高于健康对照组 (分别为 0 .86 7± 0 .2 89和 0 .4 2 1±0 0 2 4 ) ,而血清IFN γ(0 .2 13± 0 .0 17)显著低于健康对照组 (0 .2 2 4± 0 .0 0 5 )。病灶范围大或有空洞形成的患者血清IL 4显著高于病灶范围小的患者 ,复治患者IL 4和IFN γ显著低于初治患者。抗结核治疗 2个月后痰菌未转阴组与痰菌阴转组相比 ,前者治疗前血清IL 4较高而IFN γ较低。结论　未经治疗的肺结核患者存在Th1反应减弱 ,Th2反应增强 ,其中病灶范围大或有空洞形成的患者更为显著。而且Th1反应较弱者治疗效果较差。     

狼疮肾炎患者血清白细胞介素-18的升高与Th1/Th2型细胞的失衡

目的测定狼疮肾炎（LN）患者血清白细胞介素-18（IL-18）的水平以及外周血单个核细胞（PBMC）内干扰素（IFN）-γ／IL-4的表达情况，探讨LN患者体内Th1/Th2型细胞的平衡情况以及IL-18与Th1/Th2型免疫反应的相关性。方法酶联免疫吸附试验（ELISA）方法检测血清IL-18的表达：佛波酯（PMA）和离子霉素联合刺激培养，流式细胞术从单个核细胞水平检测细胞内IFN-γ/IL-4的表达情况。结果LN患者血清IL-18的水平显著高于对照组（P=0．000）；Th1型（IFN—γ^＋）细胞百分率明显高于对照组（P=0．009），Th1/Th2型细胞的比率（IFN-γ／IL-4^＋）明显增高（P=0．005）；Th1/Th2型细胞比率与尿蛋白定量（24h）呈明显正相关；Th1型细胞百分率与血清IL-18的水平呈明显的正相关。结论LN患者血清IL-18水平升高，并与Th1/Th2型免疫反应失衡有关，IL-18可以促进LN患者体内Th1型免疫反应增强。从而加重蛋白尿的发展。削弱Th1型免疫反应重建Th1/Th2型免疫反应的平衡，理论上可能会阻止狼疮肾炎的发病。     

自身免疫性甲状腺疾病患者甲状腺内Th1/Th2细胞失衡研究

目的　探讨甲状腺中Th1/Th2 细胞失衡在自身免疫性甲状腺疾病 (AITD)发病中的作用。方法　选取 13例Graves病 (GD)患者、12例桥本甲状腺炎 (HT)患者 ,并以 8例非毒性结节性甲状腺肿患者作为对照进行研究。采用免疫组化染色方法检测这些患者甲状腺内单个核细胞 (ITMC)的γ 干扰素(IFN γ)和白介素 4(IL 4)细胞因子抗原表达 (分别代表Th1,Th2 分泌的细胞因子 ) ,并与外周血甲状腺刺激性抗体 (TSAb)、甲状腺球蛋白抗体 (TGAb)、甲状腺微粒体抗体 (TMAb)等免疫学指标进行相关分析。结果　 ( 1)GD、HT患者ITMC的IL 4、IFN γ阳性表达明显高于对照组 (均P <0 .0 1) ;GD患者ITMC的IL 4阳性表达明显高于IFN γ阳性表达 ;而HT患者ITMC的IFN γ阳性表达则明显高于IL 4阳性表达(均P <0 .0 5 ) ;( 2 )GD患者ITMC的IL 4阳性表达与TSAb显著正相关 (r =0 .67,P <0 .0 1) ,ITMC的IFN γ阳性表达与TSAb无相关性 ;HT患者ITMC的IFN γ阳性表达与TGAb、TMAb均呈显著正相关(分别为r =0 .65 ,r =0 .5 9,均P <0 .0 5 ) ,但ITMC的IL 4阳性表达与TGAb、TMAb均无相关性。结论　GD患者Th1/Th2 细胞平衡失衡偏向以Th2 占优势的免疫应答 ,而HT患者Th1/Th2 平衡失衡偏向以Th1占优势的免疫应答。     

Ultraviolet-A1 phototherapy modulates Th1/Th2 and Tc1/Tc2 balance in patients with systemic lupus erythematosus

OBJECTIVE: Ultraviolet-A1 (UVA1) phototherapy is effective for a variety of dermatological diseases. We examined the effectiveness and reliability of low-dose UVA1 phototherapy (60 kJ/m2/treatment) in patients suffering from systemic lupus erythematosus (SLE). We studied the changes in immunological parameters. METHODS: The patients received a 9-week course of phototherapy according to the following regimen: five times a week during the first 3 weeks, three times a week during the second 3 weeks and twice during the last 3 weeks. Among other things, we analysed the proportions of T helper 1 (Th1), Th2, T cytotoxic (Tc1) and Tc2 cell populations in the peripheral blood of patients by flow cytometric detection of intracytoplasmic interferon gamma (IFN-gamma) and interleukin 4 (IL-4). RESULTS: Our study showed the improvement of clinical symptoms determined by the subjective clinical disease activity scoring and the SLE Disease Activity Index (SLEDAI). By the end of UVA1 phototherapy, the mean value of SLEDAI had decreased from 7.2+/-5.6 to 0.9+/-1.8, which was significant (P = 0.005). Immunological investigations detected a decrease in the frequency of IFN-gamma-producing Th1 and Tc1 cells and a decrease in the Th1/Th2 and Tc1/Tc2 ratios after UVA1 therapy. CONCLUSION: According to the literature, IFN-gamma has a pathogenic role in the development of SLE. We observed a decreased proportion of IFN-gamma-secreting cells, which we think is presumably one of the beneficial effects of UVA1 therapy. On the basis of our study, UVA1 phototherapy does seem to be an effective adjuvant in the treatment of SLE patients.     

Elevated interleukin-18 and skewed Th1:Th2 immune response in lupus nephritis

There is evidence that interleukin-18 plays a role in lupus nephritis (LN). Since interleukin -18 (IL-18) promotes polarization of the immune response toward Th1, we investigated level of IL-18 and assessed the phenotypic distribution of Th1 and Th2 type cells in LN. A predominance of Th1 type (IFN-γ+) cells and significant correlations with serum IL-18 was seen in the patients with LN compared to healthy controls. Although most patients were treated with high dosage of glucocorticoid and other immunosuppressive agents, higher level of IL-18 was found in both serum and glomeruli. However, there was no paralleled upregulation of its gene expression in peripheral blood mononuclear cells. Our findings indicate that the elevated IL-18 should be a symbol of disease activity and play a major role in the pathogenesis of LN by promoting cytokine imbalance towards Th1 type immune response. We conclude that patients with LN would benefit from it while the bioactivity of this cytokine was effectively counteracted.     

系统性红斑狼疮与Th1/Th2

198 6年Ｍｏｓｍａｎｎ等[1] 首次提出鼠的辅助性Ｔ细胞 (Ｔｈ)可分为Ｔｈ1和Ｔｈ2细胞 ,1991年Ｍａｇｇｉｅ等[2 ] 发现人的Ｔｈ细胞与鼠相似 ,也可分为Ｔｈ1和Ｔｈ2两型。Ｔｈ1主要分泌干扰素 γ (ｉｎｔｅｒｆｅｒｏｎ γ ,ＩＦＮ γ)、白细胞介素 2 (ＩＬ 2 )及淋巴毒素 ,介导细胞免疫反应及迟发超敏反应 ;Ｔｈ2主要分泌ＩＬ 4、ＩＬ 5、ＩＬ 6及ＩＬ 10等 ,介导体液免疫 ,辅助抗体生成 ;少数Ｔｈ细胞称为Ｔｈ3细胞 ,它主要分泌ＴＧＦ β ,起免疫抑制作用。它们均由前体细胞 (Ｔｈ0 )分化而来。在生理条件下 ,机体的Ｔｈ1细胞和Ｔｈ2…     

慢性移植物抗宿主病狼疮小鼠模型肾组织细胞凋亡及Th1/Th2细胞因子的研究

目的研究慢性移植物抗宿主病(cGVHD)狼疮样小鼠模型。肾组织细胞凋亡及Th1／Th2细胞因子的改变方法20只B6D2F1代杂交鼠，随机分为模型组(10只)及对照组(10只)，12周后处死采用原位末端标记法(TUNEL)染包观察肾组织细胞凋亡；免疫组织化学、Western blot和反转录-聚合酶链反应(RT-PCR)技术检测Fas、FasL基因转录及蛋白表达情况。结果TUNEL法结果显示模型组肾组织细胞凋亡较对照组增多。免疫组织化学提示：各组均有Fas、FasL表达，正常对照组有极少量Fas表达．表达部位在肾小球系膜细胞；FasL表达部位在近端肾小管上皮细胞。聚合酶链反应(PCR)结果：模型组较正常对照组Fas mRNA表达增高。模型组较正常对照组FasL mRNA表达差异无显著性。正常对照组干扰素(IFN)-γ和白细胞介素(IL)-4阳性细胞极少；模型组肾组织血管周围浸润的炎性细胞中可见IFN-γ和IL-4阳性细胞，且IL-4阳性细胞明显高于IFN-γ，提示Th2细胞表达占优势。模型组比正常对照绀INFγ／和IL-4阳性细胞明显升高，RT-PCR结果显示：模型组IFN-γ与正常对照组比较差异无显著性：模型组IL-γ较正常对照组显著升高。结论cGVHD狼疮样小鼠模样小鼠模织细胞凋亡异常及Th1/Th2细胞因子失衡，在狼疮肾炎(LN)的发病中起重要作用。     

狼疮肾炎危险因素分析

目的探讨狼疮肾炎(LN)病变的危险因素。方法对79例LN患者进行回顾性分析,并与同期住院的91例无肾炎病变的SLE患者作对照。所有实验室检查均采用标准方法。结果LN患者占同期住院患者的40.3%。与无肾炎病变的SLE患者作对照,其发病年龄明显小于对照组(P<0.001),两组性别和病程方面差异无显著性(P>0.05)。实验室指标对比显示,抗dsDNA抗体、抗Sm抗体、抗心磷脂抗体(aCL)和抗中性粒细胞胞质抗体(ANCA)在LN组有较高的阳性率,与对照组相比差异有显著性(P<0.05)。结论发病年龄小,存在抗dsDNA抗体、抗Sm抗体、aCL和ANCA阳性是SLE易并发肾炎的危险因素。     

Predominance of Th1 immune response in diffuse proliferative lupus nephritis

OBJECTIVE: Lupus nephritis, which shows various histologic patterns, is a serious complication of systemic lupus erythematosus (SLE). We previously demonstrated the importance of Thl cell-mediated immune response in patients with diffuse proliferative lupus nephritis (DPLN). The aim of this study was to examine the relationship between the peripheral blood Th1/Th2 balance and the intrarenal immune response. METHODS: The Th1:Th2 ratio in peripheral blood was measured by intracellular staining for cytokines with flow cytometry. Immunohistochemical analysis of renal biopsy specimens was performed to clarify the characterization of local infiltrating cells in 3 groups of subjects: SLE patients with World Health Organization (WHO) class IV nephritis (DPLN) (group I; n = 13), SLE patients with WHO class V nephritis (group II; n = 9), and patients with minor glomerular lesions (group III; n = 7). In addition, the histologic activity index and chronicity index were evaluated and correlated with the Th1:Th2 ratio. RESULTS: Immunohistochemical studies showed higher numbers of CD68+ macrophages, CD3 + T cells, and interferon-gamma-positive cells in group I than in groups II or III. Renal tissues from patients in group I also showed up-regulation of expression of osteopontin and CD40, with a small number of infiltrating T cells expressing interleukin-4. Overall, the Thl:Th2 ratio in group I patients (SLE with DPLN) was high and correlated significantly with the histologic activity index, but not with the chronicity index. CONCLUSION: We have identified a predominance of Thl-type response in both peripheral and renal tissues of patients with DPLN, suggesting that the peripheral blood Thl:Th2 ratio directly reflects the local histopathologic findings. In patients with lupus nephritis, the peripheral blood Th1:Th2 ratio could be useful as a parameter that reflects the renal histologic activity or the strength of the local Thl response.     

狼疮肾炎并发高血压729例相关因素分析

目的探讨影响狼疮肾炎(LN)高血压发生的相关因素。方法对729例LN患者完整临床病理资料进行回顾性分析，比较LN并发高血压组与LN不伴高血压组患者临床表现、实验室检查和病理学改变等方面的差别，利用单因素及多因素分析探讨LN并发高血压的危险因素。结果本组高血压发生率为34．3％，高血压发生率随着患者年龄增加、病程延长和肾功能恶化而逐渐增加，组间差异存在统计学意义；单因素分析提示男性，年龄≥45岁，病程≥3年，高血压家族史，尿蛋白≥2．0g／d，血肌酐≥133μmol／L，高胆固醇血症，肾小管间质指数≥5，新月体指数≥2，肾小球硬化指数≥2等是LN患者并发高血压的危险因素；多因素Logistic回归分析结果显示性别、年龄、血肌酐水平、肾小球硬化程度是LN高血压发生的独立影响因素。结论高血压是LN常见并发症。发生率高，其发生与家族史、性别、病程长短、蛋白尿程度、血肌酐水平等因素有关，应及时有效地控制血压水平。     

Th1/Th2 cells in patients with multiple myeloma

Multiple myeloma (MM) is a lymphoproliferative disorder that is characterized by a proliferation of clonal B cells in various stages of maturation that then infiltrate the bone marrow. MM has been reported to accompany various T cell abnormalities including quantitative and functional defects of CD4+ and CD8+ T cells. Recently, immunotherapy such as dendritic cell therapy, vaccination therapy, and anti-tumor antibody therapy, has been attempted in patients with MM. To develop more effective immunotherapy for patients with MM, further studies are required to identify the immunological abnormalities, especially in T cells, associated with MM. The T helper 1 (Th1) and T helper 2 (Th2) cells are characterized by distinct cytokine production patterns. The Th1 cells produce interferon gamma and interleukin-2 (IL-2), and are involved in cell-mediated immunity. The Th2 cells produce IL-4 and promote humoral immunity by stimulating antibody production, particularly IgE responses. Furthermore, Th1 and Th2 cells have been found to cross-regulate each other's development. The Th1/Th2 combination has an important role in immune response to many disorders including infection, autoimmune diseases, and malignancies. In this review, we report a Th1/Th2 imbalance in cases of MM, and discuss the relationship between T cell abnormalities and the pathology of MM.     

Prognostic factors in lupus nephritis

Systemic lupus erythematosus (SLE) is a heterogeneous disorder and its renal manifestations are protean. The course and prognosis of lupus nephritis is dependent on a large number of demographic, histopathological, serological, racial, socioeconomic and time dependent factors. Moreover, the initial and maintenance therapeutic regimens may also influence the long term renal outcome. This article reviews the important prognostic factors that have been reported in literature. The management strategy of lupus nephritis should be individualized and based on a composite of these parameters.     

Imbalance of thromboxane/prostacyclin biosynthesis in patients with lupus anticoagulant

The mechanism involved in the association between antiphospholipid antibodies and thrombosis or fetal loss remains unclear. We assessed the biosynthesis of thromboxane A2 and prostacyclin in 31 samples from 25 patients with lupus anticoagulant and in 32 controls. The urinary excretion of the major thromboxane metabolite of platelet origin (11-dehydrothromboxane B2) was very significantly increased (P less than .0003) in the patients. In contrast, the urinary metabolite reflecting the vascular production of prostacyclin (2,3-dinor-6-keto-prostaglandin F1 alpha) was much less increased (P less than .02). We found no correlation between the levels of anticardiolipin antibodies and the urinary excretion of 11-dehydro-thromboxane B2. Six patients with elevated urinary 11-dehydrothromboxane B2 were treated with low-dose aspirin (20 mg/d during 7 days). In these patients, there was a close relationship between the extent of inhibition of the thromboxane urinary metabolite (72%) and serum thromboxane B2 (79%). In contrast, the urinary excretion of 2,3-dinor-6-ketoprostaglandin F1 alpha was nearly unchanged (13% reduction). In addition, the F(ab')2 fragments isolated from six patients presenting increased urinary 11-dehydro-thromboxane B2 enhanced the generation of thromboxane B2 (P = .04) and the release of 14C serotonin (P = .009) by normal washed platelets, as compared with F(ab')2 from controls. In summary, our study shows that in patients with lupus anticoagulant, platelet activation may occur without a compensatory increment in the vascular biosynthesis of prostacyclin. This observation may be crucial to cause or reflect an increased risk for thrombosis. In addition, our results may suggest a rationale for antiplatelet agents for the prophylaxis of thrombosis in many patients with the antiphospholipid syndrome.     

狼疮性肾炎患者并发感染的临床分析

目的:分析狼疮性肾炎(LN)治疗过程中感染的临床特点和流行病学特征. 方法:回顾性分析699例Ⅱ、Ⅲ、Ⅳ、Ⅴ、Ⅳ+Ⅴ及Ⅴ+Ⅲ型LN患者在治疗过程中感染的发生率、发生时期、部位及病原体种类特点.结果:(1)699例LN患者,其中男92例,女607例,平均年龄28.4±11.1岁,平均随访46月.191例(27.3％)患者共发生225例次感染,其中30例2次感染,2例3次感染.(2)225例次感染中,124例次(55.1％)发生在诱导期,发生时间2.6±1.6月;101例次(44.9％)发生在维持期,发生时间24.3±16.6月.(3)感染部位以皮肤软组织、肺、泌尿系统为主(89.3％);感染病原体以细菌最常见(54.2％),其次为病毒(39.6％)和深部真菌(4％)感染.(4)诱导期感染部位主要为皮肤软组织(50.8％)、肺(32.3％)和泌尿系统(11.3％);维持期感染部位主要为泌尿系统(35.6％)、皮肤软组织(30.7％)和肺(16.8％).(5)诱导期病毒(50.8％ vs 25.7％,P＜0.01)和真菌(6.5％vs 1％,P＜0.01)感染比例高于维持期,而细菌感染比例低于维持期(42.7％ vs 68.3％,P ＜0.01). 结论:LN并发感染的总体发生率为27.3％,感染最常发生于诱导治疗3月内,诱导期与维持期感染部位及病原体种类均存在差异.     

康艾注射液对代偿期肝硬化患者Th1/Th2及相关细胞因子的影响

目的研究康艾注射液对代偿期肝硬化患者Th1/Th2细胞及相关细胞因子的影响。方法采用流式细胞仪检测康艾注射液治疗代偿期肝硬化患者治疗前、后血清Th1、Th2细胞的变化,用ELISA法检测两组患者治疗前、后血清IFN-γ、IL-10的变化。结果两组治疗前后血清Th1、Th2细胞均明显高于健康对照组(P<0.01),Th1/Th2比值均明显低于健康对照组(P<0.01)。治疗后两组Th1、Th2细胞均较治疗前明显下降(P<0.01),Th1/Th2比值均较治疗前明显上升(P<0.01),治疗组Th1/Th2比值明显高于对照组(P<0.01)。两组患者IL-10治疗后明显下降(P<0.01),治疗组低于对照组(P<0.05);两组患者IFN-γ治疗后明显上升(P<0.01),治疗组高于对照组(P<0.01)。结论康艾注射液可以促使代偿期肝硬化患者Th1/Th2平衡向Th1优势漂移,从而促进炎症吸收,促进病情尽早康复。