B7/CD28共刺激分子参与肾脏疾病的免疫机制研究进展

机体特异性免疫应答是一个需要一系列免疫细胞和免疫分子共同参与的异常复杂的过程,这些免疫细胞及分子之间相互调节又相互制约。目前大多数肾脏疾病发病机制尚不明确。B7(CD80)位于调节CD4+和CD8+T细胞的抗原提呈细胞上,通过与细胞上的糖蛋白CD28结合发挥信号传递作用、增强或放大免疫反应的功能,或者与细胞毒性T细胞蛋白-4(cytotoxic T lymphocyte-associated antigen4 CTLA-4)结合后抑制免疫应答。通常肾组织不表达或低表达B7,然而某些肾小球疾病的发生与B7的增加有关,其降低了足细胞附着肾小球基底膜的能力,增加炎症反应及肾脏纤维化。当B7与CTLA-4相结合时,免疫反应就会被减弱。因此通过阻断CD28或增强CTLA-4信号可能阻止疾病的发生。该文就共刺激分子B7/CD28在足细胞损伤、原发性肾小球肾炎、紫癜性肾炎、狼疮性肾炎等肾脏疾病的发病机制中的作用,以及B7阻滞剂在部分肾脏疾病靶向治疗的研究进展进行综述。     

卡介苗对哮喘患儿细胞免疫调节的研究进展

卡介苗使树突细胞正调节CD40、CD80、Ⅱ类分子等表面分子的表达,并使活化的T细胞分泌γ干扰素;使辅助T细胞Th1产生增多而Th2分泌减少,诱导Th1型免疫反应,抑制Th2型免疫应答,纠正Th1/Th2的失衡;显著抑制γδT细胞活性,使γ干扰素增高,而白细胞介素-4下降;能上调CD4+ CD25+ 调节性T细胞的表面Toll样受体表达,促进其增殖,发挥其调抑功能;促使T细胞活化抑制和凋亡,发挥负向免疫调节作用;抑制GATA-3表达,减少Th2型细胞因子生成;抑制哮喘状态下巨噬细胞集落刺激因子的表达,调节气道巨噬细胞的功能,促使巨噬细胞产生的Th1类细胞因子增多,提高Th1免疫应答,纠正Th1/Th2的失衡.卡介苗可以通过多种机制干预哮喘的发病,为哮喘的治疗提供新的思路.     

静脉注射用免疫球蛋白非敏感型川崎病诊疗进展

川崎病（Kawasaki disease，KD）是儿童最常见的自身免疫性血管炎综合征。其病因及免疫发病机制未完全清楚，大量流行病学及临床观察提示KD的发病可能与感染因素所触发的急性免疫调节紊乱有关。目前仍未检测到导致KD的单一病原微生物，已报道多种细菌、病毒、支原体及其代谢产物（如链球菌和葡萄球菌所产生的超抗原）与KD发病有关。感染致免疫活性细胞（如T细胞、单核／巨噬细胞）异常活化，所产生的炎性细胞因子可能参与血管内皮损伤及干扰自身免疫耐受：如异常产生的白细胞介素-6（IL-6）可诱导P53基因表达，导致KD患儿免疫活性细胞凋亡延迟，干扰活化诱导的细胞凋亡（AICD），破坏外周自身免疫耐受。IL-6又可抑制CD4^＋CD25^＋调节性T细胞抑制功能，进一步干扰自身免疫稳定功能。IL-1β、IL-6及TNF—α等前炎症细胞因子可诱导血管内皮细胞表达细胞间黏附分子-1（ICAM-1）及血管内皮黏附分子-1（VCAM-1）等黏附分子，导致中性粒细胞、单核／巨噬细胞、T细胞黏附聚集到血管内皮，启动血管炎综合征。     

胸腺基质淋巴细胞生成素与支气管哮喘的研究进展

胸腺基质淋巴细胞生成素(TSLP)是一种来源于上皮细胞的新型细胞因子.它通过诱导CD11+树突细胞表达协同刺激分子CD40、CD80,促进树突细胞产生招募辅助T细胞2的趋化凶子--胸腺和活化调节的趋化因子和巨噬细胞来源的趋化因子,增强原始CD4+T细胞产生前炎症因子.同时.TSLP可以协同白细胞介素(IL)-1、肿瘤坏死因子增强肥大细胞释放大量辅助T细胞2细胞因子(IL-5、6、8、13.粒-巨噬细胞集落刺激因子,IL-8)的能力,从而诱发无T细胞参与的过敏反应.因此,TSLP)作为过敏反应的始动因子在哮喘发病中发挥重要作用.     

Toll样受体与肾脏疾病研究进展

Toll样受体(TLRs)是一类Ⅰ型跨膜糖蛋白模式识别受体。至今在人类已发现11种TLRs,其可识别多种细胞内外病原体相关分子模式和损伤相关分子模式。活化的TLRs可激活转录因子,调节促炎性因子表达,参与固有免疫;启动和参与特异性免疫应答。TLRs分布广泛,多数TLRs在肾脏也有表达。TLRs信号通路介导多种感染性和非感染性肾脏疾病。调控TLRs信号通路有望成为治疗肾脏疾病的新手段。     

支气管哮喘患儿B7家族共刺激分子及其受体表达的变化

目的 探讨细胞表面共刺激分子及其受体在小儿支气管哮喘(哮喘)免疫发病机制中的作用.方法选择急性发作期哮喘患儿40例及同年龄健康对照组36例,分别以IFN-γ、IFN-γ加脂多糖(LPS)、LPS、佛波脂加离子霉素或零刺激外周血单个核细胞,流式细胞术检测CD14+细胞B7-1、B7-2、B7H1、B7DC及B7H分子表达;以免疫磁珠法分离CD4+细胞,荧光定量聚合酶链式反应检测CD28、细胞毒性T细胞相关抗原4(CTLA-4)、程序性死亡分子1(PD-1)及诱导性协同刺激分子(ICOS)mRNA表达,结果以待测基因/β-actin的CT比值表示.结果1.哮喘患儿CD14+细胞表面共刺激分子B7-1[(6.68±3.97)%]、B7-2[(10.87±5.99)%]表达均明显高于健康对照组[(1.74±0.69)%、(1.58±0.75)%Pa<0.01],其受体CD28表达与健康对照组比较也显著增高 [(0.761±0.590) vs( 0.170±0.080)P<0.01],CTLA-4表达则明显低于健康对照组[(0.42±0.23)vs (3.14±2.03)P<0.01].2.与健康对照组比较,哮喘患儿CD14+细胞共刺激分子B7H1[(25.48±14.30)% vs (75.97±25.44)%P<0.01]、B7DC[(1.31±0.29)% vs(5.86±2.69)%P<0.01]、B7H[(1.39±0.37)% vs (10.46±4.69)%P<0.01]表达明显降低;B7H1及B7DC 共有受体PD-1表达显著降低[(0.18±0.05) vs (18.31±9.46)P<0.01],B7H受体ICOS则明显升高[(11.52±5.42) vs (2.53±1.85)P<0.01].结论哮喘免疫发病机制极为复杂,B7家族共刺激分子除诱导Th2细胞介导的炎性反应外,其异常表达所致的T细胞异常活化也可能参与哮喘发病.     

慢性扁桃腺炎患儿T淋巴细胞表型及功能分析

目的　探讨慢性扁桃腺炎患儿T淋巴细胞表型和功能障碍情况,为分析其病因和发病机制提供临 床和理论依据。方法　采用免疫荧光标记和流式细胞仪技术检测了27例慢性扁桃腺炎患儿和21例健康儿童外 周血T细胞亚群、B细胞及NK细胞的表面标记和T细胞活化后表面分子(CD3+/HLA DR+T和CD3+/CD25+)的 表达;同时采用ELISA方法检测了患儿和对照组血清中Th1型细胞因子IL 2和IFN γ的水平。结果　与对照组比 较,慢性扁桃腺炎患儿CD4+T细胞和CD3+/HLA DR+T活化细胞的阳性率显著降低(28.6%±4.4%vs25.4% ±4.5%,P<0.05;5.7%±1.9%vs3.9%±1.6%,P<0.01),CD4+/CD8+比值降低(1.17±0.30vs0.92± 0.18,P<0.01);但患儿CD3+T细胞、CD8+T细胞和CD3+/CD25+阳性的T细胞与对照组比较差异均无显著意 义。患儿CD19+B细胞阳性率、与Th1细胞功能有关的IL 2和IFN γ表达水平也较对照组显著降低(P<0.05或 P<0.05);而两组CD3 /CD(16+56)+NK细胞的阳性率无显著差异。结论　慢性扁桃腺炎患儿存在CD4+T细 胞减少,T细胞活化障碍,Th1细胞功能异常及B细胞减少,这可能是患儿反复感染和病程迁延的主要原因之一。     

补体在儿童免疫和/或炎症性肾脏疾病中的新认识

补体系统是人体固有免疫不可或缺的成分,除参与机体防御反应和维持内环境稳定外,补体系统还和多种肾脏疾病的发生、发展相关。近期研究证实组织与免疫细胞来源的补体均可介导局部组织的炎症反应。补体系统不仅是连接固有免疫和获得性免疫的桥梁,也是介导组织损伤的致病性体液和细胞免疫的桥梁。越来越多的证据表明,补体系统功能缺陷或异常活化在肾脏自身免疫疾病、缺血再灌注损伤、移植排斥反应及透析相关疾病中均起着炎性介导作用。针对这一系列肾脏免疫和/或炎症性疾病,补体作用的靶向性药物可能会改善其疗效及预后,提高患者生活质量。     

FOXP3+CD4+CD25+调节性T细胞及其在重症肌无力中的研究进展

CD4+ CD25+调节性T细胞(CD4+ CD25+Tr)是具有免疫调节作用的T细胞,其主要功能是抑制自身反应性T细胞的活化和增殖,参与自身免疫调节,维持自身免疫耐受,在重症肌无力等自身免疫疾病中发挥重要作用.叉头状转录因子(FOXP3)是Fox家族重要成员之一,特异性表达于CD4+ CD25+Tr,在CD4+ CD25+ Tr的发育和功能维持方面起关键作用.重症肌无力患者中FOXP3的表达明显减少,FOXP3可能与重症肌无力的发病密切相关,因此FOXP3的研究可能为重症肌无力的治疗开辟新途径.     

间充质干细胞促进肾脏缺血再灌注损伤修复机制的研究进展

临床前研究证实,外源性间充质干细胞（MSCs）能够改善肾脏缺血再灌注损伤的肾损害和促进肾脏修复。本文着重讨论MSCs促进肾脏缺血再灌注损伤修复机制。MSCs向缺血后肾脏靶向归巢与MSCs表达CXCR4和CD44等趋化因子受体有关。MSCs直接分化为肾小管上皮细胞并非MSCs促进肾脏修复的主要机制。更主要的是,MSCs将通过旁分泌机制,分泌一系列的细胞因子和释放微泡,发挥激活肾内细胞、促进血管生成、抑制氧化应激、抗凋亡、抗炎和抗纤维化等效应,从而促进肾脏缺血再灌注损伤修复。     

Expression and Role of CD166 in the Chronic Kidney Disease

Background:

CD166, an adhesion molecule of the immunoglobulin superfamily, is one of the crucial effectors that traffic lymphocytes into tissues. Till now, the expression and role of CD166 in the chronic kidney disease remains unknown.

Objectives:

In the present study, we are to examine the expression of CD166 in the chronic kidney disease, and to explore its function with CD4+ T cells.

Materials and Methods:

CD166 expression was tested by Flow Cytometry (FACS) in the primary macrophages stimulated with LPS. In vivo, the expression of CD166 and CD4 were examined in the kidney tissues of adriamycin-induced nephropathy (AN) mice by immnohistochemistry. Macrophages and lymphocytes were co-cultured, the interaction between CD166 and CD4 was tested by immunofluorescent staining. Furthermore, the effects of CD166 on the activation and proliferation of T cells were explored.

Results:

In this study, CD166 expression was found to be upregulated on activated macrophages and glomerular endothelia in the adriamycin-induced nephropathy (AN) mice and CD4+ T cells were increased with CD166 expression in the AN mice. The interaction between macrophages and CD4+ T cells indicated that CD166 played a key role in the recruitment of lymphocytes in the chronic kidney disease, and neither proliferation nor activation of T cells was affected by CD166.

Conclusions:

CD166 expressed on macrophages and endothelia in AN kidney, and the function was related to the recruitment of CD4+ T cells into inflamed kidney, indicating that CD166 may be a potential target for reducing the inflammatory infiltrates in the chronic kidney disease.     

TOLL样受体与重症感染后急性肺损伤

Toll样受体(TLR) 是一类先天性跨膜受体,是病原体相关分子模式的重要识别受体.TLR通过识别病原微生物体,在炎症反应初期经由两条信号传导通路,激活免疫细胞内核因子-κB等转录因子,释放炎性介质,增强宿主防御能力,TLR过度表达导致失控性炎症反应,造成组织损伤.在急性肺损伤(ALI)及急性呼吸窘迫综合征(ARDS)的发病机制中,TLR对炎症反应的启动及介导免疫调控方面有不可忽视的作用,其中尤以TLR2和TLR4最为重要.与TLR相关的免疫调控,有望成为临床治疗ALI/ARDS的重要靶点.     

Expression of chemokine receptor CX3CR1 in infants with respiratory syncytial virus bronchiolitis

Respiratory syncytial virus (RSV) glycoprotein G mimics fractalkine, a CX₃C chemokine, which mediates chemotaxis of leukocytes expressing its receptor, CX₃CR1. The aim of this study was to examine the relationship between RSV infection and expression of perforin and IFN- γ in CX₃CR1-expressing peripheral blood CD8⁺ T cells. Samples were collected from infants with RSV bronchiolitis, both in the acute and convalescence phase (n = 12), and from their age- and sex-matched healthy controls (n = 15). Perforin expression and IFN- γ secretion in CX₃CR1⁺ CD8⁺ T cells were assessed by four-color flow cytometry. The NF- κ B p50 and p65 subunit levels were also determined as markers of RSV-induced inflammation. Study results showed perforin and CX₃CR1 expression to be significantly lower in the convalescent phase of infected infants than in healthy controls. There was no significant difference in IFN- γ secretion and NF- κ B binding activity between two time-points in RSV-infected infants, or when compared with healthy controls. Infants with prolonged wheezing had lower acute-phase CX₃CR1 levels in peripheral blood. These data indicate existence of an event persisting after acute RSV infection that is able to modulate effector functions of cytotoxic T cells, and also link disease severity with CX₃CR1 expression.     

Downregulation of CD5 and dysregulated CD8+ T‐cell activation

CD5 is a cell surface molecule that is expressed on most circulating T cells and a small population of B cells, and is involved in modulation of antigen‐specific receptor‐mediated activation. Downregulation of CD5 on CD8⁺ T cells is a poorly understood but increasingly recognized phenomenon that may be associated with dysregulated T‐cell activation. An increased subpopulation of activated CD8⁺ T cells with downregulation of CD5 has recently been described in patients with Epstein–Barr virus‐associated hemophagocytic lymphohistiocytosis (HLH) and familial HLH caused by perforin deficiency and Munc 13‐4 deficiency. These cells were detectable only in the acute phase of HLH, in which patients exhibited hypercytokinemia, and declined progressively after successful treatment in parallel with improvement of systemic inflammation. It is unknown whether CD8⁺ T cells from HLH with other causes have similar profiles. Assessment of CD5 expression on T cells has the potential to assist in the understanding of the diagnosis and pathogenesis of human inflammatory diseases such as HLH.     

循环内皮细胞和内皮祖细胞与儿童原发性高血压关系的研究进展

近年来,儿童原发性高血压患病率增加迅速.高血压可造成靶器官损害,其中包括心、脑、肾等重要脏器.血管损伤是高血压靶器官损害的核心问题,其机制涉及到肾素-血管紧张素-醛固酮系统的激活、氧化应激反应、血管慢性炎症及内皮细胞功能障碍等.血管内皮细胞损伤可引起血管内皮功能障碍,其本质是内皮损伤和修复之间动态平衡的破坏,是心血管疾病发生发展的始动环节.循环内皮细胞和内皮祖细胞被认为是血管损伤、重塑以及内皮功能障碍的非侵入性标志物.该文通过总结相关文献,阐述原发性高血压患儿血管损伤与内皮细胞损伤之间的关系,深化对儿童原发性高血压的发病机制的认识.     

脓毒症免疫功能紊乱及免疫调节治疗

文章扼述脓毒症免疫功能紊乱机制。病原微生物(配体)通过Toll样受体(TLR)等模式识别受体(PRR)启动固有免疫反应,所产生的炎症细胞因子导致促炎反应并触发适应性免疫,诱导初始T细胞分为Th1、Th2细胞、CD4+CD25+Foxp3+调节性细胞(Treg)及Th17细胞,介导免疫抑制和炎症反应。脓毒症促炎/抗炎反应同时异常活化,导致免疫功能紊乱。免疫调节治疗脓毒症的思路是既能清除内、外源性配体抑制PRR持续活化,又不过度抑制抗感染免疫反应。     

A prospective randomized,controlled trial of eculizumab to prevent ischemia‐reperfusion injury in pediatric kidney transplantation

Ischemia‐reperfusion injury has multiple effects on a transplanted allograft, including delayed or impaired graft function, compromised long‐term survival, and an association with an increased incidence of rejection. Eculizumab, a monoclonal antibody blocking terminal complement activation, has been postulated to be an effective agent in the prevention or amelioration of IRI. We performed a single‐center prospective, randomized controlled trial involving 57 pediatric kidney transplant recipients between 2012 and 2016. The immunosuppressive protocol included two doses of alemtuzumab; half of the patients were randomized to receive a single dose of eculizumab prior to transplantation. Maintenance immunosuppression was based on a combination of low‐dose tacrolimus and mycophenolate, without steroids. Eculizumab‐treated patients had a significantly better early graft function, less arteriolar hyalinosis and chronic glomerulopathy on a protocol biopsies taken on day 30, 1 year, and 3 years after transplantation. In the eculizumab group, four non‐vaccinated children lost their grafts during the course of a flu‐like infection. Eculizumab is associated with better early graft function and improved graft morphology; however, there was an unacceptably high number of early graft losses among the eculizumab‐treated children. While a promising strategy, the best approach to complement inhibition remains to be established.