Hodgkin Disease and the Role of the Immune System

Hodgkin disease (HD) is a malignancy of primarily B lymphocytes that has the unique ability to cause immunodeficiency, as well as provide immune evasion mechanisms to avoid self-destruction. In this review, the authors discuss Hodgkin disease, its association with Epstein-Barr virus (EBV), the immune deficiency caused by HD, and tumor immune evasion mechanisms. Specifically, the authors closely evaluate the roles of regulatory T cells in HD, cytotoxic T cells, cytokine and chemokine secretion, down-regulation of Fas ligand, and indoleamine 2,3-dioxygenase (IDO) secretion.     

Hodgkin disease and the role of the immune system

Hodgkin disease (HD) is a malignancy of primarily B lymphocytes that has the unique ability to cause immunodeficiency, as well as provide immune evasion mechanisms to avoid self-destruction. In this review, the authors discuss Hodgkin disease, its association with Epstein-Barr virus (EBV), the immune deficiency caused by HD, and tumor immune evasion mechanisms. Specifically, the authors closely evaluate the roles of regulatory T cells in HD, cytotoxic T cells, cytokine and chemokine secretion, down-regulation of Fas ligand, and indoleamine 2,3-dioxygenase (IDO) secretion.     

吲哚胺2,3-双加氧酶在哮喘小鼠模型中的作用

目的 探讨吲哚胺2,3-双加氧酶(IDO)在哮喘小鼠模型中所起的作用.方法 卵白蛋白(OVA)致敏、激发诱导哮喘小鼠模型.分别检测肺组织中IDO在蛋白水平和mRNA水平上的表达.免疫荧光组织化学方法检测树突状细胞(DCs)在肺组织中的分布和成熟状态.结果 ①OVA诱导和激发的小鼠哮喘模型的症状和肺部炎症病理改变较对照组严重;哮喘组小鼠血清总IgE为(165.50 ± 30.13)ng/ml,对照组为(94.45 ± 28.30)ng/ml,差异有统计学意义(P ＜ 0.05).②哮喘组小鼠肺部IDO的表达低于对照组.以平均累积光密度为指标检测的小鼠肺组织中IDO在蛋白水平上的表达,哮喘组为11.38 ± 6.05,对照组为23.62 ± 8.92,差异有统计学意义(P ＜ 0.05);实时荧光定量PCR检测小鼠肺组织中IDO在mRNA水平上的表达,哮喘组是对照组的33%,显著低于对照组(P ＜ 0.05).③小鼠肺组织中CD11c+CD86+细胞主要分布于肺泡壁和小血管周围.以双标阳性细胞平均累积荧光强度为指标检测小鼠肺组织中CD11c+CD86+细胞数量,哮喘组的中位数为9 961.86(7 406.52 ～ 12 724.98),对照组为15 974.60(10 006.39 ～ 16 171.46),差异有统计学意义(P ＜ 0.05).结论 哮喘小鼠肺组织表达IDO低,且成熟树突状细胞减少.提示在哮喘小鼠中,由于成熟的树突状细胞较少,产生IDO偏少,这可能在哮喘发生中起着重要作用.

Abstract：

Objective To investigate the role of indoleamine 2,3-dioxygenase(IDO)in asthma.Methods The mouse asthma model was induced by ovalbumin(OVA).IDO expression was detected on the level of protein and mRNA respectively.Distribution and maturation of dendritic cells were detected by the immunofluorescence method.Results (1)The symptoms and lung inflammation in the model group were more serious than control group.The serum total IgE was significantly higher in the model group than that in the control group,165.50 ± 30.13 ng/ml vs.94.45 ± 28.30 ng/ml(P ＜ 0.05).(2)IDO expression in the model group was lower than that in control group.On the level of protein,mean intergrated optical density was 11.38 ± 6.05 in the model group vs.23.62 ± 8.92 in the control group(P ＜ 0.05);on the level of mRNA,IDO expression of the model group was 33% of the control group(P ＜ 0.05).(3)CD11c+CD86+ cells were distributed in alveolar wall and around small vessels.The quantity of CD11c+CD86+ cells in lungs of the model group were significantly smaller than that in the control group.The median intergrated fluorescence intensity was 9961.86(range,7 406.52 ～ 12 724.98)in the model group vs.15974.60(range,10 006.39 ～ 16 171.46)in the control group(P ＜ 0.05).Conclusions IDO expression is low and matured dendritic cells are less in situ in the asthma model.These suggest that less matured DCs may produce less IDO,which may play an important role in asthma.     

布地奈德对哮喘大鼠支气管-肺组织病理及肺部TSLP表达的影响

目的：胸腺基质淋巴细胞生成素（thymic stromal lymphopoietin,TSLP）是启动树突状细胞介导的过敏反应的重要物质。本研究旨在观察布地奈德对哮喘大鼠肺部TSLP表达的影响及对支气管-肺组织病理的影响。方法：采用卵清蛋白(OVA)腹腔注射2次致敏及雾化吸入4周激发建立哮喘大鼠模型,并在激发第22天将动物随机分为布地奈德组（每天吸入布地奈德0.32 mg/kg,共7 d）、哮喘组（每天吸入等量生理盐水,共 7 d）。荧光免疫组化法、Western blot法分别检测激发后第29天、36天肺TSLP水平,并作支气管 肺组织病理检查。结果：布地奈德组第29天肺部炎症较哮喘组轻,停药7 d后肺部炎症明显加重,杯状细胞增多。激发后第29天、36天肺组织TSLP表达均低于哮喘组（P<0.05）。结论：布地奈德能抑制TSLP表达,减轻哮喘大鼠肺部炎症细胞浸润,但停药后肺部炎症再次加重。［中国当代儿科杂志,2010,12（10）：816-819］     

Das Th1/Th2-Paradigma bei allergischen Asthma bronchiale

The incidence of allergic asthma, which is characterized by chronic airway inflammation and airway hyperreactivity, has increased dramatically in the last two decades and is present in as many as 10% of individuals in industrialized nations. Allergic asthma is caused by an inappropriate immune response to common aero-allergens in genetically predisposed individuals. The central role in this immune response is played by CD4⁺ T helper(Th)2 cells. Through the release of cytokines like interleukin (IL)-4, IL-13, and IL-5, Th2 cells orchestrate the recruitment and activation of mast cells, eosinophils and basophils and induce the production of IgE by B cells. While Th2 cells promote airway inflammation in asthma, interferon (IFN)-γ producing Th1 cells are proposed to protect against allergic disease by dampening the activity of Th2 effector cells. Accordingly, new therapeutic strategies aim at inhibition of Th2 cells and promotion of Th1 cells. Recent studies demonstrated that Th1 cells are not always able to inhibit Th2 cell-mediated disease and can even be unexpectedly harmful. These studies indicate that the Th1/Th2 paradigm is more complex than initially appreciated and that suppression of allergic inflammation and Th2 activity may depend – at least in part – on cells other than Th1 lymphocytes.     

Regulation of CD31 expression and interleukin-4 production by human cord blood CD4+ T cells with interleukin-4 and interleukin-7

BACKGROUND: T helper 2 cell type cytokines, such as interleukin (IL)-4 and IL-5, play pivotal roles in the development of allergic diseases. However, the mechanism by which naive CD4+ T cells acquire the ability to produce these cytokines remains unclear. Recently, it was reported that IL-7 induces the ability to produce IL-4 as well as interferon (IFN)-gamma and IL-5 in naive CD4+ T cells without TCR stimulation. To further analyze the mechanism of acquiring IL-4-producing ability by naive CD4+ T cells, the effects of IL-7 on human cord blood CD4+ T cells were compared with those of IL-4, which induced the ability to produce IFN-gamma but not IL-4. RESULTS: Interleukin-7 preserved the population of CD4+CD31- T cells in cord blood and induced their IL-4-producing ability without T cell receptor (TCR) stimulation, while IL-4 induced CD31 on CD31- T cells and could not induce their IL-4-producing ability. Both the CD31-inducing effect and the inhibitory priming effect for IL-4-production by IL-4 were also observed after cord blood CD4+ T cells had been primed with IL-7 and acquired the IL-4-producing ability. CONCLUSIONS: Interleukin-7 induced the IL-4-producing ability in naive CD4+CD31- T cells without TCR stimulation, suggesting that the signal transduction via CD31 may have an inhibitory effect on the acquisition of the IL-4-producing ability by cord blood CD4+ T cells in the absence of TCR stimulation.     

New concepts of cytokines in asthma: Is the Th2/Th1 paradigm out the window?

Although asthma is clearly associated with a systemic propensity for allergic T helper type 2 (Th2) cell cytokine responses, independent local immune events appear to be responsible for the development of allergic airways inflammation. There is growing interest in how local immune networks interact with resident airway cell populations such as epithelial cells, which are now also recognized as key producers of cytokines, chemokines and growth factors. As well as their recognized role in airway remodelling, epithelial cells are now thought to have a role in initiating events. This review examines the role of cytokines produced by these and other cells in the development of asthma. It also highlights emerging concepts that the excessive and inappropriate immune responses seen in allergic disease may be related to dysfunction of various interleukin-10 producing regulatory cell populations.     

尘螨变应性哮喘患儿外周血T淋巴细胞中协同刺激分子和细胞因子的异常表达及其意义

目的分析变应原刺激前后变应性哮喘患儿外周血T淋巴细胞表面协同刺激分子及胞内细胞因子表达的变化,探讨CD28家族不同协同刺激信号在变应性哮喘免疫病理机制中的作用。方法选取尘螨变应性哮喘患儿(哮喘组)和健康儿童(健康对照组)各30例,密度梯度离心法分离其外周血单个核细胞,应用免疫荧光标记和流式细胞术检测尘螨刺激前后体外培养的CD4+T淋巴细胞表面协同刺激分子CD28、可诱导共刺激分子(ICOS)和细胞毒T淋巴细胞相关抗原4(CTLA-4)的表达,运用细胞内染色技术检测CD4+T淋巴细胞内细胞因子γ干扰素(IFN-γ)、IL-4和IL-13的表达。并运用统计学方法比较哮喘组和健康对照组之间的差异。结果哮喘组患儿外周血CD4+T淋巴细胞表面CD28和ICOS的表达与健康对照组比较差异均无统计学意义(Pa>0.05),而CTLA-4的表达显著降低(P<0.01);细胞内IFN-γ表达水平显著升高(P<0.000 1),而IL-4和IL-13表达水平无明显变化(Pa>0.05)。经尘螨刺激后,体外培养的哮喘患儿外周血CD4+T淋巴细胞表面ICOS的表达较健康对照组儿童显著上调(P<0.000 1),CD28和CTLA-4的表达则无明显变化(Pa>0.05);细胞内细胞因子IL-4和IL-13的表达显著上调(Pa<0.000 1),而IFN-γ的表达则无明显差异(P>0.05)。结论变应性哮喘患儿外周血存在组成性的CTLA-4的表达下调和细胞因子IFN-γ的表达上调,介导Th1型细胞的异常活化;而变应原尘螨的刺激又介导了ICOS依赖的Th2型细胞的分化,导致Th1/Th2失衡。     

肾脏缺血再灌注损伤的免疫学机制研究进展

固有免疫和适应性免疫参与肾脏缺血再灌注损伤(ischemia-reperfusion injury,IRI).在IRI急性期,肾血管内皮细胞黏附分子表达和血管通透性增加;肾小管上皮细胞补体C3沉积和Toll样受体2、4表达增加;树突状细胞早期活化导致中性粒细胞、巨噬细胞、自然杀伤细胞、CD4+T细胞和B细胞等迁移到缺血后肾脏.可溶性免疫分子(如补体活化产物、细胞因子和趋化因子)参与肾脏IRI急性损伤和(或)修复.Foxp3+调节性T细胞和旁路活化的巨噬细胞参与肾脏IRI修复;而B细胞限制IRI修复.     

Quantitative analysis of T and B cell subsets in healthy and sick premature infants.

This work proposes a serial quantitative analysis of the numbers and percentages of B and T cell subsets in 104 consecutive premature infants (PI) between birth and six months of age as compared with 21 normal term infants. First, in order to ascertain the effects of perinatal distress at birth (respiratory distress, neonatal asphyxia) on certain parameters of the immune system, the PI were divided into two groups. One comprised 36 healthy preterms, the other, 68 preterms with perinatal distress. It was then shown that healthy PI differed from full-term infants by their higher absolute numbers of T cells (CD2-positive) and helper T cell subset (CD4-positive). These increases in CD2- and CD4-positive cells correlated with gestational age (GA). An increase in B lymphocytes (CD20-positive cells) was also documented but no correlation with GA could be seen. Secondly, perinatal distress was found to be concomitant with transient decrease in percentages and absolute numbers of CD2- and CD4-positive cells, particularly in PI of less than 28 weeks of gestation. The B cells (CD20- and CD21-positive cells) were not different in absolute numbers. Respiratory distress had a more discernable effect than fetal asphyxia on the immune system. Finally, no immunological parameters tested could at any time predict the occurrence of infection in PI during the first 6 months of life.     

2007 E. Mead Johnson award: scientific pursuit of the allergy problem

My research has focused on elucidating the allergy problem over the past two decades. The primary approach has been to uncover critical mechanisms of allergic inflammation, with particular focus on eosinophils, a hallmark cellular constituent of allergic responses. Molecular processes that bridge T helper cell type 2 (TH2) immunity with eosinophilia and key checkpoints for regulating eosinophilia have been uncovered. Notably, interleukin (IL)-5 (derived from TH2 cells) has been identified as the chief hematopoietin responsible for eosinophil expansion in the circulation. Pathways for selective eosinophil mobilization from the blood stream to the tissue have been uncovered by defining the role of the eotaxin subfamily of chemokines in eosinophil chemoattraction and activation. Finally, TH2 cell derived IL-4 and IL-13 have been defined as chief inducers of the eotaxins, and upstream orchestrators of eosinophilic inflammation. These translational studies have formulated novel therapeutic strategies (currently being tested) for a variety of eosinophilic conditions, with particular attention on hypereosinophilic syndromes and eosinophil-associated gastrointestinal disorders such as eosinophilic esophagitis.     

1 alpha,25(OH)2D3 inhibits not only Th1 but also Th2 differentiation in human cord blood T cells

Human naive CD4+ T helper (Th) and CD8+ cytotoxic (Tc) T cells, which only produce IL-2, may differentiate into Th1/Tc1- or Th2/Tc2-like lymphocytes, characterized by their cytokine production profile. 1 alpha,25-dihydroxyvitamin D3 (1 alpha, 25(OH)2D3) has been reported to inhibit Th1/Tc1-related, but increase Th2/Tc2-associated cytokines in T cells from adults. In industrialized countries, vitamin D supplementation for prevention of rickets is initiated within the first days of life and continued throughout the entire first year. Epidemiologic studies suggest an association of vitamin D exposure in newborns with the incidence of allergic diseases in later life. This study addresses the effects of 1 alpha, 25(OH)2D3 on Th1/Tc1 versus Th2/Tc2 differentiation in long term cell cultures of (naive) cord blood T lymphocytes. Our results show that in CD4+ as well as CD8+ cord blood cells, 1 alpha, 25(OH)2D3 inhibits not only IL-12-generated IFN-gamma production, but also suppresses IL-4 and IL-13 expression induced by IL-4. Thus, in cord blood 1 alpha, 25(OH)2D3 induces a T cell population without predominance of Th2 related cytokines.     

胸腺基质淋巴细胞生成素在呼吸道感染中的作用

胸腺基质淋巴细胞生成素(TSLP)是一个上皮细胞来源的细胞因子,对树突状细胞的极化和Th2细胞因子的产生有极其重要的影响.在T细胞受体活化和Th2细胞因子产生过程中,TSLP也直接促进T细胞增殖.研究发现,TSLP对呼吸道感染和非特异性炎症过程有广泛的免疫调节作用.     

胸腺基质淋巴细胞生成素在呼吸道感染中的作用

胸腺基质淋巴细胞生成素(TSLP)是一个上皮细胞来源的细胞因子,对树突状细胞的极化和Th2细胞因子的产生有极其重要的影响.在T细胞受体活化和Th2细胞因子产生过程中,TSLP也直接促进T细胞增殖.研究发现,TSLP对呼吸道感染和非特异性炎症过程有广泛的免疫调节作用.     

Comparison of T cell functional changes during childhood with the ontogeny of CDw29 and CD45RA expression on CD4+ T cells.

The ontogeny of the peripheral blood mononuclear cells' responsiveness to various activators during childhood was studied and compared to the expression of CDw29 and CD45RA molecules at the surface of CD4+ T cells. The results show that newborn peripheral blood mononuclear cells are characterized by a responsiveness to mitogens that is higher than that observed in adults, at least shortly after stimulation. This contrasts with a clear decreased response to CD2 and CD3 MAb at any time after stimulation. These functional characteristics correlate with a low density of CDw29 antigen on virtually all CD4+ T cells and a high density of CD45RA antigen on most CD4+ T cells at birth. These patterns of reactivity and phenotype are similar to those found among naive adult T cells. When ageing, the response to mitogens becomes rapidly similar to the adult's values, whereas the responses to CD2 or CD3 MAb are more gradually acquired. This slow rate of functional changes grossly parallels the increase of CDw29+ CD4+ and the decrease of CD45RA+ CD4+ T cell subsets. These changes finally lead to the immunophenotypic and functional characteristics that are typical of adult memory T cells. These results suggest that iterative antigenic stimulations both induce memory T cells and create the conditions to improve the overall immune competence.     

CTLA-4 expression in T cells of patients with atopic dermatitis

Cytotoxic T lymphocyte-associated antigen-4 (CTLA-4; CD152) is a surface molecule of activated T cells with sequence homologous to CD28, and may act as a negative regulator of T-cell activation. In murine animal models, cross-linkage of CTLA-4 molecules on the cell surface results in decreased T-cell proliferation, accompanied by increased interleukin (IL)-2 production and apoptosis. To clarify the activation of peripheral blood T cells, we studied the CTLA-4 expression in 32 patients with atopic dermatitis who visited our institution, and 19 normal children who visited for pre-operative laboratory examination were used as normal controls. Whole blood was obtained from all subjects and stained with anti-CD3, anti-CD4, anti-CD8 monoclonal antibodies (mAb). After erythrocyte lysis with lysing solution, the cells were stained with anti-CTLA-4 mAb, and stained cells were analysed by fluorescence-activated cell sorter (FACScan) flow cytometer. Intracellular expression of CTLA-4 was significantly upregulated in peripheral blood CD3+ T cells (36.8%), CD4+ T cells (21.7%) and CD8+ T cells (18.7%) of patients with atopic dermatitis, compared with normal control (18.3%, 9.7%, 9.8%; respectively). Furthermore, CTLA-4-positive CD3+ T cells in patients with severe atopic dermatitis were significantly higher compared with milder group (42.8% vs. 32.2%). However, no significant difference was obtained in CD4+ and CD8+ T cells. Mean percentage of T cells expressing CTLA-4 in patients with atopic dermatitis was higher than the control group. These observations suggest the possibility that the disease activity can be correlated with the CTLA-4 level.     

卡介苗接种对新生BALB/c小鼠脾树突状细胞表型和功能的影响

目的 探讨卡介苗(BCG)接种对新生BALB/c小鼠脾树突状细胞(DC)的作用,以明确BCG影响小鼠T细胞亚群分化发育的机制.方法 BCG分别经腹腔、皮下接种新生鼠,经腹腔接种成年BALB/c小鼠.接种后4周:流式细胞仪检测脾DC表型;脾细胞体外用LPS或BCG再刺激培养后ELISA检测上清液细胞因子水平.结果 (1)新生BALB/c小鼠腹腔接种BCG后,脾CD11C+CD8α-DC百分比较对照组低[(45.00±14.14)% vs(67.00±8.27)%,P＜0.01],相应的CD11C+CD8α+DC则较高;成年BALB/c小鼠腹腔接种BCG后,脾CD11C+CDSα-DC百分比较对照组高[(70.00±5.21)% vs(57.00±6.22)%,P＜0.01],CD11C+CD8α+DC则较低;同为腹腔接种BCG,成年BALB/c小鼠脾CD11C+CDSα-DC百分比高于新生鼠,CD11C+CD8α+DC则低于新生鼠(P＜0.01).(2)新生BALB/c小鼠腹腔接种BCG后,脾DC表面共刺激分子表达较对照组高(P＜0.05);成年BALB/c小鼠腹腔接种BCG后,脾DC表达CD40、MHC-Ⅱ类分子较对照组高,CD86表达为低(P＜0.05);新生鼠和成年BALB/c小鼠腹腔接种BCG后,脾DC表面共刺激分子表达差异无明显统计学意义.(3)新生BALB/c小鼠腹腔接种BCG后,脾细胞在体外受到LPS/BCG再次刺激后,较对照组IL-12p70[(68.49±7.78)pg/ml vs(58.64±8.03) pg/ml,P＜0.05]或IL-10[(346.28,280)pg/ml vs(221.90,180) pg/ml,P＜0.05]的分泌较高,IL-6无明显改变.结论 BCG接种可通过改变新生BALB/c小鼠脾DC表型和细胞因子分泌诱导脾Th1/Tr1反应;BCG接种对成年BALB/c小鼠脾DC的影响作用与新生鼠有所不同.     

CD4+CD25(high) Treg cells in peripheral blood during remission and exacerbation of allergic asthma in children

Aim: To determine the percentage of CD4⁺CD25^high Treg cells in peripheral blood CD4⁺ T cells of allergic asthmatic children during disease remission and exacerbation. Methods: Peripheral blood mononuclear cells (PBMC) and serum samples were collected from 6‐ to 11‐year‐old children with mild‐to‐moderate allergic asthma (n = 34) and from healthy controls (n = 15). CD4⁺CD25^high T cells in PBMC were detected by flow cytometry. Total and specific IgE in serum were analysed by enzyme‐amplified chemiluminescence, and IL‐2 was measured by ELISA. Results: There was no significant difference in CD4⁺CD25^high T‐cell proportions between asthmatic children in exacerbation and remission as compared with controls. CD4⁺CD25^high T‐cell percentages were not correlated with total and specific IgE. IL‐2 was elevated in both disease remission and exacerbation but did not correlate significantly with CD4⁺CD25^high T‐cell percentages. Conclusion: CD4⁺CD25^high T‐cell proportion in the peripheral blood of total CD4⁺ T cells is not reduced in children with allergic IgE‐mediated asthma and does not differ between disease remission and exacerbation.     

Sarcoid Reaction in Primary Neuroblastoma: Case Report

We present a unique case of a 9-month-old infant with a left adrenal neuroblastoma with sarcoid reaction, detected by mass screening. There was no clinical evidence indicating systemic sarcoidosis or pulmonary mycobacterial infection. Histological examination of the resected adrenal tumor revealed many noncaseating epithelioid granulomas with lymphocytic infiltrate, composed of epithelioid cells and few giant cells, arising in tumor parenchyma and fibrovascular stroma. Most of the lymphocytes in the granulomas were CD3- or CD45RO-positive T cells, with fewer being CD20-positive B cells. The lymphocytes in the epithelioid granulomas expressed CD4 or CD8, but not CD56 and CD57. CD4-positive cells were observed more within the granulomas (internal area) than in the surrounding area (external area) of the same granulomas, while most of the CD8-positive cells were seen consistently at the outer margin of the granulomas (marginal zone). CD45RA-positive T cells were observed predominantly in the external area. The results of immunostaining demonstrated that lymphocytes in granulomas of this case showed the same distribution pattern as that seen in systemic sarcoidosis. Although the sarcoid reaction is a phenomenon known to be associated with the region of cancer, granuloma within the primary neuroblastoma is extremely rare. The sarcoid reaction in the present case of neuroblastoma may be associated with a delayed-type hypersensitivity reaction, and its significance and relevance still remain obscure. Received September 9, 1998; accepted October 21, 1999.