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 Medical Journal Reviews
医学杂志回顾
Reviewed by Prof. Richard F. Lockey, MD, WAO Web Editor-in-Chief and Guest Reviewer Gary Hellermann, PhD
1. Exhaled nitric oxide
distinguishes between subgroups of preschool children with respiratory
symptoms.
The goal of the Tucson Children's Respiratory Study is to identify the factors
that predispose nonwheezing and wheezing children
less than four yrs to develop chronic lung disease. Measurement of fractional
exhaled nitric oxide (FeNO) is suitable even for
infants and is useful in predicting exacerbations and monitoring therapy in
older children. This study of 391 children demonstrates that FeNO levels are highest in children with frequent recurrent
wheeze and a stringent index for prediction of asthma at school years. Editor's
Comment: FeNO may be useful to predict asthma
susceptibility later in life. Moeller A et al. J Allergy Clin Immunol 2008; 121:705. Bacharier LB, editorial, 710.
呼出气一氧化氮水平在有呼吸道症状的学龄前儿童的不同群体间有显著差异。
Tucson儿童呼吸道疾病研究旨在探求哪些因素促使四岁以下的儿童发生慢性肺病，无论他们有没有喘息。即使是婴儿也适合测定呼出气一氧化氮分数（FeNO），该值在较大的儿童能用于预测疾病的严重性并指导治疗。这项研究对象为391名儿童，结果显示频发哮喘的儿童其FeNO值最高，该值是预测学龄期哮喘的一个严格指标。编者点评：FeNO也许能用于预测哮喘。Moeller A et al. J Allergy Clin Immunol 2008; 121:705. Bacharier LB, editorial, 710.
Intrinsically defective skin barrier function
in children with atopic dermatitis (AD) correlates
with disease severity.
AD is a disease with multiple environmental and genetic factors. Research
implicates defects in the skin barrier layer as one cause of the pathology.
This study compares transepidermal water loss (TEWL)
in a group of African American and white children with AD, children with asthma
or allergic rhinitis but no AD, and healthy controls. Increased TEWL correlates
with a defective skin barrier and AD severity using the SCORAD index. Editor's
Comment: TEWL may be a useful biomarker for AD severity, but whether this skin
barrier defect contributes to AD remains unknown. Gupta J et al. J Allergy Clin Immunol 2008; 121:725.
特应性皮炎（AD）患儿自身皮肤屏障功能的缺损与疾病严重程度相关。
AD受多种遗传及环境因素的影响。研究显示皮肤屏障层的缺陷是该病的病理之一。本研究比较了患AD的非裔美国儿童和白种儿童、有哮喘或过敏性鼻炎但没有AD的儿童、以及健康对照这三组人群的经上皮水份丢失（TEWL）情况。结果显示TEWL与皮肤屏障的缺损及以SCORAD指数得到的AD严重性相关。编者点评：TEWL可能作为评价AD严重性的一个有用的生物指标，但是否皮肤屏障的缺损是AD的发病机制还有待解决。Gupta
J et al. J Allergy Clin Immunol 2008; 121:725.
2b.
Impaired Th17 cell differentiation in subjects with autosomal
dominant hyper-IgE syndrome (HIES).
HIES is a serious disease that impairs the immune system's ability to fight off
infections and is associated with atopic dermatitis
and abnormalities of bone and connective tissue. Mutations in the signal
transducer and activator of transcription 3 (STAT3) are present in some HIES
patients. This clinical study looks at healthy individuals, HIES patients with
STAT3 mutations and HIES patients with only some manifestations of disease. T
cells isolated from peripheral blood were sorted by flow cytometry
and analyzed for intracellular cytokines after stimulation with staphylococcal enterotoxin B. IL-17- producing T cells were found in the
blood of HIES patients without STAT3 mutations but not in those with the
mutations. This suggests a link between susceptibility to infection and the
activity of Th17 regulatory lymphocytes and between STAT3 activity and Th17
generation. Editor's Comment: The observation of HIES-like effects in those
patients with normal STAT3 means that factors in addition to Th17 exist.
Milner JD et al., Nature Letters advanced online publication 12 March 2008.
常染色体显性高IgE综合征（HIES）患者的Th17细胞分化障碍
HIES降低免疫系统防御感染的能力，与特应性皮炎和骨骼结缔组织的异常有关。某些HIES患者存在信号转导及转录3激活子（STAT3）的突变。本研究以健康人，有STAT3突变的HIES患者以及仅有部分表现的HIES患者为研究对象。从周围血分离得到的T细胞经流式细胞仪分选后，再经葡萄球菌肠毒素B刺激，分析胞内细胞因子的改变。发现无STAT3突变的HIES患者有产IL-17的T细胞，而在有该突变的患者没有发现这种T细胞。这一发现提示Th17调节T淋巴细胞的活性与机体对感染的易感性相关，而STAT3活性与Th17细胞生成相关。编者点评：具备正常STAT3的患者也有HIES的临床表现，提示除Th17细胞外还有别的因素影响HIES的发病。Milner JD et al., Nature Letters advanced online
publication 12 March 2008.
3. Treatment of patients
with hypereosinophilic syndrome (HES) with mepolizumab (M).
Proliferation of eosinophils (E) from precursor cells
requires IL-5 and targeting this cytokine may be useful in treating HES, a
disease that can result in severe organ damage. Here 85 patients with HES and
negative for F1P1L1-PDGFRA
fusion gene were given the anti-IL-5 antibody, M, or placebo in an
international, randomized, DBPC trial with the goal of reducing the amount of
prednisone (P) to 10 mg per day or less required to control their illness. M
treatment was effective in P sparing in 84% and also reduced E in 95% of the
patients. Adverse events were similar in the M and P groups. Editor's
comment: M significantly reduces P -induced side-effects in HES. Rothenberg
ME et al. New
Engl J Med 2008; 358:1215. Wechsler ME, editorial, 1293.
Mepolizumab(M)治疗高嗜酸细胞综合征患者
前体细胞分化增殖为嗜酸细胞（E）需要IL-5的刺激，拮抗该细胞因子可能用于治疗高嗜酸细胞综合征（HES）－这是一种能导致器官严重损害的疾病。在一项国际随机双盲安慰剂对照研究中，85名F1P1L1-PDGFRA融合基因阴性的HES患者接受抗IL-5抗体（M）或安慰剂治疗，研究目标是将强的松（P）减至10mg/天或更小的剂量来控制疾病。M治疗组84%的患者强的松减量，95%的患者嗜酸细胞降低。不良事件的发生率在M及P组相似。编者点评：M显著降低了HES强的松治疗的副作用。Rothenberg
ME et al. New Engl J Med 2008; 358:1215.
Wechsler ME, editorial, 1293.
4. Chronic exposure to
beta-blockers attenuates inflammation and mucin
content in a murine asthma model.
Data from the mouse model of allergic asthma show that chronic treatment
with beta blockers improves airway hyperresponsiveness
(AHR). This report examines the mechanism of the effects of chronic inhibition
of beta adrenoceptor activity in this model.
Administration of beta blockers for 28 days reduced total cell counts, eosinophils, and IL-13, IL-10, IL-5 and TGF-β1 levels
in the bronchoalveolar lavage
and attenuated epithelial mucin content and
morphologic changes. Editor's Comment: Manipulation of the beta adrenoceptor pathway for asthma treatment needs to be
reexamined. Nguyen LP et al. Am J Resp Cell Molec Biol 2008; 38:256.
长期暴露于β受体拮抗剂的大鼠哮喘模型的气道炎症和气道粘液浓度降低。
过敏性哮喘大鼠模型的研究结果显示β受体拮抗剂长期治疗可以改善气道的高反应性（AHR）。该研究探索了大鼠模型β肾上腺素受体活性被长期阻断后的效应。连续28天使用β受体拮抗剂降低了支气管肺泡盥洗液中的细胞总数，嗜酸细胞数量，以及IL-13,IL-10,IL-5及TGF-β1的水平，降低支气管上皮粘液浓度并减轻了上皮的形态改变。编者点评：有必要重新考虑干扰肾上腺素受体途径在哮喘治疗中的作用。Nguyen
LP et al. Am J Resp Cell Molec Biol 2008;
38:256.
5. Allergen induces the
migration of platelets (P) to lung tissue in allergic asthma.
There is substantial evidence that P activation is associated with increased
lung inflammation and bronchoconstriction. Ovalbumin (OVA)-allergic mice were challenged with OVA and
their lungs examined for P recruitment. Comparisons with mice lacking FcξRIγ showed platelet migration from the blood
into the lungs in response to allergen in wild-type (WT) but not in mice
deficient in IgE receptor. Platelets isolated from
human allergy patients as well as those from WT (but not FcRγ-/-)
mice also migrate in vitro toward the relevant allergen. Editor's Comment:
The role of platelets in lung inflammation needs to be elucidated along with
other inflammatory cells. Pitchford SC et al. Am J Resp Crit Care Med 2008; 177:604.
变应原诱导血小板迁移到过敏性哮喘的肺组织中。
大量证据表明血小板激活与肺炎症加重及支气管痉挛相关。卵白蛋白过敏的小鼠经卵白蛋白激发后，监测肺内血小板聚集状况。经变应原激发后，野生型小鼠的血小板从血中迁移到肺内，而有IgE受体缺陷的小鼠（即FcRI缺乏的小鼠）没有这个现象。从过敏患者及从野生型小鼠分离到的血小板在体外也向相应的变应原迁移。编者点评：需要进一步阐明血小板以及其它炎症细胞在肺炎症中所起的作用。Pitchford
SC et al. Am J Resp Crit Care Med 2008; 177:604.
6. Cetuximab(C)-induced
anaphylaxis (A) and IgE specific for
galactose-α-1,3-galactose.
C is a humanized monoclonal antibody against epidermal growth factor receptor
(EGFR) used to treat colorectal and squamous-cell
carcinoma of the head and neck. Its use is accompanied by a relatively high
incidence of A. This study shows that there were 25 hypersensitivity reactions
in 76 patients undergoing C treatment for cancer. IgE
to the sugar, galactose-α-1,3-galactose, present
on the antibody heavy chain, were found in 17 of these 25 subjects versus one
of 51 subjects without A. A occurred in some subjects
the first time they received C indicating that the offending IgE was already present. While all humans have IgG against galactose-α-1,3-galactose,
only some individuals develop the corresponding IgE. Editor's
Comment: Patients under consideration for C will most likely benefit from
screening for IgE against this oligosaccharide.
Chung CH et al. New
Engl J Med 2008; 358:1109.
Cetuximab(C)-诱导的过敏性休克（A）及半乳糖-α-1,3-半乳糖特异性IgE。
C是人抗表皮生长因子受体（EGFR）的单克隆抗体，用于治疗结直肠癌及头颈部鳞状细胞癌。此药过敏性休克发生率较高。该研究显示76位接受C治疗肿瘤的患者中有25例发生超敏反应。这25例中17例有针对糖，半乳糖-α-1,3-半乳糖的IgE，位于Cetuximab重链上；而51例没有过敏性休克的患者中只有1例有这种IgE抗体。过敏性休克发生在一些首次使用C的患者中，提示致病的IgE早已存在。然而，尽管所有人都有针对半乳糖-α-1,3-半乳糖的IgG抗体，只有某些人产生了IgE抗体。编者点评：准备用C治疗的患者在用药前筛查有无针对这一寡糖的IgE抗体是很有意义的。Chung
CH et al. New
Engl J Med 2008; 358:1109.
7. Factor analysis in the
Genetics of Asthma International Network (GAIN) family study identifies five
major quantitative asthma phenotypes.
The pathogenesis of
asthma involves a complex interplay of genetic and environmental influences,
and this report attempts to identify distinct asthma phenotypes by factor
analysis. Six countries and 11 centers form the database for the GAIN study and
from it was drawn a group of asthmatic subjects, age 7-35. They and their
symptomatic siblings were subjected to factor analysis for asthma phenotype and
five distinct factors were identified: FEV1 and FVC, allergen skin prick test (SPT), self-reported allergies, rhinitis
symptoms and asthma symptoms. Comparisons among siblings show that these
factors are consistent with shared genetic and environmental influences. Factor
scores correlate with IgE levels, methacholine
PC20, age and asthma severity and may be better for
defining asthma phenotypes than SPT or IgE alone. Editor's
Comment: While this is an important study, the fact that it is cross-sectional
rather than longitudinal is a weak point. Pillai
SG et al. Clin Exp Allergy 2008; 38:421.
哮喘遗传学国际网
(GAIN) 家族研究的因子分析结果发现五个主要的有定量作用的哮喘表型。
哮喘的发病是多种遗传因素及环境因素的复杂作用，本研究旨在通过因子分析发现哮喘的主要表型。6个国家11个中心为GAIN研究提供数据，从中抽取一组年龄在7-35岁的哮喘患者。对这些患者及其有症状的同胞进行哮喘表型的因子分析，发现五个显著因子：FEV1及FVC，过敏原皮肤点刺试验（SPT），自述过敏，鼻炎症状及哮喘症状。同胞姊妹比较后显示这些因子与他们共有的遗传及环境背景是一致的。因子积分与IgE水平，甲基胆碱PC20，以及年龄和哮喘严重程度相关，该积分可能比单纯SPT或IgE能更好的定义哮喘。编者点评：这个研究虽然很重要，但其不足在于它是一个横断面研究而不是纵向研究。Pillai SG et al. Clin Exp Allergy 2008; 38:421.
8．Factors
predicting anaphylaxis (A) to peanuts (P) and tree nuts (TN) in patients
referred to a specialist center.
Data from a group of 1094 patients with P and TN allergy compiled over 12 years
were compared in terms of whether P or TN were involved, severity of associated
disease (eczema, asthma and rhinitis), allergen-specific IgE
and SPT results, and in 122 patients, the serum level of angiotensin-converting
enzyme (ACE) and aminopeptidase P (APP). The analysis
found a higher rate of pharyngeal edema in patients with severe rhinitis and
low ACE levels. Severe bronchospasm tended to occur
in those with severe versus mild asthma and severe eczema with altered
consciousness. Editor's comment: The "allergen shock organ" and
low ACE levels help predict the clinical manifestations of A. Summers CW et
al. J Allergy Clin Immunol 2008; 121:632.
专科就诊的患者，发生花生(P)
及坚果(TN)严重过敏反应(A)的危险因素。
12年内对1094名花生及坚果过敏患者的资料进行研究。比较食入花生和坚果哪个更容易发生过敏性休克，以及过敏性休克的发生与相关疾病（湿疹，哮喘及鼻炎）的严重性、过敏原特异性IgE及SPT结果的关系；测定了其中122名患者的血清血管紧张素转换酶及氨基肽酶P（APP）。分析后发现重度鼻炎及血清ACE低的患者发生喉水肿的可能更高。重度哮喘患者比轻度哮喘患者更容易发生严重的支气管痉挛，严重湿疹患者更易出现意识改变。编者点评：“变态反应疾病休克器官“及低水平的ACE有助于预测过敏性休克的临床表型。Summers CW et al. J Allergy Clin Immunol 2008; 121:632.
9. A comparison of
inflammatory mediators released by basophils (B) of
asthmatic and control subjects in response to high-affinity IgE
receptor aggregation.
B are a small but important set of leukocytes in
allergic reactions and their effects are mediated through activation of the FcξRIs on their surface. Human B from 16 healthy and
12 asthmatic volunteers were analyzed in this study for cytokine and chemokine levels before and after binding of IgE to the receptors and correlated with histamine release
and skin prick test (SPT). Both normal and asthmatic B produced GM-CSF, MIP-5
and eotaxin. Leptin was
also produced in most samples and IL-8 in
response to IgE cross-linking. No difference in
cytokine release from B was seen in healthy versus asthmatic subjects. Editor's
Comment: The secretion of leptin by B is an
interesting finding that needs confirmation. Gilmartin
L et al. Int Arch Allergy Immunol 2008; 145:182.
哮喘患者及健康对照者的嗜硷细胞经高亲和力IgE受体聚集后炎症介质的释放情况。
嗜硷细胞在白细胞分类中虽然只占很小的比例，但在过敏反应中发挥重要的作用。它通过其表面FcRIs受体的激活而介导过敏反应。本研究比较了16名健康志愿者和12名哮喘患者的嗜硷细胞在IgE结合试验前后细胞因子及化学因子的释放情况，并且与组胺释放及皮肤点刺试验结合起来。健康对照及哮喘患者的嗜硷细胞都产生GM-CSF，MIP-5以及嗜酸细胞趋化因子。本研究还发现多数标本在IgE交联反应后产生了瘦素和Il-8。结论是健康人及哮喘患者细胞因子释放没有差异。编者点评：嗜硷细胞释放瘦素是一个很有意义的发现，但需要进一步证实。Gilmartin L et al. Int Arch Allergy Immunol 2008; 145:182.
10. Primary nasal
epithelium exposed to house dust mite (HDM) extract shows activated expression
in allergic individuals.
Epithelial cells (EC) are more than just bystanders in the establishment of an
immune response. Here EC from nasal biopsies of five allergic and five healthy
individuals were cultured with or without HDM extract and isolated RNA was used
for gene expression profiling by microarray analysis.
Results were verified by quantitative real-time PCR. HDM triggered
up-regulation of two transcription factors (NFkappaB
and AP-1) in healthy epithelium, as well as a number of chemokines,
growth factors and structural proteins. In allergic individuals, however, these
pathways were already activated and HDM did not change the expression of NFkappaB but did down-regulate AP-1. Editor's Comment:
The finding of specific differences in allergen-induced gene expression
response in allergic individuals may point the way to new diagnostic and
therapeutic tools. Vroling AB et al. Am J Resp Cell Molec Biol 2008; 38:293.
过敏患者鼻上皮暴露于户尘螨提取物后表达增加。
上皮细胞(EC)在免疫应答中不仅是旁观者。5个过敏性疾病患者及5个健康人的鼻黏膜活检标本中的上皮细胞用含尘螨及不含尘螨的培养基培养，分离到的RNA经微阵列技术进行基因表达模式的检测。检测结果经实时定量PCR验证。HDM诱发健康人鼻黏膜上皮中两种转录因子（NFkB及AP-1）以及许多化学因子，生长因子及结构蛋白的上调。然而，过敏性疾病患者的上皮细胞中已经有这些转录途径的激活，HDM的刺激不会增加NFkB的表达，但的确会下调AP-1的水平。编者点评：过敏性疾病患者经变应原诱导后基因表达的特殊变化也许能提供新的诊断和治疗方法。Vroling
AB et al. Am J Resp Cell Molec Biol 2008; 38:293。
11. Phenotypic
characterization of T lymphocytes in COPD: abnormal CD4+CD25+ regulatory
T-lymphocyte response to tobacco smoking.
Why do some smokers develop COPD and others not? That was the question posed in
this investigation of 23 patients with moderate COPD, 29 healthy smokers and
seven never-smoker volunteers. T cells were isolated from bronchoalveolar
lavage fluid (BALF) and from peripheral blood and
characterized as CD4+ or CD8+, according to the maturation (CD45RA and CD45RO),
activation CD28 markers and to explore potential Treg
abnormalities. Results show that BALF T cells from COPD patients have higher
CD8+CD45RA+ levels and lower CD8+CD45RO+ levels than smokers with normal lung
function. Compared with never-smokers, smokers with preserved lung function
showed a prominent up-regulation of Tregs absent in
COPD. T cells from peripheral blood did not show any significant differences
among the three groups of patients. Editor's Comment: The lower Treg activity in the lungs of COPD patients may be involved
in pathogenesis of the disease. Barcelo B et al. Eur
Resp J 2008; 31:555.
COPD的T淋巴细胞表型特点：吸烟导致异常的CD4+CD25+调节T淋巴细胞反应。
为什么有些吸烟的人会患COPD，而其它人不会。本研究针对这个问题，对23名中度COPD患者，29名健康吸烟者以及7名从不吸烟的志愿者进行研究。从支气管肺泡盥洗液及周围血分离到的T细胞根据其成熟标志（CD45RA及CD45RO），活化CD28标志及CD4+、CD8+表型，分析是否存在Treg的异常。结果显示比之于正常肺功能的吸烟者，COPD患者BALF 来源的T细胞CD8+CD45RA+比率更高，而CD8+CD45RO+比率更低。与从不吸烟的人相比，肺功能较好的吸烟者Tregs有明显的上调，而COPD者没有。三组人的外周血来源的T细胞没有显著差异。编者点评：COPD患者肺组织低水平的Treg与发病可能相关。Barcelo B et al. Eur Resp J 2008;
31:555.
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