Analysis of tumor necrosis factor-α production and polymorphisms of the tumor necrosis factor-α gene in individuals with a history of Kawasaki disease

BACKGROUND: Tumor necrosis factor (TNF)-alpha plays a central role in the pathogenesis of vasculitis in Kawasaki disease (KD). To address the genetic background of KD, we investigated the level of TNF-alpha production and genetic polymorphisms in the 5' flanking region of the TNF-alpha gene in healthy children with a history of KD. METHODS: For TNF-alpha production, peripheral blood mononuclear cells (PBMC) of children with a history of KD (n = 61) and of non-KD children (n = 35) were stimulated with phorbol 12-myristate 13-acetate, toxic shock syndrome toxin-1 (TSST-1) and the culture supernatant of Staphylococcus aureus derived from a KD patient (S-6), which had several superantigenic activities. The genetic background of KD was addressed by studying polymorphisms in the 5' flanking region of the TNF-alpha gene at positions -1031 (thymine (T) to cytosine (C) change, termed -1031C), -863 (C to adenine (A), -863A), -857 (C to T, -857T), -308 (guanine (G) to A, -308A) and -238 (G to A, -238A) in KD, using dot-blot hybridization with sequence-specific oligonucleotide probes. RESULTS: The PBMC of KD patients with coronary artery lesions produced slightly higher levels of TNF-alpha in response to the bacterial products (such as TSST-1 and S-6). None of the polymorphisms in the 5' flanking region of the TNF-alpha gene were related to KD. CONCLUSIONS: These results suggest that a genetic disposition towards overproduction of TNF-alpha in response to bacterial products may be involved in the pathogenesis of KD.     

Gene Polymorphisms of TNF-α<Superscript>−308</Superscript>, IL-10<Superscript>−1082</Superscript>, IL-6<Superscript>−174</Superscript>, and IL-1Ra<Superscript>VNTR</Superscript> Related to Susceptibility and Severity of Rheumatic Heart Disease

Rheumatic heart disease (RHD) is an inflammatory disease of the heart tissues caused by interactive immune, genetic, and environmental factors. The objective of this study is to test for the association of polymorphisms related to cytokine genes with susceptibility and severity of RHD among affected children from the Nile Delta region of Egypt. The study included 50 children with chronic RHD (29 males and 21 females), with a mean age of 12.2 years, in addition to 98 healthy unrelated controls. Cases were further classified on the basis of echocardiographic findings into those with only mitral valve disease (MVD) or multivalvular lesions (MVLs) and also as mild, moderate, or severe valve lesions. For all cases and controls, DNA was extracted and amplified using polymerase chain reaction with sequence-specific primers for detection of single nucleotide polymorphisms (SNPs) in the promoter regions of cytokine genes tumor necrosis factor (TNF)-alpha(-308 )G/A, interleukin (IL)-10(-1082 )G/A, and IL-6(-174 )G/C as well as a variable number of tandem repeats (VNTRs) in intron 2 of the IL-1Ra gene. All cases showed a significantly higher frequency of homozygous genotypes of TNF-alpha(-308 )A/A [odds ratio (OR) = 5.7, p < 0.001], IL-10(-1082) A/A (OR = 3.1, p < 0.05), IL-10(-1082) G/G (OR = 5.2, p < 0.05), and IL-1Ra A1/A1 (OR = 2.2, p < 0.05). Cases with MVD showed higher frequencies of genotypes TNF-alpha(-308 )A/A, G/G; IL-10(-1082) G/G; and IL-1Ra(VNTR) A1/A1 (p < 0.05). Cases with MVL showed a significantly higher frequency of homozygous A/A genotype of both TNF-alpha(-308 )(OR = 10.6, p < 0.05) and IL-10(-1082) (OR = 5.2, p < 0.05). The same was observed for cases with severe valve lesions. On the other hand, all studied groups showed significantly lower frequency of heterozygous genotypes of TNF-alpha(-308 )G/A, IL-10(-1082) G/A, and IL-1Ra(VNTR) A1/A2. No significant difference was found regarding the frequency of IL-6(-174 )G/C polymorphisms in total cases or subgroups compared to controls (p > 0.05). Predisposition to RHD is influenced by genetic factors including cytokine gene polymorphisms, with possible susceptibility to severe disease with multivalvular affection among cases with composite polymorphism (TNF-alpha(-308 )A/A and IL-10(-1082) A/A) and (TNF-alpha(-308 )A/A and IL-10(-1082) G/G).     

肿瘤坏死因子α和白细胞介素10 基因启动子区多态性与川崎病的相关性研究

目的探讨肿瘤坏死因子α(TNF-ɑ)和白细胞介素10(IL-10)基因启动子区多态性与中国汉族儿童川崎病的易感性和临床表型的关系.方法应用聚合酶链反应-限制性内切酶片段长度多态性分析(PCR-RFLP)方法检测TNF-ɑ和IL-10基因启动子区4个多态性位点,对96例川崎病患儿及160例正常对照儿童进行相关性分析.结果 (1)中国汉族健康儿童TNF-ɑ基因-308(A/G)位点等位基因频率与日本人和美国白人正常人群相近;而IL-10基因-1082(G/A)、-819(C/T)、-592(A/C)3个位点等位基因频率与英国正常人群差异有显著性(P均<0.01);(2)TNF-ɑ基因-308位点等位基因频率在川崎病组和健康对照组间差异无显著性;IL-10 -1082、-819、-592的3个位点等位基因频率和单体型在两组之间比较差异亦无显著性;(3)临床表型分析发现,TNF-α-308 A基因型在静脉注射免疫球蛋白(IVIG)非敏感型川崎病患者中的发生频率高于TNF-α-308 G基因型,比较差异有显著性(67% vs 5%,χc2=90.48,P<0.01),前者发生静脉注射用IVIG非敏感型川崎病的相对危险度(RR)是后者的42.25倍(RR 95% CI=15.81～112.88,P<0.01).IL-10-1082A/-819T/-592A单体型在川崎病合并冠状动脉损伤患者中的发生频率高于Non-ATA单体型, 比较差异有显著性 (52%vs 20%,χ2=18.36, P<0.01), IL-10基因启动子区ATA单体型合并冠状动脉损伤的RR是Non-ATA单体型的4.26倍(RR 95% CI=2.20～8.25,P<0.01).结论 TNF-α、IL-10基因启动子区多态性可能是影响川崎病疗效和预后的重要因素.     

Interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha) levels and IL-6, TNF-polymorphisms in children with thrombosis

Infection has an important role in the pathogenesis of thrombosis and it becomes more prominent in childhood cases, in whom the infection frequency is higher. It has been suggested that patients with high tumor necrosis factor (TNF)-alpha and interleukin (IL)-6 levels might be at increased risk of developing thrombotic complications owing to the effects of these cytokines on the coagulation pathway. Functional polymorphisms in the promoter regions of the genes coding for TNF-alpha and IL-6 are associated with increased plasma levels of these cytokines. The aims of this study were to evaluate the serum levels of acute phase reactants, such as C-reactive protein, and of cytokines (TNF-alpha and IL-6) and to investigate the association between the TNF-alpha-308 G/A and IL-6-174 G/C polymorphisms in Turkish pediatric patients with thrombosis. Fifty-eight children with thrombosis (group 1) and 89 controls (group 2) were included in the study. Patients who had a history of infection within the 15 days before thrombosis were classified as group 1a and those who had no infection history before thrombosis were classified as group 1b. Serum TNF-alpha did not differ significantly between the groups. However, the IL-6 level was higher in group 1a than in group 1b (P<0.05). The genotype distribution and allele frequencies of TNF-alpha G/A polymorphism were significantly higher in the thrombotic children without infection and in the control group than in the thrombotic children with an infection history (P<0.05). The IL-6-174 C/C genotype was significantly higher in thrombotic children with an infection history (P<0.05); there were no differences between the groups in mean allele frequency (Table 2). On the basis of our results, patients with a history of infection seem to have higher C-reactive protein and IL-6 levels and IL-6-174 C/C genotype. Furthermore, venous thrombosis is more frequent in this group than arterial thrombosis (P<0.05).     

Polymorphisms in the TNF-alpha promoter and variability in the granulomatous response in patients with Crohn's disease

Granulomas may be found in 30-70% of patients with Crohn's disease (CD). The etiology of granuloma formation in CD is presently unknown. Elevated levels of TNF-alpha are found within granuloma tissue, and are required to maintain granuloma formation in animal models. TNF-alpha production has been shown to influenced by TNF-alpha promoter polymorphisms. We hypothesized that heterogeneity for granulomas in CD might be influenced by the TNF-alpha promoter genotype. Patients with confirmed CD that had undergone full colonoscopy with multiple biopsies and/or surgical resection, served as the study group. One hundred healthy individuals served as a control population for genotyping. Patients and controls underwent genotyping for four TNF-alpha polymorphisms: 238G/A, 308 G/A,857 C/T, and 863 C/A. Inclusion and exclusion criteria were met in 155 patients (1-68 y). Polymorphisms in the TNF promoter were found in 16.6% (238G/A), 14.5% (308 G/A), 36.6% (857 C/T) and 30.7% (863G/A). No significant association was found for any of the individual polymorphisms with presence or absence of granulomas. In conclusion, we did not find an association between individual polymorphisms in the TNF-alpha promoter and presence of granulomas in CD. The reason for heterogeneity in granuloma formation in patients with CD remains elusive.     

Interleukin-6 -174 and -572 genotypes and the volume of deep gray matter in preterm infants

Preterm infants have smaller cerebral and cerebellar volumes at term compared with term born infants. Perinatal factors leading to the reduction in volumes are not well known. IL-6 -174 and -572 genotypes partly regulate individual immunologic responses and have also been connected with deviant neurologic development in preterm infants. Our hypothesis was that IL-6 -174 and -572 genetic polymorphisms are associated with brain lesions and regional brain volumes in very low birth weight or in very preterm infants. DNA was genotyped for IL-6 -174 and -572 polymorphisms (GG/GC/CC). Study infants (n = 175) were categorized into three groups according to the most pathologic brain finding in ultrasound examinations until term. The brain MRI performed at term was analyzed for regional brain volumes. Analyzed IL-6 genotypes did not show statistically significant association with structural brain lesions. However, IL-6 -174 CC and -572 GG genotypes associated with reduced volume of one brain region, the combined volume of basal ganglia and thalami, both in univariate and in multivariate analyses (p = 0.009, 0.009, respectively). The association of IL-6 -174 and -572 genetic polymorphisms with smaller volumes in deep gray matter provides us new ways to understand the processes leading to neurologic impairments in preterm infants.     

Interleukin (IL)-18 polymorphism 133C/G is associated with severe respiratory syncytial virus infection

BACKGROUND: Respiratory syncytial virus (RSV) is a major cause of bronchiolitis in infants. During the course of RSV infection, predominant T helper cell (TH) 2 response is associated with disease progression, whereas predominant TH1 reaction provides convalescence. Interleukin (IL)-18 plays an important role in adjusting the TH1/TH2 immune response to viral infections. Thus, we tested the hypothesis that polymorphisms in IL-18 were associated with severe RSV-associated diseases. METHODS: We chose to study the promotor polymorphisms -607A/C (rs1946518) and -137G/C (rs187238), the 2 exon polymorphisms 113T/G (rs360718) and 127C/T (rs360717), and 2 intron polymorphisms 5304A/G (rs795467) and 133G/C (rs360721) within the IL-18 gene. Genotyping was performed on 154 children with severe RSV infection as defined by strict clinical criteria and on 270 controls. Statistical analyses of single polymorphisms made use of the Armitage's trend test, haplotypes were calculated with FASTEHPLUS and FAMHAP. RESULTS: -133G/C showed association with severe RSV infection (P = 0.043). The association was further supported by haplotype analyses with all 6 polymorphisms (P < 0.00001 for association with RSV). CONCLUSIONS: This study indicates possible involvement of IL-18 in the determination of severe RSV-associated diseases. Defining the genetic basis of RSV bronchiolitis might help us in identifying new drug targets for a more specific therapy. In addition, it might enable an early identification of children at risk for RSV bronchiolitis and thus make a selective prevention feasible.     

IL-4IL-5及IgE在儿童咳嗽变异性哮喘中的价值

目的：咳嗽变异性哮喘(CVA)是一种与气道炎症相关的疾病,有研究表明IL-4,IL-5与IgE的产生有相关性,而且与哮喘的形成有关,因此推测IL-4,IL-5在CVA发病中起重要作用。该文旨在观察IL-4,IL-5及IgE在咳嗽变异性哮喘中的诊断价值。方法：用酶联免疫吸附实验(ELISA法)检测咳嗽变异性哮喘患儿、哮喘急性发作期患儿、正常同龄儿童各30例外周血单个核细胞(PBMC)内IL-4,IL-5及血清IgE水平。结果：①咳嗽变异性哮喘患儿发作期PBMCIL-4为91.57±12.19ng/L、IL-5为13.28±0.31ng/mL,显著高于缓解期的74.68±11.54ng/L,6.53±0.28ng/mL及正常对照组70.32±18.16ng/L,5.29±0.36ng/mL,(均P<0.01),但缓解期及正常对照组间差异无统计学意义;②咳嗽变异性哮喘发作期患儿血清IgE水平为279.6±41.3KU/L,显著高于缓解期153.8±37.5KU/L,两组均显著高于正常对照组的90.6±44.8KU/L,(均P<0.01);③咳嗽变异性哮喘患儿发作期IL-4,IL-5及IgE水平与哮喘患儿发作期的92.21±3.12ng/L,15.11±1.37ng/mL,287.5±41.9KU/L之间相比差异无统计学意义。结论：联合检测单个核细胞内IL-4,IL-5及血清IgE水平对咳嗽变异性哮喘的诊断有重要价值;IL-4,IL-5可能在咳嗽变异性哮喘的发病机制中起重要作用;咳嗽变异性哮喘可能存在与哮喘相同的发病机制,是典型哮喘的前驱表现。     

TNF-alpha and IL-10 gene polymorphisms versus cardioimmunological responses in sudden infant death

We hypothesized that genetic variations of cytokines could contribute to the risk of developing a fatal immunological reaction in the heart of infants. Thus, tumor necrosis factor (TNF)-alpha and interleukin (IL)-10 gene polymorphisms versus induction of cardioimmunologxical responses in victims of sudden infant death syndrome (SIDS) were explored. We genotyped 35 infants (23 cases of SIDS and 12 infants with a known cause of death), and 100 healthy adult controls for IL-10 -1082 G/A, -592 C/A and TNF-alpha-238 G/A, -308 G/A. We found a higher frequency of the ATA haplotype and ATA/ATA genotype of IL-10 associated with SIDS (13%). The frequency of homozygote infants for IL-10 haplotypes in SIDS was higher (52%) than the control group (34%). All SIDS cases were homozygotice for the TNF-alpha-238 G allele and 20 infants were homozygous for the TNF-alpha-308 G allele in the same group. None of the infants with higher levels of infiltrated T-cells (n=8) was homozygous for IL-10 gene polymorphisms, whereas in contrast 3 cases of the 6 that displayed higher levels of cardiac mast cells were homozygous. In this study, the increased number of interstitial T-cells, mast cells, and macrophages in the myocardial interstitium demonstrated no correlation with the genotype for either cytokines.     

TNF-α-308G/A和IL-6-174G/C基因多态性与呼吸道合胞病毒毛细支气管炎的相关性

目的：探讨肿瘤坏死因子(TNF)-α-308G/A、白细胞介素(IL)-6-174G/C基因多态性与呼吸道合胞病毒((RSV) 毛细支气管炎易感性的关系。方法：应用聚合酶链反应 限制性酶切片段长度多态性技术（PCR-RFLP）检测150例RSV毛细支气管炎患儿(病例组)和120例正常对照儿童(对照组)TNF-α-308G/A和IL-6-174G/C的基因多态性。结果：①病例组TNF-α-308位点GG、GA、AA基因型频率分别为68.0%、28.0%、4.0%,G、A等位基因型频率分别为82.0%,18.0%;对照组TNF-α-308位点GG,GA,AA基因型频率分别为80.8%,19.2%,0,G、A等位基因型频率分别为90.4%,9.6%;两组基因型及等位基因频率差异有显著性意义,病例组A等位基因的频率明显高于对照组(χ2=5.665,7.726,均P＜0.05);与G等位基因携带者相比,A等位基因携带者患RSV毛细支气管炎的风险增加了2.071倍(OR=2.071, P＜0.05);②病例组和对照组IL-6-174G/C位点均只见GG基因型。结论：TNF-α-308A等位基因与RSV毛细支气管炎的易感性相关,其可能是影响RSV毛细支气管炎发病的一个重要候选基因;温州地区汉族儿童未发现IL-6-174G/C基因多态性。［中国当代儿科杂志,2009,11（10）：821-824］     

Evaluation of interleukin-6, tumour necrosis factor-α and interleukin-1β for early diagnosis of neonatal sepsis

The objective of this study was to assess the contribution of interleukin-6 (IL-6), tumour necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) to an early diagnosis of early-onset neonatal sepsis. A cohort of 117 newborn infants delivered during a 1-y period had IL-6, TNF-alpha and IL-1beta, blood and cerebrospinal fluid (CSF) cultures, leucocyte and platelet count collected on the initial evaluation of possible early-onset sepsis. They were divided into four groups: I, positive blood and/or CSF cultures; II, probably infected with clinical sepsis but negative cultures; III, same as group II but mother received antibiotic antepartum; and IV, newborn infants that did not receive any antibiotic therapy. There were no differences among the four groups with respect to mean gestational ages and birthweights, median Apgar scores, type of delivery, or number of newborn infants with leucocyte count <5000 mm(-3) or >25000 mm(-3), platelet count <100000 mm(-3), immature/total neutrophil ratio >0.2, absolute neutrophil count <1000mm(-3) and median IL-1beta levels. Median IL-6 and TNF-alpha levels were significantly higher in groups with patients with a diagnosis of clinical sepsis than in controls. The optimal cut-off point was 32 pg ml(-1) for IL-6 and 12 pg ml(-1) for TNF-alpha. The combination of both provided a sensitivity of 98.5%. In conclusion, the combination of IL-6 and TNF-alpha is a highly sensitive marker of sepsis in the immediate postnatal period.     

TNF-alpha, TNF-beta, IL-6, IL-10, PECAM-1 and the MPO inflammatory gene polymorphisms in osteosarcoma

The inflammatory microenvironment of tumors is characterized by the presence of cytokines and growth factor's network both in the supporting stroma and in tumor areas. These molecules may contribute to tumoral growth and progression, facilitating metastatic process. Therefore, cancer susceptibility and severity may be associated with the functional polymorphisms of inflammatory genes. We hypothesized that inflammatory gene polymorphisms may have important role for osteosarcoma patients. We studied -308G>A TNF-alpha, +252A>G TNF-beta, -174G>C IL-6, -1082A>G IL-10, +125C>G PECAM-1, and the -463A>G MPO inflammatory gene polymorphisms in 80 osteosarcoma patients and 160 control individuals using polymerase chain reaction-restriction-fragment length polymorphism method. We found that the patients with variant genotype (GG) of the +252A>G TNF-beta gene showed an event-free survival rate of 20% at 100 months. We suggest that the presence of the variant genotype (GG) of the +252A>G TNF-beta polymorphism, which leads to higher level of cytokine production, could be a facilitator mechanism in tumor progression leading to a poor event-free survival.     

Influence of cytokine and intercellular adhesion molecule-1 gene polymorphisms on acute rejection in pediatric renal transplantation

Immune response regulation by cytokines is a key to understanding AGR. The influence of the functional polymorphisms in genes coding for TNF-alpha (-308G > A), IL-10 (-819C > T, and -1082A > G), IFN-gamma [(CA)n], TGF-beta1 (+869T > C), and iCAM-1 (R241G and E469K), in addition to HLA and gender matching on the presentation of AGR in 51 pediatric renal recipients during a 36-month post-transplantation follow-up were analyzed. Also, donors and a control group were genotyped. All groups were within Hardy-Weinberg equilibrium for all polymorphisms except IL-10-819C > T and TNF-alpha (p < 0.005 and p < 0.01, respectively) in recipients. Transplants with gender mismatch showed a higher risk for AGR than those between individuals with gender match (OR, 4.227; p = 0.010). Recipients with a high-production compared with low-production TNF-alpha allele experienced earlier AGR (p = 0.030), and those with high-production alleles of both TNF-alpha and IFN-gamma showed a further increased risk (OR = 11.129, p = 0.024). These findings support the notion that a single genotype cannot by itself explain an event as complex as AGR. The sum or combination of different specific alleles of these genes could better account for the immune response to an allograft.     

The effects of NOS1 gene on asthma and total IgE levels in Taiwanese children,and the interactions with environmental factors

Wang T‐N, Tseng H‐I, Kao C‐C, Chu Y‐T, Chen W‐Y, Wu P‐F, Lee C‐H, Ko Y‐C. The effects of NOS1 gene on asthma and total IgE levels in Taiwanese children, and the interactions with environmental factors.
Pediatr Allergy Immunol 2010: 21: 1064–1071.
© 2010 John Wiley & Sons A/S Asthma is a complex disorder, which is known to be affected by interactions between genetic and environmental factors. The aim of this study was to investigate the three microsatellite polymorphisms of GT repeats in intron 2, AAT repeats in intron 20, and CA repeats in exon 29 of the NOS1 gene in 155 asthmatic children and 301 control children, and the interaction with environmental factors in southern Taiwan. Total serum IgE, phadiatop test and genetic polymorphisms were measured. The genotype frequency of 14/14‐AAT repeats of the NOS1 gene was significantly higher in the asthmatic group (p = 0.01). Total IgE concentrations were higher in asthmatic children (p = 0.015) carrying the NOS1 14/14‐AAT genotype than in subjects with other polymorphisms. The gene and environmental interaction effects were 3.83‐fold, 6.86‐fold, and 8.04‐fold (all corrected p‐values <0.001) between subjects carrying at least one NOS1 14‐AAT allele and exposure to cockroaches, high levels of total IgE, and positive response against the phadiatop test in asthmatic children. The findings of this study provide strong evidence that NOS1 gene with 14‐AAT tandem repeats has a significant effect in asthmatic children. Environmental factors and atopic status will enhance the asthmatic risk for children who carry NOS1 susceptible allele.     

Gene polymorphisms of IL-6<Superscript>−174</Superscript> G/C and IL-1Ra VNTR in asthmatic children

Objective  To check for the association of genetic polymorphisms of IL-6-⁻¹⁷⁴G/C and IL-1RaVNTR with the susceptibility and severity of asthma in Egyptian children. Methods  Subjects included 69 asthmatic children and 98 healthy unrelated controls from the Nile Delta of Egypt. Cases consisted of 20 males and 49 females with an age mean± SD is 7.5 ± 2.1 ranging between 2-13 years. DNA amplification using PCR with sequence-specific primers was done for detection of promotor single nucleotide polymorphism of IL-6 gene as well as intron 2 VNTR of IL-1Ra gene. Frequency of case-genotypes or alleles were compared to controls using Fisher exact test and Odds ratio. Results  Cases showed significant higher frequency of the genotypes: IL-6-174 GG (P<0.05, OR=3.2, 95% CI=1.09–10) that was evident mainly in the uncontrolled asthma subgroup indicative of the possibility of being a severity genotype. All cases as well as case-subgroups showed high significant frequency of IL-1Ra A1A1 (p<0.0001, OR=1.5, 95% CI=1.3–1.8). This may be considered a susceptibility genotype. Cases have also shown significant lower frequency of IL-6⁻¹⁷⁴ GC and IL-1Ra A1A2 genotypes (P<0.001 and P<0.0001 respectively). Conclusion  IL-6 and IL-1Ra polymorphisms can be considered genetic markers for bronchial asthma susceptibility and/or severity among Egyptian children. This may have a potential impact on family counseling and management.     

Cytokines in the placenta of Pakistani newborns with and without intrauterine growth retardation

Although intrauterine growth retardation (IUGR) is a major risk factor for increased neonatal mortality and morbidity, the mechanisms behind it are not clear. We analyzed cytokine gene expression and gene polymorphisms in infants with and without IUGR in Pakistan, where IUGR is very common. 45 IUGR and 55 control mother/infant pairs were studied. mRNA for IL-10, IL-8, TNF-alpha, TGF-beta, IL-6, IL-4, IL-1beta, IL-12, IFN-gamma and GAPDH was quantified with RT-PCR from placenta. Cytokine and cytokine receptor gene polymorphisms for -1087IL10, -308TNFA, -174IL6, +915TGFB1, intron 2 IL1RN, +36TNFR1, 150V IL4RA and -159CD14 were determined from genomic DNA. The serum levels of IL-1beta, IL-6, IL-8, IL-10, IL-12, TNF-alpha and TGF-beta were measured. There was a significant decrease of IL-10 and IL-12, but increase of TGF-beta in the decidua and similarly decrease of IL-10, but increase of TGF-beta in the trophoblasts of the IUGR placentas compared with the non-IUGR placentas. We found significantly lower levels of IL-1beta in serum from the mothers of the IUGR infants and of TGF-beta in serum of the infants with IUGR compared with the non-IUGR infants. We note that the IL-10 mRNA expression in the decidua was down-regulated, but the TGF-beta mRNA up-regulated in IUGR placentas of mothers from a population with multiple risk factors for IUGR. We propose that the low IL-10 in the placenta may be involved in the pathogenesis of IUGR and might possibly be treatable.     

The association of maternal prenatal IgE and eczema in offspring is restricted to non-atopic mothers

The risk of developing eczema is thought to be influenced by both genetic and environmental factors. Prenatal factors including the intrauterine environment may influence risk. We examined the relationship of maternal total IgE obtained during pregnancy to the incidence of atopic dermatitis in their 2-yr-old offspring. Subjects were participants in an unselected Detroit area birth cohort. Serum IgE was measured from 458 mothers in the third trimester of pregnancy along with prenatal family and environmental histories. Children were evaluated at approximately 2 yr of age for current or past eczema by maternal questionnaire and physician examination. Among the 458 children, 20.3% (n = 93) had a doctor confirmed diagnosis of eczema. Prenatal IgE was higher among women whose children developed AD vs. women whose children did not [Geometric means and 95% confidence intervals 52.7 IU/ml (40.9-68.0) vs. 32.9 IU/ml (28.0-38.7), p = 0.010]. The association was only seen in a subgroup of 181 women without allergic sensitization (specific IgE >0.35 IU/ml) to a panel of eight common allergens. Of the women without allergic sensitization, the mean serum IgE was 24.1 IU/ml (15.5-37.6) among those whose children had a diagnosis of eczema. The mean serum IgE was 11.2 IU/ml (9.2-13.6) among those whose children did not have a diagnosis of eczema (p-value 0.002). Maternal prenatal IgE level among women who are not sensitized to common allergens is associated with increased risk of eczema in offspring.     

母亲糖尿病及UCP2基因多态性与子代先天性心脏病关联的病例对照研究

目的 探讨母亲糖尿病、解偶联蛋白2基因（UCP2）多态性及两者的交互作用与子代先天性心脏病（CHD）的关系。方法 采用以医院为基础的病例对照研究,选择2018年3月至2019年8月在湖南省儿童医院确诊的464例单纯CHD患儿的母亲为病例组,选择同期住院、无先天畸形的504例患儿的母亲为对照组。通过问卷调查,收集相关暴露信息,同时采集母亲静脉血5 mL,用于UCP2基因多态性检测。采用多因素logistic回归分析探讨母亲糖尿病、UCP2基因多态性及两者交互作用与子代CHD的关联性。结果 多因素logistic回归分析显示,在控制混杂因素后,患有妊娠期糖尿病（OR=2.96,95% CI：1.57~5.59）、有妊娠期糖尿病史（OR=3.16,95% CI：1.59~6.28）和妊娠前患有糖尿病（OR=4.52,95% CI：2.41~8.50）均显著增加子代CHD的风险（P < 0.05）。母亲UCP2基因两个位点rs659366（T/C vs C/C：OR=1.49,95% CI：1.02~2.16;T/T vs C/C：OR=2.77,95% CI：1.67~4.62）和rs660339（A/A vs G/G：OR=2.19,95% CI：1.34~3.58）的多态性与子代CHD的风险存在关联（P < 0.05）。交互作用分析显示,UCP2基因两个位点（rs659366和rs660339）的多态性与母亲糖尿病在子代CHD发生中存在交互作用（P < 0.05）。结论 母亲糖尿病、UCP2基因多态性及其交互作用与子代CHD发病相关。     

哮喘儿童IgE T细胞亚群细胞因子的动态观察及临床意义

目的：探讨哮喘儿童血IgE和T细胞亚群、细胞因子的动态变化及临床意义。方法：应用免疫萤光法及双抗夹心酶联免疫吸附试验(ELISA)分析方法对45例哮喘儿童发作期和缓解期分别测定IgE,T细胞亚群和细胞因子。对照组为20例健康儿童。结果：哮喘发作期、缓解期CD_3~+,CD_4~+ T细胞及CD_4~+/CD_8~+高于对照组,差异有显著性(P<0.05或0.01),CD_8~+ T细胞与对照组比差异无显著性(P>0.05)。发作期CD_4~+ T细胞及CD_4~+/CD_8~+高于缓解期(P<0.05)。发作期IL-2,EFN-γ低于对照组(P<0.01或0.05),IL-4,IL-6,IL-8和IgE高于对照组(P<0.01或0.05);缓解期IL-2,IFN-γ低于对照组(P<0.01),IL-4,IL-8,IgE高于对照组(P<0.05或0.01),缓解期IL-6与对照组比较差异无显著性(P>0.05)。结论：儿童哮喘在发作期和缓解期均存在着免疫功能紊乱,提示儿童哮喘应长期抗变应性炎症治疗。 [中国当代儿科杂志,2003,5(1):23-26]     

Interleukin-1α, interleukin-6 and tumor necrosis factor-α levels in children with sepsis and meningitis

BACKGROUND: Cytokines are thought to be important endogenous mediators of the host immune response to infection. The purpose of the present study was to evaluate the utility of serum levels of interleukin (IL)-1alpha, IL-6 and tumor necrosis factor (TNF)-alpha in the prediction and differentiation of sepsis and meningitis in children. METHODS: Blood was collected from 50 children admitted to hospital for suspicion of infection. On the basis of predetermined criteria and investigation, the children were classified into sepsis (n = 30) and meningitis (n = 20) groups, as well as into healthy controls (n = 24) and non-infected sick controls (n = 12). The sepsis group was subdivided according to culture results into S1 (proven sepsis, n = 11) and S2 (clinical sepsis, n = 19). Serum IL-1alpha, IL-6 and TNF-alpha were measured by enzyme-linked immunosorbent assay (ELISA) while C-reactive protein (CRP) was measured by nephelometer. RESULTS: In non-infected sick controls, sepsis and meningitis groups, levels of CRP (P < 0.001, P < 0.05 and P < 0.01, respectively), IL-1alpha (P < 0.001 for all), and IL-6 (P < 0.01, P < 0.001, P < 0.001, respectively) were significantly elevated compared to healthy controls. In sepsis, levels of IL-1alpha increased in the S2 subgroup (P < 0.001) and IL-6 increased in the S1 and S2 subgroups (P < 0.05, P < 0.001, respectively) compared with healthy controls. In meningitis, IL-1alpha had the highest sensitivity and negative predictive value, while IL-6 had the highest specificity and positive predictive value in non-infected sick controls, sepsis and meningitis groups. CONCLUSION: Interleukin-1alpha, IL-6 and CRP are increased in non-infected sick controls, sepsis and meningitis patients but it is not possible to differentiate between them. IL-1alpha had the highest sensitivity in meningitis while IL-6 had the highest specificity in prediction of sepsis and meningitis and their assessment together may improve accuracy in the diagnosis of childhood infection.