bluuebunny/crossref_metadata_2025 huggingface dataset:
Evidence for a role of HLA DRB1 alleles in the control of IgE levels, strengthened by interacting TCR A/D marker alleles
Authors: Mansur A. H. , Williams G. A. , Bishop D. T. , Markham A. F. , Lewis S. , Britton J. , Morrison J. F. J.
Published: March 2003

Background

MHC class II alleles at human chromosome 6p21.1 and alleles in the TCR A/D locus at human chromosome 14q11.2 have been implicated in susceptibility to specific allergies and the modulation of total serum IgE. It has also been hypothesized that HLA and TCR allelic interactions may have a strong influence on predisposition to allergic disease.

Objective

This study was performed to investigate the influence of HLA‐DRB and DQB1 alleles and D14S50 alleles (adjacent to TCR A/D locus on 14q11.2), individually and in‐combination, on total serum IgE levels, and on the development of specific allergies.

Methods

We performed an association study between HLA‐DRB, HLA‐DQB1 polymorphisms, D14S50 alleles, total serum IgE expression and specific allergies to house dust mite, grass pollens and cat fur. A sample of 181 individuals was drawn from a larger set of 2415 adults, sampled at random from a district in Nottingham.

Results

Strong association was observed between HLA‐DRB1*0701 allele and high total serum IgE expression (P < 0.001). D14S50 alleles alone showed no evidence for independent association. However, there was a significant interaction between DRB1*0701 and D14S50 allele 170 such that, when both were present, there was a further increase in total serum IgE levels.

Conclusion

This study suggests that DRB1*0701 allele is involved in the modulation of total serum IgE, and that there is an interaction between DRB1*0701 and a marker adjacent to TCR A/D in the control of IgE expression.
Nitric oxide‐dependent neutrophil recruitment: role in nasal secretion
Authors: Cardell L.‐O. , Agustí C. , Nadel J. A.
Published: March 2003

Leukotriene B4 (LTB4), an inflammatory mediator, is a potent chemoattractant for neutrophils that plays an important role in nasal secretion via release of elastase. Nitric oxide (NO) is an important modulator of leucocyte–endothelial cell interactions, endogenously produced in large quantities in the paranasal sinuses.

To examine the role of NO in LTB4‐stimulated nasal secretion.

A newly‐developed method for isolating and superfusing a nasal segment in dogs was used.

Instillation of LTB4 into the nasal segment caused a time‐dependent increase in the volume of airway fluid and in the recruitment of neutrophils. N(G)‐nitro‐l‐arginine‐methylester (L‐NAME), an inhibitor of NO synthase, prevented LTB4‐induced neutrophil recruitment and nasal secretion.

These studies show that NO modulates LTB4‐induced neutrophil recruitment and subsequent fluid secretion in the nose, and they suggest a therapeutic role for NO inhibitors in modulating neutrophil‐dependent nasal secretion.
Hydrocortisone enhances allergen‐specific IgE production by peripheral blood mononuclear cells from atopic patients with high serum allergen‐specific IgE levels
Authors: Cho Y.‐J. , Hong S.‐J. , Moon H.‐B.
Published: March 2003

Background

Although there is convincing evidence that human B cells can be induced to produce IgE by a combination of interleukin 4 (IL‐4) and hydrocortisone (HC) in atopic subjects, it is still uncertain if this performs the same functions in allergen‐specific IgE synthesis.

Objective

This study was designed to investigate the differences of IgE regulation between atopics and nonatopics, interactions of HC with IL‐4, and the correlation between in vitro total IgE, allergen‐specific IgE synthesis and serum IgE levels.

Methods

Peripheral blood mononuclear cells (PBMCs) from 16 atopic asthma patients sensitive to Dermatophagoides farinae and seven nonatopic controls were cultured with IL‐4 and/or HC. Total IgE and D. farinae‐specific IgE in culture supernatant were measured by ELISA and FAST.

Results

IL‐4 increased total IgE synthesis in PBMCs from both atopics and nonatopics, whereas, HC had this effect only in some atopics who showed spontaneous IgE production in vitro. HC acted synergistically with IL‐4 in total IgE synthesis. Their effects were more remarkable in cases with lower total serum IgE levels. PBMCs from eight of 16 atopics produced D. farinae‐specific IgE in vitro either spontaneously or by IL‐4 and/or HC. HC had more profound effects than IL‐4 in these patients. They also showed higher total IgE synthesis by HC, and higher specific serum IgE levels than the others. IL‐4 and/or HC did not induce any D. farinae‐specific IgE synthesis by PBMCs from nonatopics.

Conclusion

HC had a more profound effect than IL‐4 on the induction of D. farinae‐specific IgE synthesis in atopic patients with high serum allergen specific IgE levels. Further studies to determine the causes of these effects, such as the presence of long lived allergen specific B cells as the result of the priming effect of IL‐4 in vivo, may be needed.
Relation between exhaled carbon monoxide levels and clinical severity of asthma
Authors: Yamaya M. , Hosoda M. , Ishizuka S. , Monma M. , Matsui T. , Suzuki T. , Sekizawa K. , Sasaki H.
Published: March 2003

Carbon monoxide (CO) can be detected in exhaled air and is increased in asthmatic patients not treated with corticosteroids. However, it is uncertain whether exhaled CO is related to severity of asthma.

To study whether exhaled CO is related to severity of asthma in clinical courses, exhaled CO concentrations were measured on a CO monitor by vital capacity manoeuvre in 20 mild asthmatics treated with inhaled β2‐agonists alone, 20 moderate asthmatics treated with inhaled corticosteroids, and 15 stable asthmatics treated with high dose inhaled corticosteroids and oral corticosteroids once a month over 1 years. Exhaled CO concentrations were also measured in 16 unstable severe asthmatics who visited the hospital every 7 or 14 days for treatment with high dose inhaled corticosteroids and oral corticosteroids.

The mean values of exhaled CO in severe asthma over 1 year were 6.7 ± 9.5 p.p.m. (n = 31, mean ± SD) and significantly higher than those of non‐smoking control subjects (1.2 ± 0.9 p.p.m., n = 20, P < 0.01). Exhaled CO concentrations in unstable severe asthmatics were significantly higher than those in stable severe asthmatics. However, exhaled CO concentrations in mild and moderate asthmatics did not differ significantly from those in non‐smoking control subjects (P > 0.20). There was a significant relationship between the exhaled CO concentrations and forced expiratory volume in one second in all asthmatic patients.

These findings suggest that exhaled CO concentrations may relate to the severity of asthma and measurements of exhaled CO concentrations may be a useful means of monitoring airway inflammation in asthma.
Measurement of personal exposure to aerosols of Nephrops norvegicus (Scampi) using a monoclonal‐based assay
Authors: Griffin P. , Allan L. , Gibson M. , Elms J. , Wiley K. , Curran A. D.
Published: March 2003

Background The industrial processing of scampi (Nephrops norvegicus) generates bioaerosols which can cause occupational respiratory disease in exposed individuals. The objective of this study was to develop a monoclonal antibody‐based immunoassay to measure scampi proteins collected using standard personal air sampling methods.

Methods A monoclonal antibody was generated which predominantly bound to a single 97 Kd scampi protein, which we have shown to be a major allergen. This protein was shown by SDS PAGE immunoblotting to be present in various aqueous extracts from wastes produced during scampi processing. A quantitative immunoslotblot method was developed to quantify scampi from air sample filters.

Results We demonstrated the utility of this method by showing a significant difference (P = 0.015) in the level of exposure of two groups of 12 workers processing scampi at a traditional open workstation (GM = 607 ng m−3) and at an enclosed workstation (GM = 451 ng m−3).

Conclusion We conclude that this assay can be used, in conjunction with health surveillance, to monitor exposure and the efficacy of measures to reduce exposure to airborne scampi allergen in an occupational environment.
Serum interleukin‐5 in aspirin‐induced asthma
Authors: Mastalerz L. , Sanak M. , Szczeklik A.
Published: March 2003

Background Eosinophilopoetic cytokine IL‐5 enhances cysteinyl‐leukotriene (cys‐LT) synthesis in eosinophils in vitro. In patients with aspirin‐induced asthma (AIA) bronchial biopsies revealed eosinophil infiltration and a marked increase in IL‐5 positive cells.

Objective We wondered whether in AIA patients the bronchial IL‐5 increase is reflected in peripheral blood, and if so, whether it is related to overproduction of cys‐LT.

Methods In 11 stable patients with AIA, 32 with ATA (aspirin‐tolerant asthma) and in 16 controls we measured serum IL‐5 concentrations and urinary LTE4, believed to reflect global cys‐LT production.

Results Serum IL‐5 was detectable in 12 of 43 asthmatics, but in none of the control subjects. It was highest in the ATA group and differed significantly from the controls. There was no significant difference in IL‐5 levels between: (i) the asthmatic groups studied, and (ii) AIA patients and controls. No relationship was found between serum IL‐5 and urinary cys‐LT.

Conclusion Overexpression of IL‐5 reported in the airways of aspirin‐sensitive patients with asthma was not reflected in their blood. If IL‐5 affects cys‐LT production, it is rather in the bronchi of the patients than in the blood.
Linkage to atopy on chromosome 19 in north‐eastern Italian families with allergic asthma
Authors: Venanzi S. , Malerba G. , Galavotti R. , Lauciello M. C. , Trabetti E. , Zanoni G. , Pescollderungg L. , Martinati L. C. , Boner A. L. , Pignatti P. F.
Published: March 2003

Background Allergic asthma is a multifactorial disease for which there is a widely assessed, although poorly understood, genetic involvement. Genome‐wide screens reported evidence for linkage of allergic asthma‐related phenotypes to several chromosomal locations. Markers on chromosome 19 have been linked to allergic asthma phenotypes in different populations in independent studies.

Objective The aim of this study was to perform a genetic linkage analysis on chromosome 19 to search for DNA markers linked to phenotypes related to allergic asthma.

Methods Using non‐parametric multipoint linkage analysis on a total of 22 random DNA markers in 2 stages, a sample of 111 families (542 subjects) from north‐eastern Italy, recruited through an asthmatic allergic proband, was investigated. Phenotypes examined were: clinical asthma, total serum elevated IgE, skin prick test positivity, bronchial hyper‐responsiveness, and atopy defined as skin prick test positivity and/or elevated IgE. Simulation studies were performed to confirm the significance of the results.

Results A novel linkage of atopy and skin prick test positivity to marker D19S601 (19q13.3) was found. Modest evidence for linkage of atopy, skin prick test positivity, and IgE was also found to marker D19S591 (19p13.3). Simulation analysis for atopy gave an NPL‐Z > 3.326 in 2 replicates out of 1000 (P = 0.002) for D19S601, and an NPL‐Z > 2.56 in 16 replicates out of 1000 (P = 0.016) for D19S591.

Conclusions On chromosome 19, suggestive linkage of atopy and skin prick test positivity with marker D19S601 (19q13.3) and modest evidence of linkage of marker D19S591 (19p13.3) to the atopic phenotypes investigated were found. These results suggest that these regions may contain susceptibility loci associated to atopic phenotypes.
Immuno‐regulatory cytokines in asthma: IL‐15 and IL‐13 in induced sputum
Authors: Komai‐Koma M. , McKay A. , Thomson L. , McSharry C. , Chalmers G. W. , Liew F. Y. , Thomson N. C.
Published: March 2003

Background The importance of Th2‐type lymphocyte function in asthmatic airway inflammation is well recognized, but less is known about the factors which regulate the function of these lymphocytes in asthma. The macrophage‐derived cytokine, interleukin (IL)‐15 has a number of T cell regulatory properties which might be of relevance to asthma and its treatment.

Objective The aims were to identify and quantify the T cell regulatory cytokine IL‐15 in induced sputum samples from asthmatic patients, in comparison with IL‐13, and to relate the levels of these cytokines to treatment with inhaled steroids.

Methods Induced sputum was collected from 16 asthmatics (eight steroid and eight non‐steroid treated) and eight normal controls. IL‐15 and IL‐13 levels were measured by enzyme‐linked immunoassay (ELISA) in sputum. IL‐15 levels were also measured in sputum cell culture supernatants and localized to specific sputum cells by immuno‐cytochemistry.

Results IL‐15 levels were increased and IL‐13 levels were decreased in sputum fluid from steroid‐treated compared with non‐steroid‐treated asthmatics. IL‐15 was localized specifically to macrophages and the proportion of these cells expressing IL‐15 correlated with sputum fluid IL‐15 and IL‐15 levels in cell culture supernatants, and all were higher in the steroid‐treated asthmatics.

Conclusion IL‐15 and IL‐13 production appears to be reciprocally regulated by steroid therapy in asthma patients. The steroid‐associated increase in IL‐15 may regulate a fundamental shift away from an inflammatory Th2‐type environment in asthma and may be an essential component of the cytokine modulation underlying the therapeutic benefit of corticosteroids in this condition.
Sodium cromoglycate attenuates pulmonary inflammation without influencing bronchial responsiveness in healthy subjects exposed to organic dust
Authors: Larsson K. , Larsson B.‐M. , Sandström T. , Sundblad B.‐M. , Palmberg L.
Published: March 2003

Background Inhalation of organic dust from a pig house induces airway inflammation and increases bronchial responsiveness to methacholine in healthy subjects.

Objective To study whether sodium cromoglycate influences the airway inflammatory reaction and the increase in airway responsiveness induced by inhalation of organic dust.

Methods Bronchoalveolar and nasal lavages, and bronchial methacholine challanges were performed and blood samples were drawn in 32 healthy subjects before and after exposure to dust in a pig farm. Sodium cromoglycate was inhaled (20 mg, twice a day) and administered intranasally (5.2 mg, twice a day) by 16 and a corresponding placebo was given to the other 16 healthy controls for two weeks prior to exposure.

Results Exposure induced a significant increase in inflammatory cells and soluble components (pro‐inflammatory cytokines, inflammatory mediators) in bronchoalveolar and nasal lavage fluid in both groups. The increase in neutrophils, interleukin (IL)‐6 and tumour necrosis factor (TNF)‐α as well as myeloperoxidase and soluble intracellular adhesion molecule (ICAM)‐1 in bronchoalveolar lavage (BAL) fluid was significantly reduced by treatment with sodium cromoglycate. Although sodium cromoglycate inhalation largely influenced a variety of inflammatory indices in bronchoalveolar lavage fluid it had no effect on the increase in bronchial responsiveness to methacholine.

Conclusion Sodium cromoglycate alters the airway inflammatory response to inhaled organic dust without influencing the dust‐induced increase in bronchial responsiveness to methacholine.
Wheezing in relation to atopy and environmental factors in Estonian and Swedish schoolchildren
Authors: Annus T. , Björkstén B. , Mai X.‐M. , Nilsson L. , Riikjärv M.‐A. , Sandin A. , Bråbäck L.
Published: March 2003

Background The prevalence of asthma and allergic diseases is significantly lower in post socialist Eastern Europe than in Western industrialized countries. The reason for this difference is largely unknown. Different types of childhood wheezing could be related to different risk factors.

Objective To compare the prevalence of respiratory symptoms, asthma and atopic diseases among Estonian and Swedish schoolchildren and to evaluate characteristics for wheezing in the two countries.

Methods In a prevalence study, population‐based random samples of 10–11‐year‐old schoolchildren in Tallinn (n = 979), Estonia and in Linköping (n = 911) and Östersund (n = 1197), Sweden were studied by a parental questionnaire and skin prick tests (SPT). All 275 children with wheeze in the past 12 months and 710 randomly selected controls within the original cohorts were invited to a case‐control study involving a parental questionnaire, examination for flexural dermatitis and bronchial challenge with hypertonic saline. The study adhered to the International Study of Asthma and Allergies in Childhood (ISAAC) Phase II protocol.

Results The prevalence of current wheezing was similar (8–10%) in the three centres, while diagnosed asthma and atopic symptoms were more common in Sweden and cold‐related respiratory symptoms were more prevalent in Estonia. Frequent wheezing was more common in Sweden than in Estonia (but significantly so only in Östersund). Wheezing children in Sweden had a high rate of positive SPT (49% in Linköping and 58% in Östersund) bronchial hyper‐responsiveness (BHR) (48% in Linköping and Östersund) and anti‐asthmatic treatment (63% in Linköping and 81% in Östersund). In Estonia, the proportion of wheezing children with positive SPT, BHR and anti‐asthmatic treatment was only 26%, 13% and 17%, respectively. Domestic crowding was inversely related to wheezing in one of the study areas (Östersund). The mean baseline forced expiratory volume in one second (FEV1) was higher in Estonia than in Sweden, both in wheezing and non‐wheezing children.

Conclusions Our study suggested that although wheezing symptoms were equally common in Estonia and Sweden, they were less severe in Estonia. More frequent symptoms and a high rate of atopy, BHR and anti‐asthmatic medication characterized wheezing children in Sweden. In contrast, BHR, atopy and medication were uncommon among wheezing children in Estonia.
The tryptase inhibitor APC‐366 reduces the acute airway response to allergen in pigs sensitized to Ascaris suum
Authors: Sylvin H. , Dahlbäck M. , Van Der Ploeg I. , Alving K.
Published: March 2003

Background Tryptase is a mast cell serine protease that is released during mast cell degranulation. It has been implicated as an important enzyme in the pathophysiology of asthma, but its role in this disease is not fully elucidated.

Objective In this study, we investigated the effects of a tryptase inhibitor, APC‐366, on the acute allergic airway reaction in specific pathogen‐free pigs sensitized to the antigen Ascaris suum.

Methods APC‐366 (5 mg in 1 mL of water, each dose) was given as an aerosol to seven pigs two times (t); at t = − 60 min and t = − 15 min Control pigs received water. Ascaris antigen (in 2 mL saline) was nebulized to the airways over approximately 5 min at t = 0. All aerosols were generated with an ultrasonic nebulizer.

Results The allergen challenge caused an acute reaction with a significant increase in airway resistance (Raw) in the control pigs from 3.3 ± 0.6 cmH20/l/s to 10.2 ± 2.3 cmH20/l/s, while in the APC‐366‐treated pigs, the Raw increased from 2.6 ± 0.4 cmH20/l/s to 4.5 ± 0.7 cmH20/l/s (P < 0.05 compared to controls). The dynamic lung compliance (Cdyn) decreased significantly in the control pigs, but not in the APC‐366‐treated animals. The histamine concentration in urine in the control pigs was elevated immediately after allergen challenge, while this release was markedly reduced in the APC‐366‐treated pigs.

Conclusion The tryptase inhibitor APC‐366 reduces the acute airway response to allergen significantly. There is also a reduced elevation in urine histamine concentration after challenge in the treated pigs, compared to controls. These results indicate that inhibition of mast cell tryptase might be a useful anti‐allergic treatment in asthma.
Prevalence of occupational allergy to bell pepper pollen in greenhouses in the Netherlands
Authors: Groenewoud G. C. M. , De Jong N. W. , Van Oorschot‐van Nes A. J. , Vermeulen A. M. , Van Toorenenbergen A. W. , Mulder P. G. H. , Burdorf A. , De Groot H. , Van Wijk R. Gerth
Published: March 2003

Background An increasing number of allergic complaints appear to have occurred among bell pepper greenhouse employees.

Objective The aim of this study was to estimate the prevalence of work‐related allergic symptoms and the prevalence of sensitization to specific occupational allergens and its determinants.

Methods We studied 472 employees who were invited to answer an extensive questionnaire and to be tested on location with inhalant allergens and home‐made extracts of the bell pepper plant. In addition, peak expiratory flow monitoring and RASTs were performed.

Results Work‐related symptoms were reported in 53.8% of all cases. Sensitization to the bell pepper plant was found in 35.4%. Positive reactions to leaf, stem and/or juice, however, were associated in nearly 90% with sensitization to pollen, which appeared to be most important allergen of the plant. Sensitization to the bell pepper plant and inhalant atopy were considered the most important risk factors for the occurrence of work‐related symptoms of the upper airways (PRR 2.63, CI 2.11–3.25 and PRR 2.25, CI 1.82–2.79) as well as of the lower airways (PRR 4.08, CI 2.38–7.00 and PRR 3.16, CI 1.87–5.33).

Conclusion There is a surprisingly high prevalence of work‐related respiratory symptoms (53.8%) in bell pepper horticulture. In two‐thirds of the employees, symptoms at work were associated with an IgE‐mediated allergy due to the high and chronic exposure to bell pepper pollen. Complaints at work without specific sensitization to bell pepper pollen can be caused by non‐specific hyper‐reactivity or atopy to other occupational allergens. The extent of this occupational allergy has important consequences for the health care of this large, still growing occupational group.
Lipoteichoic acid from Staphylococcus aureus induces Th2‐prone dermatitis in mice sensitized percutaneously with an allergen
Authors: Matsui K. , Nishikawa A.
Published: March 2003

Background We found previously that lipoteichoic acid (LTA) from Staphylococcus aureus has the ability to induce Th2 cytokine production by peripheral blood mononuclear cells (PBMC) from patients with atopic dermatitis (AD). However, it is not known whether LTA can induce a Th2‐dominant cytokine response in the skin of AD patients.

Objective The purpose of this study was to determine the effects of LTA in mice sensitized percutaneously with a house dust mite antigen (MA) through barrier‐disrupted skin, as an experimental animal model of AD.

Methods Mice were sensitized with MA by a single topical application to barrier‐disrupted abdominal skin. Seven days after the sensitization, the mice were challenged on the dorsal skin by LTA to elicit localized skin inflammation. The cytokine response in the dorsal skin was investigated by reverse transcription‐polymerase chain reaction (RT‐PCR) and immunohistological analysis. The infiltration of inflammatory cells in the skin was also observed by histological staining.

Results Injection of LTA into the dorsal skin of MA‐sensitized mice, which show a Th2‐dominant cytokine response against the homologous antigen, increased the expression of mRNA for IFN‐γ, IL‐4 and IL‐5, but not IL‐2. Immunohistological analysis demonstrated that levels of IFN‐γ, IL‐4 and IL‐5 transcripts corresponded with those of protein synthesis. In addition, the dorsal skin of MA‐sensitized mice challenged with LTA showed significantly increased numbers of neutrophils, eosinophils, mononuclear cells and mast cells compared with control mice challenged with LTA.

Conclusion These results suggest that LTA has the ability to induce localized Th2‐prone dermatitis in an allergen‐independent manner in the skin of AD patients and may explain the role of colonization with S. aureus in AD patients.
Interaction among human leucocyte antigen–peptide–T cell receptor complexes in cow's milk allergy: the significance of human leucocyte antigen and T cell receptor–complementarity determining region 3 loops
Authors: Sakaguchi H. , Inoue R. , Kaneko H. , Watanabe M. , Suzuki K. , Kato Z. , Matsushita S. , Kondo N.
Published: March 2003

Background Allergic individuals respond to only a few specific antigens, therefore allergic diseases are characterized by antigen specificity. Clarification of the mechanism of antigen specificity will lead to progress in the therapy of allergic diseases.

Objectives The purpose of this study is to determine the specific association among T cell epitopes, antigen‐presenting molecules and T cell receptor (TCR), and to determine the TCR usage in the pathogenesis of allergies using antigen‐specific T cell clones (TCCs). The results can clarify the mechanism of the antigen specificity of allergic diseases, and provide new therapeutic possibilities using analogue peptides.

Methods Short‐term T cell clones specific to β‐lactoglobulin (BLG) were established from peripheral blood mononuclear cells (PBMCs) collected from five patients allergic to cow's milk. We then identified the T cell epitopes and antigen‐presenting molecules, and examined TCR usage. We also determined the sequence of the TCR‐complementarity‐determining region 3 (CDR3).

Results Six TCCs established from the five patients recognized three different peptides, and BLGp97–117 was recognized by four of the six TCCs. BLGp101–112 (KYLLFCMENSAE) was the core sequence in the fragment. Sequence analysis of TCR by the RT‐PCR method revealed a marked heterogeneity in TCR usage, and similar amino acid sequences were recognized in the CDR3 region. Four of the six TCCs recognized BLG in association with human leucocyte antigen (HLA)‐DRB1*0405 as antigen‐presenting molecules.

Conclusion We proposed the motif of the interaction between the HLA‐DRB1*0405 allele and antigen peptide, and suggested that HLA‐DRB1*0405 is an immunoregulatory gene product for T cell responses to BLG.
Immune responses to birch in young children during their first 7 years of life
Authors: Böttcher M. F. , Jenmalm M. C. , Björkstén B.
Published: March 2003

Background The character of immune responses to allergens during the first years of life may decide whether the individual will become tolerant or develop allergy later in life.

Objective To study the development of immune responses to the seasonal inhalant allergen birch over the first 7 years of life.

Methods Blood samples were obtained from 21 children who were followed prospectively from the second to the seventh pollen season of life. Birch‐induced cytokine production and IgG subclass antibodies to rBet v 1 were analysed with ELISA, mRNA expression with real time PCR, IgE antibodies to birch with Magic LiteTM and birch‐induced mononuclear cell proliferation with 3H‐thymidine incorporation.

Results Birch‐induced IFN‐γ and IL‐10 production increased with age, both in atopic and non‐atopic children, while birch‐induced IL‐13 production decreased. The two children who were sensitized and developed clinical allergy to birch showed persistent IL‐4 and IL‐5 production and IL‐9 mRNA expression, as well as Th2‐associated IgG4 responses. Transient Th2‐like responses were observed among the other children. Proliferative responses and IgG1 antibodies were seen in all children.

Conclusions Immune responses to birch can be demonstrated in all children, during the first 7 years of life, regardless of atopic status. A transient early Th2‐like response is down‐regulated after the fourth pollen season, except in children who develop clinical allergy to the particular allergen.
High prevalence of current asthma and active smoking effect among the elderly
Authors: Kim Y.‐K. , Kim S.‐H. , Tak Y.‐J. , Jee Y.‐K. , Lee B.‐J. , Kim S.‐H. , Park H.‐W. , Jung J.‐W. , Bahn J.‐W. , Chang Y.‐S. , Choi D.‐C. , Chang S.‐I. , Min K.‐U. , Kim Y.‐Y. , Cho S.‐H.
Published: March 2003

Background Although asthma is a common cause of morbidity in adults, relatively few objectively measured population studies of asthma prevalence in adult populations have been conducted.

Objective To evaluate the prevalence of asthma, based on both a questionnaire and methacholine bronchial provocation test, and to determine the risk factors of asthma prevalence in an adult population.

Methods A total of 2467 adults, who were randomly selected from metropolitan urban, non‐metropolitan urban and rural areas, responded to the modified ISAAC questionnaire, and underwent methacholine bronchial provocation tests and skin prick tests to locally common aeroallergens.

Results The prevalence of current asthma based on the questionnaire and the methacholine challenge was 2.0% in adults younger than 40, 3.8% in 40‐ to 54‐year‐olds, 7.7% in 55‐ to 64‐year‐olds and 12.7% in those aged 65 or higher. For subjects of 55–64 years, active smoking was found to be significantly related with the prevalence of current asthma and bronchial hyper‐responsiveness, although smoking was positively associated with percentage predictive value of forced expiratory volume of 1 s (FEV1).

Conclusion The prevalence of current asthma is common among the elderly, and active smoking may play an important role in the development of asthma and bronchial hyper‐responsiveness among the elderly.
Concentrations of exhaled nitric oxide in asthmatics and subjects with allergic rhinitis sensitized to the same pollen allergen1
Authors: Prieto L. , Gutiérrez V. , Uixera S. , Bruno L.
Published: March 2003

Background Some studies have reported that the levels of exhaled nitric oxide (ENO) in asthmatics are similar to those in subjects with allergic rhinitis, and it has been postulated that atopic status might be the determinant of enhanced nitric oxide production in asthma.

Objectives The aim of this study was to determine differences in ENO levels between asthmatics and subjects with allergic rhinitis sensitized to the same allergen, and to correlate these levels with airway responsiveness.

Methods Nineteen patients with asthma and 18 subjects with allergic rhinitis monosensitized to Parietaria pollen were enrolled in the study. ENO values and airway responsiveness to methacholine and adenosine 5′‐monophosphate (AMP) were measured during the pollen season. The response to each bronchoconstrictor agent was measured by the provocative concentration required to produce a 20% fall in FEV1 (PC20). ENO was measured with the single‐exhalation method.

Results The geometric mean (95% confidence interval) ENO values were significantly higher in asthmatics than in subjects with allergic rhinitis: 72.4 p.p.b. (54.9–93.3 p.p.b) vs. 44.7 p.p.b. (30.9–64.6 p.p.b., P = 0.03). In asthmatics, a significant correlation was found between ENO and PC20 AMP values (ρ = −0.57, P = 0.02), whereas no correlation was detected between ENO and PC20 methacholine (ρ =− 0.35, P = 0.14).

Conclusions Our results suggest that atopy is not the only determinant of increased ENO levels detected in subjects with asthma, and that responsiveness to AMP may be a more sensitive marker for assessing airway inflammation in asthma compared to methacholine.
Persistence of bronchopulmonary hyper‐reactivity and eosinophilic lung inflammation after anti‐IL‐5 or ‐IL‐13 treatment in allergic BALB/c and IL‐4Rα knockout mice
Authors: Proust B. , Nahori M. A. , Ruffie C. , Lefort J. , Vargaftig B. B.
Published: March 2003

Background Antigen‐induced bronchopulmonary hyper‐reactivity (BHR) is generally associated with eosinophilia. It involves cytokines produced by Th2 lymphocytes, including IL‐4, IL‐5 and IL‐13, which are implicated in IgE production, eosinophil differentiation and attraction, and related events relevant to allergic inflammation, whose mechanisms remain unclear.

Objective To investigate the mechanisms by which Th2 cytokines mediate eosinophilia and subsequent BHR using ovalbumin (OVA)‐immunized and OVA‐challenged IL‐4Rα–/– and IL‐4–/– mice, which fail to transduce and/or to produce IL‐4 and IgE as compared with wild type (WT) mice, and specific neutralizing antibodies.

Methods On days 0 and 7, mice were immunized subcutaneously (s.c.) with OVA. At day 14, anti‐IL‐5 or anti‐IL‐13 antibodies were administered intranasally and/or intravenously before allergenic challenge. Different functional and cellular parameters were studied in vivo and cytokine production was followed with a newly described ex vivo procedure using lung explants.

Results IL‐4Rα–/– and IL‐4–/– mice developed BHR and pulmonary eosinophilia, even though eosinophil recruitment to the bronchoalveolar liquid lavage (BALF) was reduced. In vivo, IL‐4–/– and IL‐4Rα–/– mice produced, respectively, no or reduced amounts of IL‐5 in the BALF/serum as compared with WT mice, whereas no IL‐13 in the BALF was detected. By contrast, ex vivo, surviving lung explants from WT and IL‐4–/– or IL‐4Rα–/– mice produced IL‐13 and large amounts of IL‐5. The neutralization of IL‐5 in vivo (BALF and serum) and ex vivo (from lung explant) in IL‐4Rα–/– and WT mice failed to suppress BHR and lung eosinophilia, and to modify IL‐13 production ex vivo. In addition, neutralization of IL‐13 in vivo from lung explant also failed to abrogate BHR and lung eosinophilia, whereas IL‐5 was unchanged.

Conclusion Antigen‐induced BHR can develop independently from IL‐4, IL‐5 or IL‐13 and from the IL‐4α receptor chain, suggesting a possible novel IL‐4, IL‐5 and IL‐13‐independent pathway for the development of BHR in allergic BALB/c mice. The failure of IL‐5 or IL‐13 antibodies to prevent BHR in IL‐4Rα–/– mice suggests that neither is indispensable for BHR but does not exclude a role for lung tissue eosinophilia.
Anti‐inflammatory effects of high‐dose montelukast in an animal model of acute asthma
Authors: Wu A. Y. , Chik S. C. , Chan A. W. , Li Z. , Tsang K. W. , Li W.
Published: March 2003

Background Asthmatic inflammation is mediated by a network of cytokines, chemokines and adhesion molecules. Corticosteroids are the only effective agents available to control asthmatic inflammation. We investigated the effect of high‐dose montelukast (MK), a selective cysteinyl leukotriene receptor 1 antagonist, on mediators of airway inflammation.

Objective The aim of this study was to determine the effect of a 3‐day course of high‐dose MK on mediators of airway inflammation induced by a single allergen challenge in sensitized mice.

Methods Ovalbumin (OVA)‐sensitized BALB/c mice were treated with 25 mg/kg of MK or saline intravenously for 3 days. On the third day, a single inhalation challenge with OVA was given. Cellular infiltration was assessed in the bronchoalveolar lavage (BAL) and in the lung. Expression of IL‐4, IL‐5, IL‐13 and eotaxin in the BAL, and the lung was determined. Serum IL‐5 and total IgE was measured. IL‐5 and eotaxin mRNA expression in the lung was determined. Finally, eotaxin and VACM‐1 expression in the lung was assessed by immunohistochemistry.

Results MK reduced the number of eosinophils in the BAL by > 90%. There was also significant reduction in IL‐5 in the BAL, lung and the serum, and IL‐5 mRNA expression in the lung. IL‐4 level in the lung and BAL, and IL‐13 level in the lung also significantly decreased. Serum IgE level and lung VCAM‐1 expression was also significantly lower in treated animals, but eotaxin protein and mRNA expression in the lung remained unchanged.

Conclusion MK exerts its anti‐inflammatory effect through the suppression of T helper type‐2 (Th2) cytokines. The use of high‐dose MK as an anti‐inflammatory agent in acute asthma should be further explored.
Inverse modulation of IL-10 and IL-12 in the blood of women with preneoplastic lesions of the uterine cervix
Authors: Jacobs N , Giannini S L , Doyen J , Baptista A , Moutschen M , Boniver J , Delvenne P
Published: March 2003

It has been postulated that an impaired immune response may contribute to the progression of human papillomavirus (HPV)-associated preneoplastic lesions. Based on this hypothesis, we evaluated the cytokine production in the blood of patients with squamous intraepithelial lesions (SIL) of the uterine cervix. The levels of type-1 (interferon-gamma (IFN-γ) and IL-12) and type-2 (IL-4 and IL-10) cytokines were measured in whole blood culture supernatants of patients with low- and high-grade SIL and control women. There was no difference in IL-4 and IFN-γ levels between patients with SIL and the control group. In contrast, the ratio of IL-12/IL-10 levels was significantly lower in patients with SIL compared with the control group. A lower IL-12/IL-10 ratio in women with SIL was also observed when peripheral blood mononuclear cell (PBMC) culture supernatants and plasma samples were analysed. In patients, neither the lower expression of the CD3ε chain nor the higher frequency of HLA-DRB1*1501 expression could be correlated with abnormal cytokine production. These results suggest that a part of the cytokine network, namely IL-10 and IL-12, is perturbed in patients with SIL. A better knowledge of the role of these cytokines in regulating the growth of HPV-associated SIL might have practical implications for the development of vaccines or immunomodulatory strategies in the treatment of cervical cancers.
A restricted T cell response to myelin basic protein (MBP) is stable in multiple sclerosis (MS) patients
Authors: Uccelli A , Giunti D , Salvetti M , Ristori G , Fenoglio D , Abbruzzese M , Mancardi G L
Published: March 2003

The close resemblance of MS to the animal model experimental autoimmune encephalomyelitis (EAE) has provided compelling data sustaining a pathogenic role of circulating T cells reactive against MBP. T cell antigen receptor (TCR) usage in EAE is commonly considered restricted; nevertheless, dynamic changes of TCR usage correlate with the course of EAE, resulting in a limited repertoire during early stages of disease activity followed by the recruitment of other T cells reactive against new determinants. Although a broader TCR repertoire mediates the response to MBP in humans, a restricted intra-individual heterogeneity may occur in some MS patients. In the present study we characterize the response to MBP in MS subjects with relapsing remitting disease from two sampling time points 12 months apart. MBP-specific T cell lines (TCL) were first generated from eight MS individuals and two healthy subjects. New TCL were obtained after 12 months from one control and three MS patients whose response, at the first time point, was directed against a single epitope. Interestingly, these three subjects had a stable and mild disease. Few TCL obtained at two time points from the MS individuals recognized the same immunodominant epitope and shared identical TCR Vβ sequences. In the control we could not detect a restriction of the repertoire. These findings suggest that in some MS patients with benign disease a predominant T cell response to a single determinant may be detectable at different moments and is mediated by clonally expanded populations.
Apoptosis of colorectal adenocarcinoma (COLO 201) by tumour necrosis factor-alpha (TNF-α) and/or interferon-gamma (IFN-γ), resulting from down-modulation of Bcl-2 expression
Authors: Koshiji M , Adachi Y , Sogo S , Taketani S , Oyaizu N , Than S O E , Inaba M , Phawa S , Hioki K , Ikehara S
Published: March 2003

Fas antigen is constitutively expressed in the normal colon epithelium, but considerably diminished in most colorectal carcinomas. In the present study, we examine the relationship between Fas antigen expression and apoptosis using the colorectal carcinoma cell line COLO 201, on which a low grade of Fas antigen is expressed. Anti-Fas antibody had no effect on the induction of apoptosis of COLO 201. However, TNF-α and/or IFN-γ, independently and additively, up-regulated Fas antigen expression on COLO 201 and induced apoptosis in a dose-dependent manner. Both cytokines also increased the COLO 201 sensitivity to anti-Fas antibody, resulting from the down-modulation of Bcl-2 and the up-regulation of Bax. These findings indicate that cytokine(s) plus anti-Fas antibody (which mimics natural Fas ligand) are more effective in inducing apoptosis of COLO 201 than cytokine(s) alone. These findings suggest that immunotherapy in combination with cytokine(s) and lymphokine-activated killer (LAK) cells will become a more effective therapy for cancer than cytokine(s) or LAK cells alone, since the Fas ligand is expressed on activated T cells, natural killer cells and macrophages.
Mapping epitopes for 20 monoclonal antibodies to CR1
Authors: Nickells M , Hauhart R , Krych M , Bala Subramanian V , Geoghegan-Barek K , Marsh H C , Atkinson J P
Published: March 2003

Complement receptor type one (CR1; CD35) binds and processes C3b and C4b opsonized immune complexes and regulates complement activation. We have characterized the epitopes of 13 previously reported and seven new MoAbs to human CR1. The MoAbs formed seven groups based on their reactivity with a panel of deletion forms of CR1. Seventeen of the MoAbs reacted with CR1 at more than one site, a consequence of its repetitive sequence. All five of the MoAbs recognizing epitopes in the nearly identical repeats 3, 10, and 17, as well as one MoAb which reacted with repeats 8 or 1/2 of 9 and 15 or 1/2 of 16, blocked cofactor activity for C3b. Knowledge of the repeats bearing the epitopes for these MoAbs should facilitate the further characterization of CR1.
Recombinant human IL-16 inhibits HIV-1 replication and protects against activation-induced cell death (AICD)
Authors: Idziorek T , Khalife J , Billaut-Mulot O , Hermann E , Aumercier M , Mouton Y , Capron A , Bahr G M
Published: March 2003

The chemoattractant cytokine IL-16 has been reported to suppress lymphocyte activation and to inhibit HIV-1 replication in acutely infected T cells. We have cloned and expressed human IL-16 in Escherichia coli and investigated whether the recombinant protein could regulate the level of lymphocyte apoptosis from HIV-1-infected subjects. After purification and refolding, only 2–10% of the recombinant cytokine was present in a biologically active homotetrameric form. This could explain the need for high concentrations of the bacterially derived IL-16 to induce significant inhibition of HIV-1 replication. Addition of IL-16 to unstimulated peripheral blood mononuclear cell (PBMC) cultures from HIV-1-infected subjects did not modify the observed level of spontaneous lymphocyte apoptosis. In contrast, IL-16 added to PBMC cultures stimulated with anti-CD3, anti-CD95 or dexamethasone reduced significantly the percentage of lymphocytes undergoing AICD. This effect was found to correlate with the ability of the cytokine to decrease CD95 expression on activated CD4+ T cells. Comparative studies on PBMC from healthy individuals indicated that the regulation of apoptosis levels by IL-16 is a complex phenomenon and could depend on the nature of the activator used and/or the immune status of lymphocytes tested. The outcome of CD4 cross-linking on T cells by various ligands is discussed in the context of the observed beneficial activities of IL-16 and its potential role in the treatment of HIV disease.
Somatic hypermutation of immunoglobulin genes is independent of the Bloom's syndrome DNA helicase
Authors: Sack S Z , Liu Y , German J , Green N S
Published: March 2003

Immunoglobulin gene somatic mutation leads to antibody affinity maturation through the introduction of multiple point mutations in the antigen binding site. No genes have as yet been identified that participate in this process. Bloom's syndrome (BS) is a chromosomal breakage disorder with a mutator phenotype. Most affected individuals exhibit an immunodeficiency of undetermined aetiology. The gene for this disorder, BLM, has recently been identified as a DNA helicase. If this gene were to play a role in immunoglobulin mutation, then people with BS may lack normally mutated antibodies. Since germ-line, non-mutated immunoglobulin genes generally produce low affinity antibodies, impaired helicase activity might be manifested as the immunodeficiency found in BS. Therefore, we asked whether BLM is specifically involved in immunoglobulin hypermutation. Sequences of immunoglobulin variable (V) regions were analysed from small unsorted blood samples obtained from BS individuals and compared with germ-line sequences. BS V regions displayed the normal distribution of mutations, indicating that the defect in BS is not related to the mechanism of somatic mutation. These data strongly argue against BLM being involved in this process. The genetic approach to identifying the genes involved in immunoglobulin mutation will require further studies of DNA repair- and immunodeficient individuals.
Sulphatide-binding properties are shared by serum amyloid P component and a polyreactive germ-line IgM autoantibody, the TH3 idiotype
Authors: Wheeler P R , Raynes J G , O'Sullivan G M , Duggan D , McAdam K P W J
Published: March 2003

Serum amyloid P component (SAP) concentration was elevated in sera from leprosy patients, significantly so above endemic controls in lepromatous cases. In the sera of lepromatous leprosy (LL) patients who experienced an erythema nodosum leprosum (ENL) episode the SAP fell at the onset of ENL and remained low throughout, in two of three cases. Changes in SAP concentration parallel anti-sulphatide IgM concentrations. TH3, a monoclonal IgM germ-line antibody derived from a LL patient, and SAP share similar binding patterns. In this study we demonstrate binding to heparin and sulphatide. Moreover, SAP inhibited the binding of TH3 to sulphatide, as well as anti-sulphatide IgM found in a range of sera, and anti-sulphatide IgG in the only sera sample in which it was found. The observation that anti-TH3 idiotype monoclonal and polyclonal anti-SAP antibodies both inhibited the binding of TH3 and IgM in sera (but not IgG) to sulphatide without binding to sulphatide themselves further demonstrated similar binding specificities. The observations of similarity in binding reinforce ideas that SAP may function as a primitive opsonin, but the clear ability to inhibit binding of autoantibodies suggests that SAP may play a role in ameliorating tissue and particularly nerve damage in leprosy patients.
Quantitative intracellular cytokine measurement: age-related changes in proinflammatory cytokine production
Authors: O'Mahony L , Holland J , Jackson J , Feighery C , Hennessy T P J , Mealy K
Published: March 2003

The proinflammatory cytokines play a central role in mediating cellular and physiological responses, and levels may reflect immune system effectiveness. In this study, the effect of ageing on the inflammatory response was examined using a novel method to detect production of the proinflammatory cytokines, i.e. tumour necrosis factor-alpha (TNF-α), IL-6 and IL-1β. Peripheral blood mononuclear cells (PBMC) obtained from healthy donors of different ages were incubated for 0, 24, 48 and 72 h with or without phorbol 12-myristate 13-acetate (PMA) stimulation. At each time point these cells were permeabilized and incubated with secondary conjugated FITC MoAbs specific for each cytokine. A flow cytometric system was developed to quantify specific intracellular fluorescence in T cells (CD3+) and monocytes (CD14+). TNF-α, IL-6 and IL-1β production in cell culture supernatants was also measured using ELISAs. In older subjects, flow cytometry detected significant increases in intracellular T cell TNF-α and IL-6 (P < 0.05). IL-1β was not detected in any of the T cell samples. Likewise, the monocytes of older subjects demonstrated increased intracellular levels of all three cytokines, but these increases were not significant (P > 0.05). These changes in intracellular proinflammatory cytokine levels may explain some of the exaggerated inflammatory responses seen in elderly patients.