bluuebunny/crossref_metadata_2025_split huggingface dataset:
Single nucleotide polymorphism screening and association analysis – exclusion of integrin β7 and vitamin D receptor (chromosome 12q) as candidate genes for asthma
Authors: Vollmert C. , Illig T. , Altmüller J. , Klugbauer S. , Loesgen S. , Dumitrescu L. , Wjst M. 
Published: December 2004

SummaryBackground
The human genes coding for integrin β7 (ITGB7) and vitamin D receptor (VDR) are two of the several candidate genes for asthma and related phenotypes found in a promising candidate region on chromosome 12q that has been identified in multiple genomewide screens and candidate gene approaches.Methods
All exons, including parts of the neighbouring introns, and the predicted promoter region of the ITGB7 gene were screened for common polymorphisms in 32 independent asthmatic and healthy probands, resulting in the detection of two single nucleotide polymorphisms (SNPs) unknown so far. In addition to these SNPs, five already described SNPs of the ITGB7 and one in the human VDR gene were analysed in a Caucasian sib pair study of 176 families with at least two affected children, using matrix assisted laser desorption/ionization time of flight mass spectrometry. All confirmed SNPs were tested for linkage/association with asthma and related traits (total serum IgE level, eosinophil cell count and slope of the dose–response curve after bronchial challenge).Results
Two new variations in the ITGB7 gene were identified. The coding SNP in exon 4 causes a substitution of the amino acid GLU by VAL, whereas the other variation is non‐coding (intron 3). None of the eight analysed SNPs, of either the ITGB7 or the VDR genes, showed significant linkage/association with asthma or related phenotypes in the family study.Conclusions
These findings indicate that neither the human ITGB7 nor the VDR gene seem to be associated with the pathogenesis of asthma or the expression of related allergic phenotypes such as eosinophilia and changes in total IgE level.
Surfactant protein D deficiency influences allergic immune responses
Authors: Schaub B. , Westlake R. M. , He H. , Arestides R. , Haley K. J. , Campo M. , Velasco G. , Bellou A. , Hawgood S. , Poulain F. R. , Perkins D. L. , Finn P. W. 
Published: December 2004

SummaryBackground
The collectin surfactant protein D (SP‐D) confers protection against pulmonary infection and inflammation. Recent data suggest a role for SP‐D in the modulation of allergic inflammation.Objective
The aim of this study is to characterize the immune responses of SP‐D‐deficient (SP‐D−/−) mice in a kinetic model of allergic inflammation. We determined whether allergic parameters were enhanced in SP‐D−/− mice in vivo. Further, we examined whether functional immune responses in vitro such as lymphocyte proliferation (LP) and cytokine production were modulated in the absence of SP‐D.Methods
In vivo, wild‐type (WT) and SP‐D−/− mice were sensitized and challenged with the allergen ovalbumin (OVA) and assessed for allergic parameters (bronchoalveolar lavage (BAL) eosinophils, IL‐13 production, pulmonary IFN‐γ, IL‐10 expression) at early time points (1 and 3 days of challenge) in comparison with late time points (7 days of challenge). In vitro, spleen cells from WT and SP‐D−/− mice were stimulated with the mitogen concanavalin A (ConA) and lipid A (LpA) and analysed for LP, IL‐13 and IFN‐γ production. Toll‐like receptor 4 (TLR4), ligand for LpA, was assessed by mRNA expression and immunohistochemistry in vivo.Results
Following allergen exposure in vivo, SP‐D−/− mice expressed higher BAL eosinophils and IL‐13 concentrations and lower IFN‐γ expression at early time points compared with WT mice. IL‐10 expression was increased at early time points in SP‐D−/− compared with WT mice. Allergen‐induced TLR4 expression was increased in WT, but not in SP‐D−/− mice. After stimulation with LpA and ConA in vitro LP was increased and IFN‐γ concentration was decreased in SP‐D−/− mice.Conclusion
SP‐D may be critical for the modulation of early stages of allergic inflammation in vivo.
Serum ovalbumin‐specific immunoglobulin G responses during pregnancy reflect maternal intake of dietary egg and relate to the development of allergy in early infancy
Authors: Vance G. H. S. , Grimshaw K. E. C. , Briggs R. , Lewis S. A. , Mullee M. A. , Thornton C. A. , Warner J. O. 
Published: December 2004

SummaryBackground
The value of allergen elimination diets during pregnancy for primary prevention of infant allergy has been questioned. However, dietary compliance may influence effectiveness.Objectives
To monitor egg intake during a randomized controlled trial of egg avoidance throughout pregnancy and lactation by serial measurements of serum ovalbumin (OVA) IgG concentration in conjunction with dietary diary record and also, to analyse specific IgG concentrations at birth in relation to infant allergic outcome.Methods
Pregnant women, with personal or partner atopy, were randomized to complete dietary egg exclusion or an unmodified healthy diet before 20 weeks gestation. The infants were evaluated for atopy at 6 months of age. Serum food‐specific IgG concentrations were determined by ELISA in maternal samples collected at study recruitment and during labour, and in infant samples at birth (umbilical cord).Results
Serum‐specific IgG to OVA, but not the unrelated allergen, cow's milk β‐lactoglobulin, decreased over pregnancy in egg‐avoiding women only (P<0.001). Cord OVA IgG concentration correlated with maternal IgG at delivery (r=0.944; P<0.001), and for infants born to atopic women, cord concentration was higher than that of their mother's (P<0.001). Infants with the lowest and highest cord IgG concentrations were the least likely, and those with mid‐range concentrations were the most likely, to be atopic by 6 months of age (P=0.008).Conclusion
Serum OVA IgG concentration reflects egg consumption, thereby indicating dietary allergen doses to which the developing immune system might be exposed. Trans‐placental maternal IgG must be considered among early life factors that regulate infant atopic programming.
Expression of tyrosine hydroxylase and neuropeptide tyrosine in mouse sympathetic airway‐specific neurons under normal situation and allergic airway inflammation
Authors: Dinh Q. T. , Groneberg D. A. , Witt C. , Peiser C. , Cifuentes L. B. , Frossard N. , Klapp B. F. , Fischer A. 
Published: December 2004

SummaryBackground
The traditional neurotransmitter catecholamine and the neuropeptide tyrosine in sympathetic airway nerves have been proposed to be involved in the pathogenesis of airway diseases.Objective
The aim of the present study was to investigate the effect of allergic airway inflammation on the expression of catecholamine enzyme tyrosine hydroxylase (TH), neuropeptide tyrosine (NPY) and tachykinins in mouse sympathetic airway ganglia.Methods
Using neuronal tracing in combination with immunohistochemistry, the present study was designed to characterize TH, NPY and tachykinin profiles of superior cervical (SCG) and stellate ganglia after allergen challenge.Results
The vast majority of fast blue‐labelled SCG neurons (allergen: 97.5±1.22% (mean±SEM) vs. controls: 94.5±1.48%, P=0.18) and stellate neurons (allergen: 95.3±1.01% vs. controls: 93.6±1.33%, P=0.34) were immunoreactive for TH. Of the TH immunoreactive and fast blue‐labelled SCG neurons, 52.0±1.01% allergen vs. 51.2±3.58% controls (P=0.83) and stellate neurons, 57.3%±0.97 allergen vs. 56.4±1.65% controls (P=0.64) were positive for TH only but not NPY, whereas 45.3±1.05% allergen vs. 43.3±1.18% controls (P=0.47) of fast blue‐labelled SCG neurons and 37.9±0.86% allergen vs. 37.1±1.24% controls (P=0.62) of fast blue‐labelled stellate neurons were immunoreactive for both TH and NPY immunoreactivities. There was a trend of an increase, but not significant one, in the percentage of TH‐/NPY‐immunoreactive and fast blue‐labelled neurons in allergen‐treated animals in comparison with the controls. Tachykinins, however, were not expressed by sympathetic neurons and were also not induced in sympathetic neurons after allergen challenge.Conclusion
The present study indicates that allergic airway inflammation does not alter the expression of noradrenalin and NPY in sympathetic ganglia and also shows that sympathetic neurons do not respond to allergic airway inflammation with tachykinins induction. However, a participation of catecholamine and NPY in the pathogenesis of allergic airway inflammation cannot be excluded in the present study as a higher neurotransmitter output per neuron following allergen challenge could be possible.
Molecular and structural analysis of immunoglobulin E‐binding epitopes of Pen ch 13, an alkaline serine protease major allergen from Penicillium chrysogenum
Authors: Lai H.‐Y. , Tam M. F. , Chou H. , Lee S.‐S. , Tai H.‐Y. , Shen H.‐D. 
Published: December 2004

SummaryBackground
Through proteomic and genomic approaches we have previously identified and characterized an alkaline serine protease that is a major allergen (88% frequency of IgE binding) of Penicillium chrysogenum (Pen ch 13).Objective
The aim of the present study is to identify the linear IgE‐binding epitopes of Pen ch 13.Methods
IgE‐binding regions were identified by dot‐blot immunoassay using 11 phage‐displayed peptide fragments spanning the whole molecule of Pen ch 13. The minimal epitope requirements for IgE binding were further defined with overlapping peptides synthesized on derivatized cellulose membranes using SPOTs technology. The critical residues on the immunodominant epitopes were mapped through site‐directed mutagenesis. The locations of the IgE epitopes identified were correlated with a three‐dimensional structure of Pen ch 13.Results
IgE antibodies in 35 serum samples reacted with at least one of the 11 peptide fragments of Pen ch 13. Peptide f‐2n (residues 31–61) showed a high‐intensity and the highest frequency (77%) of IgE binding. The frequencies of IgE binding to peptide f‐4 (residues 93–133), f‐1 (residues 1–37) and f‐7 (residues 168–206) were 51%, 34% and 31%, respectively. SPOTs assay narrowed down the region of IgE binding of f‐2n to residues 48–55 (GHADFGGR). Three, two and one epitope(s) that are four to nine amino acids in length, within f‐4, f‐1 and f‐7, respectively, were found. Site‐directed mutagenesis of Pen ch 13 revealed that substitution of His49 and/or Phe52 on Pen ch 13 with methionine resulted in proteins with drastic loss of IgE binding in seven sera tested. Proteins with amino acid replacements at residues 15–18 (RISS), or at residues 112 (I) and 116 (D) have lower IgE‐binding reactivity in one of the two patient's sera tested. Substituting residues 117 (W), 119 (V) and 120 (K) also block most of the IgE binding in one of the two patient's sera tested. In addition, replacing residues 203 (V) and 204 (D) along with a deletion at residue 206 (Y) diminished the IgE binding in two serum samples tested. A model was constructed based on the structure of P. cyclopium subtilisin protease that has >90% (256 out of 283 amino acids) sequence identity with Pen ch 13. The major epitope (GHADFGGR) on Pen ch 13 formed a loop‐like structure and was located at the surface of the allergen.Conclusions
Several linear IgE‐reactive epitopes and their critical core amino acid residues were identified for the Pen ch 13 allergen. The major linear IgE‐binding epitope, 48GHADFGGR55, formed a loop‐like structure at the surface of the allergen. Substitution of His49 and/or Phe52 with methionine significantly reduced IgE‐binding to Pen ch 13. Mapping of these results on a 3D model of the allergen provides valuable information about the molecular basis of allergenicity for Pen ch 13 and for designing specific immunotherapeutics.
Biological effects of montelukast, a cysteinyl‐leukotriene receptor‐antagonist, on T lymphocytes
Authors: Spinozzi F. , Russano A. M. , Piattoni S. , Agea E. , Bistoni O. , De Benedictis D. , De Benedictis F. M. 
Published: December 2004

SummaryBackground
Montelukast (MNT), a cysteinyl‐leukotriene receptor (Cys‐LTR) antagonist, has anti‐inflammatory activity in the treatment of allergic diseases. If this effect is due only to blocking leukotrienes or also owing to inhibiting proliferation and survival of inflammatory cells, is actually unknown.Objective
Testing the hypothesis that MNT could influence T lymphocyte functional behaviour in vitro.Methods
Normal T lymphocytes were analysed for surface expression of Cys‐LTR1 and Cys‐LTR2 by means of monoclonal antibodies (mAbs), in the resting state and after activation with T helper type 2 cytokine or T cell receptor (TcR) stimulation. Proliferative activity, as well as IL‐4 andIFN‐γ production, were simultaneously determined in samples exposed to molar concentrations of MNT from 10−8 to 10−5. Programmed cell death in cultured samples was evaluated by means of propidium iodide and fluorescein isothiocyanate‐conjugated anti‐Annexin V mAb staining. The complementary DNA microarray technique was adopted to identify gene products involved in apoptosis induction.Results
Resting T cells expressed low levels of Cys‐LTR. Upon anti‐CD3 mAb activation, a progressive increase in Cys‐LTR1 and ‐LTR2 expression was observed. Exposure to MNT reduced proliferative response to TcR engagement, increased IFN‐γ production and led to apoptosis at minimal concentrations of 10−6 m. A progressive loss in BAD and B cell lymphoma/leukaemia‐2 activities, and an increase in the expression of CD27, TRAF3, TRAIL, p53 and Fas genes were also observed.Conclusions
Biological effects of MNT delineate a complex picture of gene activation and repression, probably induced by Cys‐LTR blockade. The induction of apoptosis in allergen‐specific T cell population, as a final result, appears fundamental in the treatment of asthma.
The effect of specific immunotherapy on the expression of costimulatory molecules in late phase reaction of the skin in allergic patients
Authors: Plewako H. , Arvidsson M. , Oancea I. , Hasséus B. , Dahlgren U. , Rak S. 
Published: December 2004

SummaryBackground
Specific immunotherapy (SIT) modulates immune responses to allergens resulting in improvement of allergic symptoms. However, the mechanisms behind the clinical changes are not clear. Participation of costimulatory molecules on antigen‐presenting cells and T cells in the process of antigen recognition is suggested to be of essential importance. The SIT effect on expression of costimulatory molecules has not been earlier examined.Methods
Forty‐one birch‐allergic patients were treated with SIT or placebo. After 1 year of treatment skin biopsies were obtained 24 h following allergen challenge. Sections were stained with antibodies against: EG2 (eosinophils), CD4 (T cells), CD68 (macrophages), CD1a (Langerhans cells), CD28 (on T cells) and costimulatory molecules (CD80, CD86).Results
Following allergen challenge number of the CD4+ and CD68+ cells increased significantly (P=0.002, 0.0001, respectively) in the placebo, but not in the SIT‐treated patients. The difference between groups was significant (P=0.003, 0.01, respectively). The numbers of EG2+ cells increased significantly in both groups. CD80+ cell numbers increased in the placebo (P=0.01) but not in the SIT group. The number of CD86+ cells increased in both groups (placebo, P=0.001; SIT, P=0.01) but significantly less in the SIT group (P=0.05). The numbers of CD28+ cells increased in the placebo (P=0.001) but remained unchanged in the SIT group. The difference between the groups was significant (P=0.05).Conclusion
There were lower numbers of cells expressing costimulatory molecules in SIT‐treated than in placebo‐treated patients. Decreased costimulation may lead to diminished immune response following allergen exposure. This could be an important factor contributing to the clinical improvement after SIT.
Reticular basement membrane thickening in airways of lung transplant recipients is not affected by inhaled corticosteroids
Authors: Ward C. , De Soyza A. , Fisher A. J. , Pritchard G. , Forrest I. A. , Corris P. A. 
Published: December 2004

SummaryIntroduction
Chronic rejection is a major problem for all lung transplant programmes, which is functionally manifested by fixed airflow limitation, Bronchiolitis Obliterans Syndrome (BOS). The inclusion of a Pre‐BOS category, BOS0∼p, in newly revised guidelines, recognizes the potential importance of early changes. We have previously demonstrated reticular basement membrane (Rbm) thickening in clinically stable lung transplant recipients free from BOS. The present study extends this, testing the hypothesis that inhaled corticosteroid (ICS) therapy will lead to a decrease in Rbm thickness in lung transplant recipients.Methods
A parallel group, bronchoscopic intervention study of clinically stable lung allograft recipients, free from BOS, but with evidence of airway inflammation. Following baseline assessment of Rbm thickening, subjects were randomized to 3 months of either chlorofluorocarbon‐driven beclomethasone diproprionate (BDP) 400 μg b.i.d., or a formulation designed to yield at least an equivalent dose, hydrofluoroalkane‐driven BDP, 200 μg b.i.d.Results
Three months treatment with a moderate dose of ICS, including a formulation designed for preferential small airway deposition, had no effect on Rbm thickening (13±3 vs. 14±5 μm post‐ICS).Conclusion
Our data would suggest that airway remodelling can occur early in lung allografts and is not affected by moderate dose ICS therapy. Longitudinal studies are required to describe the pathophysiological processes involved in BOS, and specifically to elucidate potential relationships between airway remodelling, airflow obstruction and allograft failure.
Identification of anti‐inflammatory drugs according to their capacity to suppress type‐1 and type‐2 T cell profiles
Authors: Moed H. , Stoof T. J. , Boorsma D. M. , Von Blomberg B. M. E. , Gibbs S. , Bruynzeel D. P. , Scheper R. J. , Rustemeyer T. 
Published: December 2004

SummaryBackground
Down‐regulation or modulation of T cell activity by immunosuppressive drugs is an effective treatment in diseases where exaggerated T cell responses play a role. A primary effect of the anti‐inflammatory drugs (AIDs) is inhibition of the synthesis of growth factors, such as IL‐2, thereby down‐regulating T cell proliferation. However, it is still largely unknown to what extent these AIDs are able to down‐regulate specifically type‐1 or type‐2 T cell cytokine production, and whether they can down‐modulate chemokine receptor expression, thereby preventing migration of T cells to the site of inflammation.Objective
We investigated the suppressive effect of dermatologically used AID (cyclosporin A (CsA), lactoferrin (LF), 1α, 25‐dihydroxyvitamin D3 (VD3), hydrocortisone (HC), di‐methyl‐fumarate (DMF), diclofenac (DF)) on both type‐1 and type‐2 T cells. Since allergic contact dermatitis is a skin disorder in which an exaggerated T cell response of both types of T cell subsets can be observed, we used this disorder as a model to study the capacity of AID to suppress type‐1 or type‐2 T cell responses.Methods
Peripheral blood mononuclear cells of nickel allergic patients were cultured in the presence of allergen and increasing concentrations of AID. Proliferation was determined by measuring 3H thymidine incorporation; chemokine receptor (CCR10, CCR4, CXCR3) expression was studied by flow cytometric analysis and IFN‐γ or IL‐5 cytokine production was measured by ELISA.Results
Three major patterns can be distinguished regarding the effect of AID on T cell responses. The first group, including CsA and LF, inhibited non‐selectively T cell proliferation, chemokine receptor expression and cytokine production, with CsA as the most potent drug tested. A second group of AID, which included VD3, HC and DMF, suppressed mainly type‐1 T cell responses, as revealed by strong interference with IFN‐γ production and CXCR3 expression, and limited effects on either or both IL‐5 and CCR4 expression. The third pattern was displayed by DF, which down‐regulated IL‐5 production and CCR4 expression, whereas IFN‐γ and CXCR3 were unaltered.Conclusions
Using a contact allergy model, we have demonstrated that various AIDs show distinct pharmacological profiles in that either type‐1 or type‐2 or both T cell responses are suppressed. These results should contribute to a more rational selection of AID in treating inflammatory skin diseases mediated by either or both of these T cell subsets.
Determination of the T cell epitopes of the lipocalin allergen, Rat n 1
Authors: Jeal H. , Draper A. , Harris J. , Taylor A. Newman , Cullinan P. , Jones M. 
Published: December 2004

SummaryBackground
Laboratory animal allergy (LAA) is an important cause of occupational sensitization and asthma. Rats are a frequent cause of LAA and the major rat allergen, Rat n 1, is a member of the lipocalin protein family, which includes several other animal allergens such as the cow allergen, Bos d 2. To date, Bos d 2 is the only mammalian lipocalin allergen to have been studied in detail.Objective
We undertook a cross‐sectional study of a large population of individuals exposed to laboratory rats to determine the proliferative responses of peripheral blood mononuclear cells (PBMCs) to the major rat allergen, Rat n 1.Methods
Eighty‐three cases (defined by a positive skin prick test (SPT) 3 mm and/or a positive RAST 2% binding) and 274 referents without specific IgE to rats were tested for their proliferative responses of PBMCs to rat allergen. Cytokine release to rat urinary protein was examined in 28 sensitized and 42 non‐sensitized exposed individuals.Results
Proliferation to rat urinary protein was weak in all individuals. Four regions within Rat n 1 were identified as containing potential immunodominant T cell epitopes and three of these co‐localized within the conserved regions of the lipocalin molecule. All four regions within Rat n 1 overlapped considerably with the characterized epitopes of the lipocalin allergen, Bos d 2. IL‐5 and ratios of IL‐5/IFN‐γ were significantly increased in cases.Conclusion
The response to Rat n 1 is remarkably similar to the cow lipocalin allergen Bos d 2. T cell epitopes within lipocalins appear to co‐localize with the conserved regions of the molecule. LAA is characterized by an increased production of IL‐5. Investigation of other lipocalin allergens will provide further information about the allergenicity of this group of proteins.