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Background Haemopoietic progenitor cells ( HPC) migrate to sites of allergic inflammation where, upon stimulation with epithelial cytokines, they produce Th2 cytokines and differentiate into mature eosinophils and basophils. They also express Toll-like receptors ( TLR) involved in antimicrobial responses. Objective The objective of this study was to compare TLR expression on peripheral blood HPC and TLR-induced responses, in particular changes in epithelial cytokine receptors, in healthy and asthmatic subjects at baseline and following allergen challenge. Methods Ten healthy and 11 allergic asthmatic subjects were studied. HPC-enriched cell populations were stimulated with TLR-2, TLR-4 or TLR-9 ligands. TLR expression by circulating HPC and interleukin ( IL)-25 ( IL-17 RB), IL-33 ( ST2) and thymic stromal lymphopoietin receptor ( TSLPR) expression after TLR ligation were examined by flow cytometry at baseline and, in asthmatics, following allergen challenge. The effects of dexamethasone (Dex) on TLR-induced responses were also assessed. Results Asthmatics had significantly lower circulating HPC expressing TLR-2 and TLR-9 with a similar trend for TLR-4. TLR-4 stimulation of HPC yielded higher numbers of TSLPR+ cells in asthmatics compared with healthy subjects. A similar trend was seen for TLR-9 ligation, an effect further augmented by allergen inhalation. Allergen challenge also enhanced TLR-induced ST2 expression on HPC. Treatment with Dex in vitro increased TLR-4-induced TSLPR expression but had no effect on other epithelial cytokine receptors. Conclusions and Clinical Relevance These data demonstrate an interaction between allergen and TLR ligand exposure in asthmatics. Allergen inhalation augments the TLR-induced inflammatory response by HPC, possibly leading to increased 'in situ haemopoiesis' through up-regulation of TSLPR. These findings show that HPC may be a part of the pro-inflammatory cascade in pathogen-induced asthma exacerbation through their increased responsiveness to TLR stimulation. [ABSTRACT FROM AUTHOR]

Prenatal and early-life environmental exposures play a key role in the development of atopy and allergic disease. The Family Atherosclerosis Monitoring In earLY life Study is a general, population-based Canadian birth cohort that prospectively evaluated prenatal and early-life traits and their association with atopy and/or allergic disease. The study population included 901 babies, 857 mothers and 530 fathers. Prenatal and postnatal risk factors were evaluated through questionnaires collected during the antenatal period and at 1 year. The end points of atopy and allergic diseases in infants were evaluated through questionnaires and skin prick testing. Key outcomes included atopy (24.5%), food allergy (17.5%), cow’s milk allergy (4.8%), wheezing (18.6%) and eczema (16%). The association between infant antibiotic exposure [odds ratio (OR): 2.04, 95% confidence interval (CI): 1.45–2.88] and increased atopy was noted in the multivariate analysis, whereas prenatal maternal exposure to dogs (OR: 0.60, 95% CI: 0.42–0.84) and acetaminophen (OR: 0.68, 95% CI: 0.51–0.92) was associated with decreased atopy. This population-based birth cohort in Canada demonstrated high rates of atopy, food allergy, wheezing and eczema. Several previously reported and some novel prenatal and postnatal exposures were associated with atopy and allergic diseases at 1 year of age. [ABSTRACT FROM PUBLISHER]

Background Hematopoietic progenitor cells, especially those committed to the Eo/ B lineage, are known to contribute to allergic inflammation. Objective The aim of the present study was to investigate whether environmental factors are associated with changes in numbers of circulating Eo/ B progenitors at 1 year of age. Methods Peripheral blood from 60 1-year-old children enrolled in the LINA (Lifestyle and environmental factors and their Influence on Newborns Allergy risk) birth cohort was assessed for Eo/ B progenitor cells ( Eo/ B CFU) using standardized and validated methylcellulose assays. Frozen peripheral blood mononuclear cells ( PBMC) were cultured in the presence of IL-3, IL-5 or GM- CSF, and Eo/ B CFUs enumerated. Clinical outcomes and exposure to environmental tobacco smoke ( ETS) were documented by standardized questionnaires, and indoor volatile organic compound ( VOC) concentrations were assessed by passive sampling. Results Children with skin manifestations (atopic dermatitis or cradle cap) within the first year of life had higher numbers of circulating IL-3-, IL-5- or GM- CSF-stimulated Eo/ B CFUs ( P < 0.05) at 1 year. In children with cradle cap, a positive correlation was found between Eo/ B CFUs and exposure to ETS-related VOCs during pregnancy or at 1 year of age ( P < 0.05). Conclusions and Clinical Relevance This is the first demonstration that environmental exposures are positively associated with levels of circulating Eo/ B progenitors. The recruitment and differentiation of Eo/ B progenitors in response to environmental triggers may play a role in the development of skin manifestations during the first year of life. [ABSTRACT FROM AUTHOR]

The article presents information on allergic rhinitis and its impact on asthma (ARIA). It informs that allergic rhinitis is a symptomatic disorder of the nose which is induced when exposed to allergen by an immunoglobulin E-mediated inflammation of the membranes lining the nose. It is noted that allergic rhinitis is a global health problem and the World Health Organization in the ARIA workshop updated guidelines concerning the disorder.

Nervous system involvement in systemic lupus erythematosus (SLE) is typically diagnosed on the basis of clinical psychiatric and/or neurologic syndromes (NPSLE). Neuropsychological tests can be used to assess nervous system integrity even in the absence of major NP syndromes. Their application has uncovered significant cognitive dysfunction, ranging from mild to severe, in a sizeable proportion of SLE patients irrespective of clinical NP status. Cognitive dysfunction has now been accepted as a bona fide manifestation of NPSLE. The heterogeneity of clinical NPSLE manifestations is paralleled by the diversity of cognitive deficits reported in different studies and within different patients. The success of attempts to explain these deficits on the basis of potential pathogenetic mechanisms, such as antibrain antibodies and proinflammatory cytokines, has been uneven. To date, the most robust findings have emerged in relation to antiphospholipid antibodies, which carry with them important therapeutic implications. [ABSTRACT FROM AUTHOR]

Increasing levels of proinflammatory cells, including eosinophils and basophils, are seen at the site of allergen challenge in allergic disease of the airways. Mechanisms for the recruitment of these cell types could involve either specific upregulation of adhesion molecule and chemoattraction, or the initiation of proliferation and differentiation of inflammatory cell progenitors derived from the bone marrow. In this study, we demonstrate, in two systems of eosinophilic–basophilic lineage-committed granulocytes of relative immaturity, that eosinophilic differentiation in vivo implies the induction of a distinct adhesion phenotype, characterized by the upregulation of β 7 integrin and downregulation of β 1 and α 5 integrins. Moreover, the eosinophilic differentiation induced an upregulation of complement receptor type 1 and type 3, and the expression was further enhanced upon a short-course in vitro activation with ionomycin. These data indicate a sequential alteration of disparate members of the integrin family during eosinophilic–basophilic differentiation, which may attribute to specific adhesion requirements at distinct stages of cell maturation. [ABSTRACT FROM AUTHOR]

Summary Eosinophils elaborate a number of proinflammatory mediators, including immunoregulatory cytokines and chemokines. Interleukin (IL)-4 and RANTES are important cytokines that have previously been shown to be expressed by mature eosinophils. We hypothesized that de novo synthesis of IL-4 and RANTES occurs in nascent eosinophils, leading to storage of newly produced proteins in crystalloid granule-like structures. Cytokine mRNA and protein expression were examined in cultured eosinophil colonies, which were derived from purified cord blood CD34+ cells and generated in semisolid media (methylcellulose) in the presence of recombinant human (rh)IL-3 and rhIL-5. Cytokine mRNA profiles were analysed by the reverse transcription–polymerase chain reaction (RT–PCR) to determine transcription of IL-4 and RANTES in cells on days 0, 7, 14, 21 and 28 of culture. The expression of translated cytokine products and granule major basic protein (MBP) was confirmed, from day 23 onwards, for colonies cultured in semisolid media, by immunofluorescent labelling and confocal laser-scanning microscopy (CLSM). We found that mRNA sequences encoding IL-4 and RANTES were expressed in freshly prepared, non-differentiated CD34+ cells. Furthermore, RANTES mRNA localized to carbol chromotrope 2R-positive colony cells, as assessed using in situ RT–PCR on day 21 of culture in semisolid media, and was found to gradually decrease (relative to β2-microglobulin) in rhIL-3- and rhIL-5-treated colony cells (comprising > 90% eosinophil-like cells) up to day 28. Immunoreactivity for IL-4 and RANTES co-localized with MBP in maturing colony eosinophils on day 23 of culture in semisolid media, as judged by CLSM. These results suggest that synthesis and storage of immunoregulatory cytokines, essential for processes associated with adaptive immunity, occurs in nascent eosinophils during their growth and differentiation. [ABSTRACT FROM AUTHOR]

Background: The sequence of adhesion-molecule expression during eosinophil differentiation remains unclear. Methods: We analyzed the surface expression of α4, β1, and β7 integrins and compared it to established myeloid developmental markers, using the eosinophilic cell line HL-60 clone 15, as well as cord and peripheral blood differentiation assays. Results: Cells induced to eosinophil differentiation by treatment with butyric acid, IL-5, and GM-CSF showed a significant upregulation of β7 integrin expression coincident with a marked upregulation of CD35 and attenuation of CD33 and β1 integrin expression. In addition, adhesion of induced HL-60 clone 15 cells to fibronectin was attenuated by a β7 integrin antibody. Conclusions: Our data show that protein synthesis-dependent upregulation of the functional β7 integrin occurs under conditions when α4 and β1 integrins are fully expressed, indicating a sequential appearance of specific adhesion molecules on differentiating eosinophil progenitors. [ABSTRACT FROM AUTHOR]

Focuses on the role of the bone marrow in providing an ongoing source of differentiating inflammatory cells to the upper and lower airways. Relationship between rhinitis and asthma; Sensitivity of a systemic hemopoietic process to inhaled corticosteroids; Production of growth factors.

The effect has been investigated of local administration of beclomethasone dipropionate (BDP) on cell numbers of nasal epithelial metachromatic cell (NMC) sub-populations. Twenty-one patients with perennial allergic rhinitis were studied in four groups according to the duration of treatment or after treatment with BDP. Nasal scrapings were taken after 1 week (Group 1) or 2 weeks (Group 2) of BDP treatment, or after discontinuing BDP for 1 week (Group 3) or 2 weeks (Group 4). Cells were fixed with Mota's lead acetate or 10% buffered formalin followed by toluidine blue staining to count the number of NMC and to classify these according to morphological sub-types (basophils or mast cells). Formalin-sensitive mast cells and basophils in nasal scrapings were reduced more than formalin-resistant mast cells with BDP treatment. Formalin-sensitive mast cells were also more prompt to recover from BDP than formalin-resistant mast cells. The results suggest that the formalin-sensitive NMC is a sub-population of cells which responds to BDP treatment in allergic rhinitis. [ABSTRACT FROM AUTHOR]

We have described functional and biochemical characteristics of a distinct T-cell dependent guinea- pig basophil-stimulating factor (BSF), measured using a sensitive 7-day bone marrow culture assay, standardized with high-activity BSF present in serum-free splenic cell-conditioned medium (CM). In the present studies, the in vivo relevance of BSF was explored during protocols of induction of peripheral blood or tissue basophil responses to ovalbumin (OA) injection or Amblyomma wnerkanwn tick feeding. Pooled immune serum, taken from OA-injected inbred or outbred animals during induction of blood and marrow basophilia, contained an in vitro inhibitor to BSF at high concentrations and BSF-like activity at low concentrations; maximal stimulation of histamine synthesis by bone marrow cells in vitro was found in the presence of Day 4 OA-immune serum. In vivo studies in the OA model demonstrated maximal serum BSF-like activity at 48-72 hr before peak bone marrow basophil response, followed by a levelling off to 50% of maximum at 2 weeks. In the tick model, serum BSF-like activity was present in Day 8, but not Day I, post-primary infection and was maximal at Day 3 post-secondary infection; post-primary Day I serum was inhibitory to basophil growth in vitro. These observations suggest that BSF regulates the appearance of basophils in response to antigen in vivo by an effect on basophil progenitors. The observations stress the potential application of guinea-pig models to understanding the regulation of basophil production in allergic disorders. [ABSTRACT FROM AUTHOR]

Intestinal mastocytosis begins to develop in rats, depending on the strain, at 14 (outbred Sprague-Dawley, SD) or 16 (inbred Lewis, L) days after infection with the nematode Nippostrongylus brasiliensis (Nippo). We have investigated in vitro mastopoiesis from mesenteric lymph node (MLN) cells cultured at various intervals post-infection, using a modified Marbrook liquid system. Greater increases in mast cells (MC) were observed in cultures of SD-MLN removed on day 14 after Nippo infection (IMLN-14) than from MLN removed from uninfected animals (NMLN): seven- to twenty-fold versus up to two-fold at 2 weeks and forty- to two hundred-fold versus up to twenty- fold at 4 weeks, respectively (P«0.002). In contrast, similar differential increases in MC and histamine compared to uninfected controls, were demonstrated in 2 week cultures of MLN from L strain rats removed 17 (IMLN-17) and 20 (IMLN-20) but not 14 days after Nippo infection (P«0.001). The presence of phytohaemagglutinin (PHA) in vitro was associated with enhanced MC differentiation from both IMLN-17 and IMLN-20, while worm antigen (Ag) stimulated mastopoiesis from IMLN-17, but suppressed the response from IMLN-20 (P « 0.02). Conditioned media (CM) prepared from unstimulated or PHA-stimulated IMLN-32 (i.e. removed 32 days after Nippo infection) caused significant mastopoiesis from NMLN ha vitro when compared to no CM or Ag-stimulated CM (P«0.01). Either MC precursors or cells which help MC differentiation exist in increased numbers in MLN of Nippo-infected rats. Mitogenic or antigenic stimulation modulates in vitro mastopoiesis, either directly or through soluble factors derivable from MLN cells. These in vitro methods can be utilized to understand further mechanisms of intestinal mastocytosis in the rat. [ABSTRACT FROM AUTHOR]

This article focuses on basophil mast cell and eosinophil growth and differentiation factors in human allergic disease. The synergistic action of cytokines and the involvement of tissue micro-environments, including factors from fibroblasts, endothelial cells and epithelial cells, appear to be important determinants of both the numbers of effector cells, as well as their phenotype and heterogeneity in various tissues such as the nasal mucosa, lung, gastrointestinal tract and skin. It is tempting to speculate that the genetic underpinnings of the allergic diathesis involve basic defects in epithelial, endothelial or other micro-environmental controls, for classical and lineage-specific haemopoietic, and/or pro-inflammatory cytokine production.

The article discusses the hemopoietic progenitors and cytokines in allergic inflammation. It highlights the hemopoietic mechanisms in mucosal inflammatory disease including allergen-induced bronchial hyperresponsive analysis in asthma using human and animal test controls. It also determines the participation of bone marrow in the production of immunoglobulin E receptor-positive inflammatory cells.

Airways inflammation involves accumulation of inflammatory cells such as eosinophils, basophils and mast cells, which are derived from progenitors in marrow and blood. The inflamed tissue of the airways, through its structural (epithelium, stroma) and inflammatory cell components, produces an array of cytokines which can influence the differentiation of inflammatory cell progenitors. It is particular mechanism that we have investigated, showing that molecules such as GM-CSF, G-CSF, IL-6, IL-8 and SCF can be produced by airways epithelial cells and fibroblasts in quantities sufficient to induce hemopoietic events, either systemically or locally. Corticosteriods may act therapeutically, at least in part, to block inflammatory cell differentiation, and thus recruitment, into the allergic inflammatory process in the airways. [ABSTRACT FROM AUTHOR]

Respiratory epithelial mast cells are an expression of airway inflammatory processes. Nasal epithelial mast cells are known to be increased in allergic rhinitis and have now been examined in patients with nasal polyps. Metachromatic cell counts (mean ± standard error) expressed as the sum of large mast cells, atypical mast cells and basophils in epithelial scrapings of the inferior turbinates assessed after Carnoy's fixation and toluidine blue staining (pH 0.5), were 37.5±29 in non-allergic normal control subjects (n = 11), 435±130 in polyp patients who were allergic (n = 18), and 699±267 in polyp patients who were not allergic (n = 8). Metachromatic - cell counts in epithelial scrapings obtained in vivo from nasal polyps of allergic patients (n = 8) were 1769±962, and 2308±1544 from polyps of non-allergic patients (n = 5); metachromatic counts were 2089±633 in epithelial scrapings from excised polyps of allergic patients (n = 14). and 2214±640 from polyps of non-allergic patients (n = 13). It is concluded that the number of metachromatic cells in the epithelium of nasal polyps and the adjacent nasal mucosa is elevated compared with normal nasal epithelium and the increased number does not depend upon allergy. [ABSTRACT FROM AUTHOR]

Objective: To examine specific lymphocyte or neuronal antigens immuno-precipitated by systemic lupus erythematosus (SLE) sera.Method: SLE sera were screened for the presence of antibodies binding to surface antigens of CD4(+) HUT-78 or SK-N-SH and IMR-6 neuroblastoma cells using Western blotting or radioimmunoprecipitation.Results: IgG eluates from both lymphocytes and neuroblastoma cells recognised a 52 kd band in HUT 78 cell lysates. Eight sera studied further using radioimmunoprecipitation also demonstrated binding to a 52 kd antigen (4/8 on HUT-78, 8/8 on SK-N-SH cells), partially depleted by absorption with viable HUT-78.Conclusion: A 52 kd antigen recognised by SLE sera on lymphocytes and neuronal cells may play a role in the pathogenesis of neuropsychiatric-SLE. [ABSTRACT FROM AUTHOR]

The hypothesis that lymphocytotoxic antibodies are associated with neuropsychiatric involvement in systemic lupus erythematosus (NP-SLE) is re-evaluated in this study. In an unselected cohort of 98 women with SLE a cross-sectional study has been performed to analyse associations among standardised clinical, neurological, and neuropsychological assessments and lymphocytotoxic antibodies measured by microcytotoxicity assay. Fifty patients showed objective clinical evidence of continuing or past NP-SLE and 54 patients had cognitive impairment. In accordance with previous observations 44% (24/54) of the cognitively impaired group did not have clinically detectable evidence of NP-SLE. Although lymphocytotoxic antibodies were found to be only marginally more prevalent in those patients with a clinical diagnosis of NP-SLE than in those without (32% v 23%), these antibodies were significantly associated with cognitive impairment (chi 2 = 5.42; p less than 0.02). No association was detected between lymphocytotoxic antibodies and either overall systemic disease activity or other organ system involvement, suggesting that the association between lymphocytotoxic antibodies and cognitive dysfunction in SLE is specific. [ABSTRACT FROM PUBLISHER]

To determine the significance of changes in serum antineuronal antibody levels in systemic lupus erythematosus, 9 patients who had a rise and 11 patients who had a fall in neuronal antibody titre over a mean duration of 2.1 years (range 0.25-5.2) were identified. These changes were examined in the light of concurrent changes in other serological variables, overall disease activity, neuropsychiatric disease and neuropsychological tests. Changes in antineuronal antibodies were frequently associated with concurrent changes in anti-DNA antibodies and overall disease activity. When neuropsychiatric disease or cognitive dysfunction were present, their course showed a close correlation with changes in antineuronal antibody levels. The results support the association between antineuronal antibodies and neuropsychiatric-systemic lupus erythematosus, but suggest that their measurement will provide useful information of disease status in only a subpopulation of patients. [ABSTRACT FROM PUBLISHER]

The purpose of this study was to examine airway responsiveness, sputum cells and the effects of inhaled corticosteroid in the chronic cough syndrome associated with eosinophilic bronchitis. We studied nine consecutive referrals with chronic cough, sputum with >10% eosinophils, normal spirometry, and normal methacholine airway responsiveness. Clinical assessment, sputum analysis, allergy skin tests and a methacholine inhalation test were performed at the first visit. Peak expiratory flow (PEF) was measured twice daily for 1 week followed by an adenosine monophosphate (AMP) inhalation test. Subjects were then treated with inhaled beclomethasone 0-4 mg twice daily for 7 days. Sputum analysis and measurement of methacholine responsiveness were then repeated. Excessive airway narrowing to methacholine was not present in any of the subjects. A methacholine plateau response was present in five subjects. Hyperresponsiveness to AMP was absent in six of the nine subjects, and PEF variability was not increased for eight subjects. Corticosteroid therapy led to a reduction in sputum eosinophil counts from 40.1 (SD 21.4)% to 4.0 (4.5)% but there was no significant change in metachromatic cell counts (0.8 SD 0.5% vs 0.6 SD 0.6%) or total cell counts. Methacholine responsiveness improved within the normal range in the three subjects in whom it could be determined. Chronic cough associated with eosinophilic airway inflammation can occur in the absence of variable airflow obstruction (asthma) and can improve after treatment with inhaled corticosteroid. This treatment can reduce the level of methacholine responsiveness within the normal range and reduces sputum eosinophils but not mast cells. These results suggest that the occurrence of variable airflow obstruction depends on the baseline level of methacholine responsiveness, the degree of eosinophilic infiltration and the degree to which methacholine responsiveness becomes heightened. [ABSTRACT FROM AUTHOR]

This study evaluated a research method to examine an exacerbation of asthma induced by corticosteroid withdrawal. Ten non-smoking adult asthmatics who were stable on treatment with inhaled steroid underwent a graded reduction of the daily dose by 200 pg at weekly intervals until an exacerbation of symptoms occurred. A daily symptom, peak expiratory flow rate (PEF) and medication diary was kept. Weekly clinic visits were used to assess symptoms, spirometry, methacholine airway responsiveness (expressed as the provocative concentration to cause a fall in FEV1 of 20%,PC20), circulating eosinophils, basophils and their progenitors (Eo/B-CFU), and sputum inflammatory cells. The laboratory tests were performed blind to the clinical details. Each subject developed an exacerbation of symptoms, on average at 16 (7-26) days after the onset of steroid reduction. This was accompanied by a deterioration in each of the objective measures. There was a fall in FEV, by 320 ml (s.e.m. 95) and in PC20 from 0.8 to 0.43 mg/ml. Circulating eosinophils rose from 114 (24) × 10³/ml to 227 (50) × 10³/ml and Eo/B-CFU rose from 31 (5.6) to 44 (11.3)/106 cells. Sputum developed in five subjects and contained 36 (5.2)% eosinophils and 1.98 (0.21)% metachromatic cells (mast cells or basophils). The symptom diary and weekly questionaire were demonstrated to be valid and responsive to change. A deterioration indicated by the daily symptom score preceded changes in PEF. Treatment by an increase in steroid was followed by reversal of each of the changes. We conclude that this research method can safely produce and examine a mild exacerbation of asthma, and that an increase in airway inflammation is an early feature. [ABSTRACT FROM AUTHOR]