Crystal-ball gazing--the future of immunological research viewed from the cutting edge.
Explore the source record for details and available documents.
Allergy and Immunology↗
Biomedical subjects
S T Holgate
Publications and source records attributed to S T Holgate.
Current research priorities in chronic fatigue syndrome/myalgic encephalomyelitis: disease mechanisms, a diagnostic test and specific treatments.
Chronic fatigue syndrome (CFS) is an illness characterised by disabling fatigue of at least 6 months duration, which is accompanied by various rheumatological, infectious and neuropsychiatric symptoms. A collaborative study group has been formed to deal with the current areas for development in CFS research--namely, to develop an understanding of the molecular pathogenesis of CFS, to develop a diagnostic test and to develop specific and curative treatments. Various groups have studied the gene expression in peripheral blood of patients with CFS, and from those studies that have been confirmed using polymerase chain reaction (PCR), clearly, the most predominant functional theme is that of immunity and defence. However, we do not yet know the precise gene signature and metabolic pathways involved. Currently, this is being dealt with using a microarray representing 47,000 human genes and variants, massive parallel signature sequencing and real-time PCR. It will be important to ensure that once a gene signature has been identified, it is specific to CFS and does not occur in other diseases and infections. A diagnostic test is being developed using surface-enhanced, laser-desorption and ionisation-time-of-flight mass spectrometry based on a pilot study in which putative biomarkers were identified. Finally, clinical trials are being planned; novel treatments that we believe are important to trial in patients with CFS are interferon-beta and one of the anti-tumour necrosis factor-alpha drugs.
Fatigue Syndrome, Chronic↗
Enhanced upregulation of smooth muscle related transcripts by TGF beta2 in asthmatic (myo) fibroblasts.
BACKGROUND: Transforming growth factor beta (TGF beta) upregulates a number of smooth muscle specific genes in (myo)fibroblasts. As asthma is characterised by an increase in airway smooth muscle, we postulated that TGFbeta(2) favours differentiation of asthmatic (myo)fibroblasts towards a smooth muscle phenotype. METHODS: Primary fibroblasts were grown from bronchial biopsy specimens from normal (n = 6) and asthmatic (n = 7) donors and treated with TGF beta2 to induce myofibroblast differentiation. The most stable genes for normalisation were identified using RT-qPCR and the geNorm software applied to a panel of 12 "housekeeping" genes. Expression of alpha-smooth muscle actin (alpha SMA), heavy chain myosin (HCM), calponin 1 (CPN 1), desmin, and gamma-actin were measured by RT-qPCR. Protein expression was assessed by immunocytochemistry and western blotting. RESULTS: Phospholipase A2 and ubiquitin C were identified as the most stably expressed and practically useful genes for normalisation of gene expression during myofibroblast differentiation. TGF beta2 induced mRNA expression for all five smooth muscle related transcripts; alpha SMA, HCM and CPN 1 protein were also increased but desmin protein was not detectable. Although there was no difference in basal expression, HCM, CPN 1 and desmin were induced to a significantly greater extent in asthmatic fibroblasts than in those from normal controls (p = 0.041 and 0.011, respectively). CONCLUSIONS: Although TGF beta2 induced the transcription of several smooth muscle related genes, not all were translated into protein. Thus, while TGF beta2 is unable to induce a bona fide smooth muscle cell phenotype, it may "prime" (myo)fibroblasts for further differentiation, especially if the cells are derived from asthmatic airways.
Adult↗
The cysteinyl-leukotriene type 1 receptor polymorphism 927T/C is associated with atopy severity but not with asthma.
BACKGROUND: The cysteinyl-leukotriene receptor type 1 (CysLT1) mediates the bronchoconstrictor and pro-inflammatory actions of cysteinyl-leukotrienes (LTC4, LTD4, LTE4) in asthma and is the molecular target of the lukast class of oral anti-leukotriene drugs. We screened the CYSLTR1 gene on chromosome Xq13-21 for coding region polymorphisms, and investigated their associations with allergy and asthma. METHODS: Solid-phase chemical cleavage was used to screen polymorphisms in the coding region of CYSLTR1. A TaqMan allelic discrimination assay was used to genotype a 927T/C SNP and oligonucleotide ligation assays were used to genotype the previously reported 617T/C and 898G/A SNPs of CYSLTR1 in 341 asthmatic families from the UK. Associations with asthma diagnosis, atopic status, serum-specific IgE and severity of allergy and asthma were examined. RESULTS: Family-based association tests showed that the 927 T allele was associated with atopy severity, especially in female subjects, but not with asthma diagnosis or severity, atopic status, bronchial hyper-responsiveness to methacholine or forced expiratory volume in 1 s. CONCLUSION: Mutation screening identified only one polymorphism, 927T/C, in the coding region of the CysLT1 receptor. This polymorphsim is predictive of atopy severity, but not associated with asthma.
Adolescent↗
A need for circulating biomarkers of severe persistent asthma and its treatment.
Explore the source record for details and available documents.
Anti-Inflammatory Agents↗
The contribution of transforming growth factor-beta and epidermal growth factor signalling to airway remodelling in chronic asthma.
Asthma is increasing in prevalence in the developing world, affecting approximately 10% of the world's population. It is characterised by chronic lung inflammation and airway remodelling associated with wheezing, shortness of breath, acute bronchial hyperresponsiveness to a variety of innocuous stimuli and a more rapid decline in lung function over time. Airway remodelling, involving proliferation and differentiation of mesenchymal cells, particularly myofibroblasts and smooth muscle cells, is generally refractory to corticosteroids and makes a major contribution to disease chronicity. Transforming growth factor-beta is a potent profibrogenic factor whose expression is increased in the asthmatic airways and is a prime candidate for the initiation and persistence of airway remodelling in asthma. This review highlights the role of transforming growth factor-beta in the asthmatic lung, incorporating biosynthesis, signalling pathways and functional outcome. In vivo, however, it is the balance between transforming growth factor-beta and other growth factors, such as epidermal growth factor, which will determine the extent of fibrosis in the airways. A fuller comprehension of the actions of transforming growth factor-beta, and its interaction with other signalling pathways, such as the epidermal growth factor receptor signalling cascade, may enable development of therapies that control airway remodelling where there is an unmet clinical need.
Asthma↗
Tumour necrosis factor (TNFalpha) as a novel therapeutic target in symptomatic corticosteroid dependent asthma.
BACKGROUND: Tumour necrosis factor alpha (TNFalpha) is a major therapeutic target in a range of chronic inflammatory disorders characterised by a Th1 type immune response in which TNFalpha is generated in excess. By contrast, asthma is regarded as a Th2 type disorder, especially when associated with atopy. However, as asthma becomes more severe and chronic, it adopts additional characteristics including corticosteroid refractoriness and involvement of neutrophils suggestive of an altered inflammatory profile towards a Th1 type response, incriminating cytokines such as TNFalpha. METHODS: TNFalpha levels in bronchoalveolar lavage (BAL) fluid of 26 healthy controls, 42 subjects with mild asthma and 20 with severe asthma were measured by immunoassay, and TNFalpha gene expression was determined in endobronchial biopsy specimens from 14 patients with mild asthma and 14 with severe asthma. The cellular localisation of TNFalpha was assessed by immunohistochemistry. An open label uncontrolled clinical study was then undertaken in 17 subjects with severe asthma to evaluate the effect of 12 weeks of treatment with the soluble TNFalpha receptor-IgG1Fc fusion protein, etanercept. RESULTS: TNFalpha levels in BAL fluid, TNFalpha gene expression and TNFalpha immunoreative cells were increased in subjects with severe corticosteroid dependent asthma. Etanercept treatment was associated with improvement in asthma symptoms, lung function, and bronchial hyperresponsiveness. CONCLUSIONS: These findings may be of clinical significance in identifying TNFalpha as a new therapeutic target in subjects with severe asthma. The effects of anti-TNF treatment now require confirmation in placebo controlled studies.
Adult↗
Anti-immunoglobulin E treatment with omalizumab in allergic diseases: an update on anti-inflammatory activity and clinical efficacy.
Omalizumab is a humanized monoclonal anti-IgE antibody developed for the treatment of allergic disease, with established efficacy in patients with moderate-to-severe allergic asthma and in patients with intermittent (seasonal) and persistent (perennial) allergic rhinitis (AR). Omalizumab is known to result in a marked reduction in serum levels of free IgE and down-regulation of IgE receptors on circulating basophils. Recent work has shed further light on its mechanism of action, showing significant and profound reductions in tissue (nasal and bronchial) eosinophils and in bronchial IgE+ cells (mast cells), as well as T cells and B cells. Omalizumab treatment was also shown to be associated with down-regulation of IgE receptors on circulating (precursor) dendritic cells, suggesting that blocking IgE may inhibit more chronic aspects of allergic inflammation involving T cell activation. Further work with omalizumab demonstrated it to have important benefits in patients with poorly controlled asthma despite high-dose inhaled corticosteroid therapy, and analysis of clinical data suggests that the patients who are the best 'responders' to anti-IgE treatment are those with asthma at the more severe end of the spectrum. Notably, systemic anti-IgE therapy with omalizumab has been shown to improve symptoms, quality of life and disease control (asthma exacerbations) in patients with concomitant asthma and persistent AR. These impressive clinical data and the studies elucidating the anti-inflammatory profile of omalizumab also serve to emphasize the fundamental importance of IgE in the pathogenesis of allergic diseases.
Antibodies, Anti-Idiotypic↗
Risk factors and characteristics associated with severe and difficult to treat asthma phenotype: an analysis of the ENFUMOSA group of patients based on the ECRHS questionnaire.
BACKGROUND: Severe and difficult to treat asthma impairs health status and accounts for about half of asthma expenditure. In 1994, a European Network For Understanding Mechanisms of Severe Asthma (ENFUMOSA) was formed. A large group of patients from nine European countries has been selected. OBJECTIVE: To examine the risk factors and symptoms associated with a phenotype of severe/difficult to treat asthma. METHODS: The present report presents data assessed through the use of the European Community Respiratory Health Survey (ECRHS) Questionnaire in 148 mild-moderate controlled and 155 severe asthmatics from the ENFUMOSA group. RESULTS: There is a negative association of severe asthma with reported allergy and with a family history of allergy (Odds ratio (OR)=0.45). Sharing a bedroom before the age of five is associated with a higher risk of severe asthma (OR=1.5) while childhood infections, play school attendance and exposure to allergens or animals are not. A larger proportion of severe asthma patients report symptoms at work (OR=2.7) or have to change jobs (OR=4.3) and fewer severe than mild patients are currently employed (OR=0.39). Smoking and exposure to smoke is similar in mild and severe asthma. Dietary habits do not differ between the groups, but severe asthmatics report eating less savoury snacks and there is a trend for lower intake of sweets. CONCLUSIONS: Analysis of the ECRHS questionnaire in the ENFUMOSA study shows that severe asthma patients experience more symptoms and their health status is impaired by their inability to work and perhaps eat freely. Personal and maternal history of allergy is associated with mild but not severe asthma. Other than sharing a bedroom before the age of 5 years, no childhood exposure risk factors associated with severe asthma could be identified from this analysis.
Adolescent↗
Improving the management of atopic disease.
Asthma, wheeze, eczema, and, to a certain extent, rhinitis are very common conditions among children. The prevalence of allergic disease in the general population has increased alarmingly over the past 25 years, particularly in Western industrialised countries. However, it is important to remember that the symptoms often associated with allergy can have other aetiologies. Evidence suggests that in most circumstances, only 30-40% of chronic allergic-type symptoms are due to allergy. Accurate diagnosis of the presence of allergy is therefore an important issue, particularly given the interventions that such a diagnosis may initiate. In this review, we examine management options for allergy, provide the evidence as to what proportions of patients with common allergic-type symptoms are actually allergic, and list other causes of such symptoms. The importance of allergy testing and the options available are described, particularly with reference to the role of the non-allergist.
Allergens↗
Gene expression in peripheral blood mononuclear cells from patients with chronic fatigue syndrome.
BACKGROUND: Chronic fatigue syndrome (CFS) is a multisystem disease, the pathogenesis of which remains undetermined. AIMS: To test the hypothesis that there are reproducible abnormalities of gene expression in patients with CFS compared with normal healthy persons. METHODS: To gain further insight into the pathogenesis of this disease, gene expression was analysed in peripheral blood mononuclear cells from 25 patients with CFS diagnosed according to the Centers for Disease Control criteria and 25 normal blood donors matched for age, sex, and geographical location, using a single colour microarray representing 9522 human genes. After normalisation, average difference values for each gene were compared between test and control groups using a cutoff fold difference of expression > or = 1.5 and a p value of 0.001. Genes showing differential expression were further analysed using Taqman real time polymerase chain reaction (PCR) in fresh samples. RESULTS: Analysis of microarray data revealed differential expression of 35 genes. Real time PCR confirmed differential expression in the same direction as array results for 16 of these genes, 15 of which were upregulated (ABCD4, PRKCL1, MRPL23, CD2BP2, GSN, NTE, POLR2G, PEX16, EIF2B4, EIF4G1, ANAPC11, PDCD2, KHSRP, BRMS1, and GABARAPL1) and one of which was downregulated (IL-10RA). This profile suggests T cell activation and perturbation of neuronal and mitochondrial function. Upregulation of neuropathy target esterase and eukaryotic translation initiation factor 4G1 may suggest links with organophosphate exposure and virus infection, respectively. CONCLUSION: These results suggest that patients with CFS have reproducible alterations in gene regulation.
Adolescent↗
Epithelial stress and structural remodelling in childhood asthma.
BACKGROUND: In adult asthma the bronchial epithelium shows high expression of the epidermal growth factor receptor (EGFR) and the cyclin dependent kinase inhibitor, p21waf, linked to ongoing stress and injury. METHODS: To determine if these are early markers of disease, sections of bronchial specimens obtained post mortem or by bronchoscopy from non-asthmatic (n = 7), moderate (n = 7), or severe (n = 9) asthmatic children aged 5-15 years were examined immunohistochemically. All severe and one moderately asthmatic children were receiving inhaled corticosteroids. RESULTS: The lamina reticularis of the asthmatic biopsy sections was found to be thicker (p = 0.01) than normal with increased deposition of collagen III (p = 0.007); submucosal eosinophil numbers did not differ between groups. As in adults, there was an asthma-related increase in epithelial EGFR (p<0.002) but there was no evidence of proliferation, with Ki67 being reduced (p = 0.001) and p21waf increased (p<0.004). The thickness of the lamina reticularis was significantly correlated with epithelial EGFR (rho = 0.77, p<0.001). CONCLUSIONS: These data provide evidence that, in asthmatic children, the epithelium is stressed or injured without significant eosinophilic inflammation. This change in the epithelial phenotype is associated with collagen deposition in the lamina reticularis, suggesting that the epithelial mesenchymal trophic unit is active early in, and may contribute to, the pathogenesis of asthma.
Adolescent↗
Is big beautiful? The continuing story of ADAM33 and asthma.
Explore the source record for details and available documents.
ADAM Proteins↗
Altered protein tyrosine phosphorylation in asthmatic bronchial epithelium.
A disease-related, corticosteroid-insensitive increase in the expression of epidermal growth factor (EGF) receptor (EGFR) tyrosine kinase in asthmatic bronchial epithelium has been shown previously by the current authors. To determine whether this is associated with enhanced intracellular signalling, the aim of this study was to evaluate epithelial tyrosine phosphorylation. Bronchial biopsies were analysed for the presence of phosphotyrosine by immunohistochemistry. Bronchial epithelial cells were exposed to EGF, hydrogen peroxide or tumour necrosis factor-alpha in vitro for measurement of tyrosine phosphorylated signalling intermediates and interleukin (IL)-8 release. Phosphotyrosine was increased significantly in the epithelium of severe asthmatics when compared with controls or mild asthmatics; however, in mild asthma, phosphotyrosine levels were significantly decreased when compared with controls. There was no significant difference between phosphotyrosine levels before or after 8 weeks of treatment with budesonide. Stimulation of bronchial epithelial cells resulted in tyrosine phosphorylation of several proteins, including EGFR, Shc and p42/p44 mitogen-activated protein kinase. In the presence of salbutamol, a transient partial suppression of EGFR phosphorylation occurred, whereas dexamethasone was without effect. Neither salbutamol nor dexamethasone inhibited EGF-stimulated IL-8 release. These data indicate that regulation of protein tyrosine kinase activity is abnormal in severe asthma. The epidermal growth factor receptor and/or other tyrosine kinase pathways may contribute to persistent, corticosteroid-unresponsive inflammation in severe asthma.
Administration, Inhalation↗
Summary of recommendations for the design of clinical trials and the registration of drugs used in the treatment of asthma.
With new drugs being introduced to treat asthma it is timely to review criteria that can be used to assess efficacy in clinical trials. Anti-asthma drugs are classified into symptoms-modifying, symptom preventers and disease modifying agents. Attention is drawn to the types of experimental evidence required in preclinical studies to support further clinical development of a new therapy. Clinical trials demand careful selection of patients to maximise the strength of the efficacy signal according to the type of trial being designed. While provocation tests are useful in suggesting efficacy, negative tests do not necessarily indicate lack of anti-asthma activity. Therapeutic trial designs need to take account of duration of treatment, dose-response relationships and confirmatory trials. Outcome measures include symptoms, lung function, reduction in concomitant medication, exacerbations, quality of life and measures of inflammation. Interpretation of results need to include the clinical relevance of any changes as well as statistical significance. Special consideration needs to be given to the evaluation of drugs for acute severe asthma, asthma in children and older people, co-morbidity such as rhinitis, and inhaler devices. As with all drugs introduced into practice, careful attention needs to be paid to both short- and long-term safety.
Acute Disease↗
Toll-like receptor 4 polymorphism and severity of atopy in asthmatics.
Endotoxin exposure may have a protective effect against asthma and atopy. An Asp299Gly polymorphism in the Toll-like receptor 4 (TLR4) gene reduces responsiveness to endotoxin. This study determined the effect of TLR4 polymorphism on the risk and severity of asthma and atopy. In all, 336 UK Caucasian families with > or = 2 affected sibs (physician's diagnosis of asthma and current medication use) and 179 Caucasians without asthma or a family history of asthma were genotyped using ARMS-PCR. No association of the TLR4 polymorphism was found with the risk of developing asthma, either in parent-affected sibling trios, or in case-control analyses (P>0.05). In the first affected asthmatic siblings, the atopy severity score (based on size and number of positive skin-prick tests and specific IgE) was higher in those with the Asp/Gly or Gly/Gly genotypes (mean 1.8, s.d. 1.1, n=39) compared to those with the Asp/Asp genotype (mean 1.2, s.d. 1.0, n=279) (P=0.003, t-test). No associations were found with total IgE, FEV(1) % predicted, slope of FEV(1) response to methacholine or asthma severity score (P>0.05). This study confirms the previously observed lack of association of TLR4 polymorphisms with asthma. In contrast, the findings suggest that genetically determined hyporesponsiveness to endotoxin may increase atopy severity.
Amino Acid Substitution↗
Lack of association of HLA class I genes and TNF alpha-308 polymorphism in toluene diisocyanate-induced asthma.
BACKGROUND: Toluene diisocyanate (TDI)-induced asthma is a common cause of occupational asthma and it affects 5-15% of the exposed population suggesting an underlying genetic susceptibility. METHODS: To investigate the role of genetic factors in the development of TDI-induced asthma, we analyzed the distribution of human leukocyte antigen (HLA) class I genes and of tumor necrosis factor (TNF)-alpha A-308G polymorphism in 142 patients with TDI-induced asthma and in 50 asymptomatic exposed subjects. RESULTS: Neither the distribution of HLA class I antigens nor the distribution of TNF-alpha A-308G polymorphism was different between patients with TDI-induced asthma and asymptomatic exposed subjects. CONCLUSIONS: These results suggest that HLA class I antigens and TNF-alpha A-308G are not associated with susceptibility or resistance to the development of TDI-induced asthma.
Adult↗
Lessons learnt from the epidemic of asthma.
Explore the source record for details and available documents.
ADAM Proteins↗