Macrophage activation by endogenous danger signals

Macrophages are cells that function as a first line of defence against invading microorganisms. One of the hallmarks of macrophages is their ability to become activated in response to exogenous 'danger signals'. Most microbes have molecular patterns (PAMPS) that are recognized by macrophages and trigger this activation response. There are many aspects of the activation response to PAMPS that are recapitulated when macrophages encounter endogenous danger signals. In response to damaged or stressed self, macrophages undergo physiological changes that include the initiation of signal transduction cascades from germline-encoded receptors, resulting in the elaboration of chemokines, cytokines and toxic mediators. This response to endogenous mediators can enhance inflammation, and thereby contribute to autoimmune pathologies. Often the overall inflammatory response is the result of cooperative activation signals from both exogenous and endogenous signals. Macrophage activation plays a critical role, not only in the initiation of the inflammatory response but also in the resolution of this response. The clearance of granulocytes and the elaboration of anti-inflammatory mediators by macrophages contribute to the dissolution of the inflammatory response. Thus, macrophages are a key player in the initiation, propagation and resolution of inflammation. This review summarizes our understanding of the role of macrophages in inflammation. We pay particular attention to the endogenous danger signals that macrophages may encounter and the responses that these signals induce. The molecular mechanisms responsible for these responses and the diseases that result from inappropriately controlled macrophage activation are also examined.     

Apoptosis signals in atopy and asthma measured with cDNA arrays

A variety of studies have stressed the importance of the control of inflammatory cell longevity and the balance of pro-survival and pro-apoptotic signalling. Recently, asthma was found to be associated with reduced apoptosis of inflammatory cells in lung tissue. The aim of the study was to investigate the systemic activation of apoptosis pathways using cDNA array technology in atopy and asthma. Eighteen atopic asthmatics (AA), eight atopic non-asthmatic (AN) and 14 healthy control subjects (C) were included in the study. Peripheral blood mononuclear cells were separated with gradient centrifugation, mRNA purified and the reverse-transcribed probes hybridized to cDNA arrays. The signals were compared by standardizing to the 100 most expressed genes and group differences assessed with the Mann-Whitney U-test. We found a concerted up-regulation of several pro-survival cytokines and growth factors in AN and AA. FAS and FASL were not differentially expressed, but FAST kinase was over-expressed in AN and AA. The tumour necrosis factor pathway was activated in AN and AA with increased cytokine and receptor levels and increased TRAF2, an intracellular signalling product. There were indications of a down-regulated p53 system. In contrast, the Bcl-2 family of genes showed a net pro-apoptotic profile in AN and AA. The group of caspases showed a constant gene expression pattern in all groups. In conclusion, significant differences in the expression of apoptosis-related genes were found in peripheral blood of atopic individuals with and without asthma. cDNA array technology proved to be useful and may be complementary to DNA-based studies in order to analyse interactive and multidimensional pathways as shown here for apoptosis.     

Endotoxin, atopy and asthma

Endotoxin is infamous for its ability to exacerbate existing allergy and asthma symptoms. Current research supports this phenomenon, demonstrating its significance in the home, as well as in the workplace. At the same time, evidence is emerging that exposure to endotoxin may drive immune development away from the T-helper lymphocyte type 2-mediated allergy and asthma profile. This fits in nicely with the 'hygiene hypothesis', which attributes the past century's rise in allergy and asthma to a reduction in microbial burden. Indeed, infections have been associated with less atopy and asthma. Recent investigations have suggested that naturally-occurring non-infectious exposure to microbial components such as endotoxin might mitigate atopy and asthma as well.     

Pets, parental atopy, and asthma in adults

BACKGROUND: Studies of exposure to pets and the risk of asthma have provided conflicting results. OBJECTIVE: We conducted a population-based incident case-control study to assess the relationship of current and previous pet keeping with the risk of adult-onset asthma. We also investigated whether genetic propensity as a result of parental atopy modifies these relations. METHODS: From the source population of 441,000 inhabitants of a geographically defined area in South Finland, we systematically recruited, during a 2.5-year period, all new cases of asthma in 21- to 63-year-old adults and randomly selected control subjects. The clinically diagnosed case series consisted of 521 adults with newly diagnosed asthma and a control series of 932 control subjects. Information on current and past exposure to hairy pets was collected by using a self-administered questionnaire. RESULTS: In logistic regression analysis the risk of asthma was lower among subjects with pets during the past 12 months (adjusted odds ratio [OR], 0.74; 95% confidence interval [CI], 0.57-0.96) but higher among subjects with pets more than 12 months previously (adjusted OR, 1.39; 95% CI, 1.05-1.84). Parental atopy increased the risk of asthma (OR, 1.88; 95% CI, 1.47-2.41), but there was no interaction between parental atopy and pet exposure. CONCLUSIONS: The present results are consistent with the hypothesis that both keeping furry pets and parental atopy increase the risk of asthma development in adulthood. Parental atopy does not modify the effects of pet exposure. The negative association between current pets and the risk of asthma is consistent with selective avoidance of these pets by symptomatic individuals.     

Drug metabolism, danger signals, and drug-induced hypersensitivity

One of the most difficult challenges for the practicing allergist/immunologist today is that of evaluating and managing patients who present with histories of drug-induced reactions. Adverse drug reactions are heterogeneous, and a single drug can often cause a multitude of reactions. Because the mechanisms responsible for many of these reactions are not known, they can be, and often are, difficult to classify. Moreover, for those that have features consistent with immune-mediated mechanisms, our diagnostic tools remain limited, because little is known about the relevant immunogenic determinants of most drugs. Despite these challenges, management approaches must be devised for patients who present with histories of drug-induced disease. Simply telling such a patient to avoid all drugs that have been associated with previous adverse events leaves both the patient and the referring physician frustrated. The initial part of this review focuses on exciting current research that is furthering our understanding of the mechanisms responsible for drug-induced reactions. Because it will take time to translate this new information into clinical practice, the latter part of the review focuses on ways to evaluate and manage patients who present with drug-induced reactions using the tools and the knowledge that are currently available.     

The burden of atopy and asthma in children

Background:  There has been a world-wide increase in the prevalence of atopic diseases. These atopic diseases, including asthma, allergic rhinoconjunctivitis and atopic eczema/dermatitis, are common in childhood and create a challenge of management for physicians and parents.
Methods:  MEDLINE was searched for articles related to atopy, allergy asthma, allergic rhinoconjunctivitis and atopic eczema/dermatitis.
Results and conclusions:  The conditions of asthma, allergic rhinoconjunctivitis and atopic eczema/dermatitis cause very significant burdens regarding the discomfort to the affected individual, management problems for the parent and physician and the economic cost to the family and the nation.     

Interactions between breast-feeding, specific parental atopy, and sex on development of asthma and atopy

BACKGROUND: The influence of breast-feeding on the risk of developing atopy and asthma remains controversial. OBJECTIVE: To examine asthma and atopy outcomes by sex, reported specific parental history of atopy, and breast-feeding. METHODS: In a birth cohort, we examined childhood asthma and atopy (positive skin prick tests) by sex and breast-feeding in relation to maternal and paternal atopy. Interactions were explored in logistic regression models. RESULTS: For boys, breast-feeding (odds ratio [OR], 1.63; 95% CI, 0.93-2.87; P = .09) and maternal atopy (OR, 1.95; 95% CI, 0.93-4.08; P = .08) were each associated with atopy at age 13 years. Breast-feeding increased the risk for atopy among boys with paternal atopy (OR, 7.39; 95% CI, 2.21-24.66) compared with non-breast-fed boys with paternal atopy, but did not significantly further increase risk among subjects with maternal atopy. For girls, breast-feeding (OR, 0.74; 95% CI, 0.41-1.31) and maternal and paternal atopy were not independent risk factors for atopy at age 13 years. However, breast-feeding increased the risk for atopy in girls with maternal atopy (OR, 3.13; 95% CI, 1.20-8.14) compared with non-breast-fed girls with maternal atopy. There was no such effect among subjects with paternal atopy. Results for the outcome of asthma followed a similar pattern. CONCLUSION: The influence of breast-feeding on development of atopy and asthma differs by sex and by maternal and paternal atopy, and is most significant among subjects at lower baseline risk. CLINICAL IMPLICATIONS: Analyses of environmental risk factors for asthma and atopy should be stratified by specific parental atopy and sex.     

Genes for atopy and asthma

The genetic basis of atopic diseases is represented by a complex network of interacting genes or common genetic variants rather than a few disease-causing mutations. The individual risk of developing asthma or other atopic diseases is defined by the concert of interaction of these hereditary factors and environmental stimuli. The first decade of asthma genetics has been spent identifying those genetic regions through linkage analysis, which are likely to harbour asthma genes. At the same time, several candidate genes for asthma and atopy have been identified and their variants characterized, some of them even to a level of functional understanding. Rather than adding new candidate regions and genes to the pool of knowledge, the interest in the past year has moved to a more sophisticated statistical evaluation of the given linkage and association data and a more precise definition of so-called 'intermediate phenotypes'. Some of the results are quite surprising and have helped us to understand the underlying pathophysiology. For example, the distinct clinical traits of asthma, such as atopic sensitization or inflammation of the bronchial epithelium, seem to be defined by distinct subsets of predisposing genes. At the same time, the very same subsets of genes might underlie further clinical diseases with similar clinical features. Polymorphisms within IL-4R alpha, which had been shown to be associated with asthma and atopy, have also been shown to be associated with kidney allograft rejection, systemic lupus erythematosus and Crohn's disease. There might thus just be a few asthma and atopy genes. Finally, asthma and atopy genetics has now reached a point of practical application. The genetics of susceptibility to environmental stimuli, pharmacogenetic data, and the advent of new pharmaceutical targets will greatly influence the whole field of asthma and atopy.     

Links between pollen, atopy and the asthma epidemic

Pollen allergy has been found in 80-90% of childhood asthmatics and 40-50% of adult-onset asthmatics. Despite the high prevalence of atopy in asthmatics, a causal relationship between the allergic response and asthma has not been clearly established. Pollen grains are too large to penetrate the small airways where asthma occurs. Yet pollen cytoplasmic fragments are respirable and are likely correlated with the asthmatic response in allergic asthmatics. In this review, we outline the mechanism of pollen fragmentation and possible pathophysiology of pollen fragment-induced asthma. Pollen grains rupture within the male flowers and emit cytoplasmic debris when winds or other disturbances disperse the pollen. Peak levels of grass and birch pollen allergens in the atmosphere correlated with the occurrence of moist weather conditions during the flowering period. Thunderstorm asthma epidemics may be triggered by grass pollen rupture in the atmosphere and the entrainment of respirable-sized particles in the outflows of air masses at ground level. Pollen contains nicotinamide adenine dinucleotide phosphate (reduced) oxidases and bioactive lipid mediators which likely contribute to the inflammatory response. Several studies have examined synergistic effects and enhanced immune response from interaction in the atmosphere, or from co-deposition in the airways, of pollen allergens, endogenous pro-inflammatory agents, and the particulate and gaseous fraction of combustion products. Pollen and fungal fragments also contain compounds that can suppress reactive oxidants and quench free radicals. It is important to know more about how these substances interact to potentially enhance, or even ameliorate, allergic asthma.     

Polymorphisms in eosinophil pathway genes, asthma and atopy

BACKGROUND: Eosinophilic inflammation is considered to play an important role in the development as well as in the perpetuation of asthma. As eosinophil production and survival is under genetic control we investigated whether polymorphisms in eosinophil regulation pathway genes (IL-3, IL-5, GM-CSF and their respective enhancers and receptors) may influence the development of atopic diseases. METHODS: In two large study populations of children, the German part of the International Study of Asthma and Allergy in Childhood (ISAAC II) and the German Multicentre Atopy Study (MAS), 3099 and 824 children, seven polymorphisms previously associated with the development of atopic diseases were genotyped: two in and around the GM-CSF gene (Ile117Thr and T3085G), one in IL-3 (Pro27Ser), in IL-5 (C-746T), and in the IL-5 high affinity receptor chain IL-5R (G-80A) and two in the common receptor chain CSFR2b for IL-3, IL-5, and GM-CSF (Asp312Asn and Glu249Gln). Statistical analyses were performed using chi-squared tests and variance analyses. Gene by gene interactions were evaluated in logistic regression models. RESULTS: The T allele at position -746 in the IL-5 gene was significantly protective for atopy in the ISAAC II population (P = 0.006). Furthermore, the risk for atopic asthma was decreased in carriers of the T allele (P = 0.036) and evidence for interaction with the enhancer polymorphism 3085 bp 3' of GM-CSF was detected. CONCLUSIONS: IL-5 C-746T influenced atopic outcomes and showed evidence for gene by gene interaction. No significant associations were found with all other tested polymorphisms in the eosinophil regulation pathway after correction for multiple testing.     

Seeking common pathophysiology in asthma, atopy and sinusitis

Asthma and chronic sinusitis are inexplicably common airway diseases that are linked to atopy and allergic inflammation. T helper type 2 (Th2) cells and the associated cytokines are believed to play crucial pathogenic roles in asthma, but the environmental factors that instigate allergic airway disease remain poorly understood. Environmental proteinases are highly allergenic and are candidate inducers of airway Th2 responses. Determining the proteinases and their sources that are relevant to airway disease, however, remains challenging. In this Opinion, we summarize the evidence that implicates fungi as both a relevant source of allergenic proteinases and a potential cause of asthma, atopy and chronic sinusitis through airway infection. Clarification of the extrinsic causes of these processes will markedly improve diagnosis, prognosis and therapy.