Collin Brooks

The hygiene hypothesis in allergy and asthma: an update.

Purpose of reviewIt has been hypothesized that increased cleanliness, reduced family size, and subsequent decreased microbial exposure could explain the increases in global asthma prevalence. This review considers the recent evidence for and against the ‘hygiene hypothesis’. Recent findingsRecent evidence does not provide unequivocal support for the hygiene hypothesis: the hygiene hypothesis specifically relates to atopic asthma, but some of the protective effects (e.g. farm exposures) appear to apply to both atopic and nonatopic asthma; asthma prevalence has begun to decline in some western countries, but there is little evidence that they have become less clean; Latin American countries with high infection rates have high asthma prevalence and the hygiene hypothesis relates to early-life exposures, but exposures throughout life may be important. SummaryThere is a considerable body of evidence which warrants scepticism about the hygiene hypothesis. However, these anomalies contradict the ‘narrow’ version of it in which microbial pressure early in life protects against atopic asthma by suppressing T-helper 2 immune responses. It is possible that a more general version of the hygiene hypothesis is still valid, but the aetiologic mechanisms involved are currently unclear.

Asthma nervosa: old concept, new insights

Stress has long been recognised to be associated with asthma. Hippocrates stated that to prevent an asthma attack “the asthmatic should guard himself against his own anger” 1. Maimonides in his treatise of asthma suggested that “mental anguish, fear, mourning or distress” may cause asthma whereas “gaiety and joy” which “gladden the heart and stimulate the blood and mental activity” may have the opposite effect 2. In his treatise, H.H. Salter wrote that “asthma is essentially, and with perhaps the exception of a single class of cases, exclusively a nervous disease; the nervous system is the seat of the essential pathological condition” 3, and W. Osler referred to asthma as “a neurotic affection” 4. Thus, until the second half of the 20th century, asthma was predominantly viewed as a psychosomatic disorder in which emotional stress and imbalances in the nervous system were key factors in its aetiology. As a result, relief of anxiety was considered the main therapeutic intervention for “asthma nervosa”; as it has been referred to historically. Although the increased awareness in the second half of the 20th century of other triggers of asthma (allergens and air pollution) has shifted the focus away from psychosocial factors, these old concepts are going through a renaissance, with an increasing number of publications reporting consistent positive associations between psychosocial stress and asthma. Associations with asthma have been shown for a wide range of stressors including: post-traumatic stress disorder (PTSD) 5, 6; psychiatric disorders 7, 8; community violence 9; stressful life events 10; partner violence and housing quality 11; war-related stress 12; neuroticism and relational problems 13; perceived safety 14; social depravity and high crime rates 15; anxiety and attention disorders 16; psychological distress 17; …

Innate immunity in asthma

Asthma is a complex disorder and evidence now suggests that it is not solely attributable either to allergy or eosinophilia. Non-eosinophilic asthma accounts for up to one half of all cases and a large proportion have a non-allergic aetiology. The innate immune system responds to a variety of triggers, including viral and bacterial components which are known non-allergic triggers of asthma. The innate immune response may be involved in both the development of and protection against asthma. Factors which are likely to determine the nature of the response include the timing of the exposure (childhood or adulthood), baseline asthma inflammatory subtype (eosinophilic or non-eosinophilic) and the dose of the exposure. Gene-environment interactions are likely to modify the response. Further research is required to elucidate the specific mechanisms involved in the innate immune response in asthma and will be important in the identification of new targets for therapy and management.

Relationship between airway neutrophilia and ageing in asthmatics and non-asthmatics

Increased sputum neutrophilia has been observed in asthma, but also during normal ageing in asthmatics and non‐asthmatics. It remains unclear what constitutes ‘normal’ neutrophil levels in different age groups.

Importance of allergy in asthma: an epidemiologic perspective.

There has been a global epidemic of asthma during the past half-century. More recently, the prevalence has leveled off or declined in many Western countries, whereas the prevalence in less affluent nations is still increasing. The reasons for this and the different geographical patterns of asthma prevalence remain unclear. This paper provides an epidemiologic perspective on whether allergen exposure and allergies can explain these trends. In particular, the paper discusses 1) geographical and temporal trends in asthma and the role of allergens and allergy, 2) the importance of nonallergic mechanisms, 3) nonallergenic exposures that may modify the risk of allergies and asthma, and 4) new and emerging risk and protective factors. Although allergy and asthma are closely related, allergen exposure and allergy alone cannot explain current time trends and geographical patterns of asthma. Population-based studies focusing on recently identified risk and protective factors may provide further insight.

The Inhibitory Receptor NKG2A Determines Lysis of Vaccinia Virus-Infected Autologous Targets by NK Cells

Signals transduced by inhibitory receptors that recognize self-MHC class I molecules prevent NK cells from being activated by autologous healthy target cells. In order for NK cells to be activated upon contact with an infected cell, the balance between the activating and inhibitory signals that regulate NK cell function must be altered in favor of activation. By studying liver-derived NK cells, we show that only a subpopulation of NK cells expressing high levels of the inhibitory receptor NKG2A are able to lyse autologous vaccinia-infected targets, and that this is due to selective down-regulation of HLA-E. These data demonstrate that release from an inhibitory receptor:ligand interaction is one mechanism that permits NK cell recognition of a virally infected target, and that the variegated expression of inhibitory receptors in humans generates a repertoire of NK cells with different antiviral potentials.

Functional invariant natural killer T-cell and CD1d axis in chronic lymphocytic leukemia: implications for immunotherapy

Invariant natural killer T cells recognize glycolipid antigens such as α-galactosylceramide presented by CD1d. In preclinical models of B-cell malignancies, α-galactosylceramide is an adjuvant to tumor vaccination, enhancing tumor-specific T-cell responses and prolonging survival. However, numerical and functional invariant natural killer T-cell defects exist in patients with some cancers. Our aim was to assess this axis in patients with chronic lymphocytic leukemia. The numbers of circulating invariant natural killer T cells and the expression of CD1d on antigen-presenting cells were evaluated in patients with chronic lymphocytic leukemia and age-matched controls. Cytokine profile and in vitro proliferative capacity were determined. Patient- and control-derived invariant natural killer T-cell lines were generated and characterized, and allogeneic and autologous responses to α-galactosylce-ramide-treated leukemia cells were assessed. Absolute numbers and phenotype of invariant natural killer T cells were normal in patients with untreated chronic lymphocytic leukemia, and cytokine profile and proliferative capacity were intact. Chemotherapy-treated patients had reduced numbers of invariant natural killer T cells and myeloid dendritic cells, but α-galactosylceramide-induced proliferation was preserved. Invariant natural killer T-cell lines from patients lysed CD1d-expressing targets. Irradiated α-galactosylceramide-treated leukemic cells elicited allogeneic and autologous invariant natural killer T-cell proliferation, and α-galactosylceramide treatment led to increased proliferation of conventional T cells in response to tumor. In conclusion, the invariant natural killer T-cell and CD1d axis is fundamentally intact in patients with early-stage chronic lymphocytic leukemia and, despite reduced circulating numbers, function is retained in fludarabine-treated patients. Immunotherapies exploiting the adjuvant effect of α-galactosylceramide may be feasible.

Metagenomic Detection of Viruses in Aerosol Samples from Workers in Animal Slaughterhouses

Published studies have shown that workers in animal slaughterhouses are at a higher risk of lung cancers as compared to the general population. No specific causal agents have been identified, and exposures to several chemicals have been examined and found to be unrelated. Evidence suggests a biological aetiology as the risk is highest for workers who are exposed to live animals or to biological material containing animal faeces, urine or blood. To investigate possible biological exposures in animal slaughterhouses, we used a metagenomic approach to characterise the profile of organisms present within an aerosol sample. An assessment of aerosol exposures for individual workers was achieved by the collection of personal samples that represent the inhalable fraction of dust/bioaerosol in workplace air in both cattle and sheep slaughterhouses. Two sets of nine personal aerosol samples were pooled for the cattle processing and sheep processing areas respectively, with a total of 332,677,346 sequence reads and 250,144,492 sequence reads of 85 bp in length produced for each. Eukaryotic genome sequence was found in both sampling locations, and bovine, ovine and human sequences were common. Sequences from WU polyomavirus and human papillomavirus 120 were detected in the metagenomic dataset from the cattle processing area, and these sequences were confirmed as being present in the original personal aerosol samples. This study presents the first metagenomic description of personal aerosol exposure and this methodology could be applied to a variety of environments. Also, the detection of two candidate viruses warrants further investigation in the setting of occupational exposures in animal slaughterhouses.

Synergism of tapasin and human leukocyte antigens in resolving hepatitis C virus infection

CD8+ T‐cell responses to hepatitis C virus (HCV) are important in generating a successful immune response and spontaneously clearing infection. Human leukocyte antigen (HLA) class I presents viral peptides to CD8+ T cells to permit detection of infected cells, and tapasin is an important component of the peptide loading complex for HLA class I. We sought to determine if tapasin polymorphisms affected the outcome of HCV infection. Patients with resolved or chronic HCV infection were genotyped for the known G/C coding polymorphism in exon 4 of the tapasin gene. In a European, but not a US, Caucasian population, the tapasin G allele was significantly associated with the outcome of HCV infection, being found in 82.5% of resolvers versus 71.3% of persistently infected individuals (P = 0.02, odds ratio [OR] = 1.90 95% confidence interval [CI] = 1.11‐3.23). This was more marked at the HLA‐B locus at which heterozygosity of both tapasin and HLA‐B was protective (P < 0.03). Individuals with an HLA‐B allele with an aspartate at residue 114 and the tapasin G allele were more likely to spontaneously resolve HCV infection (P < 0.00003, OR = 3.2 95% CI = 1.6‐6.6). Additionally, individuals with chronic HCV and the combination of an HLA‐B allele with an aspartate at residue 114 and the tapasin G allele also had stronger CD8+ T‐cell responses (P = 0.02, OR = 2.58, 95% CI‐1.05‐6.5). Conclusion: Tapasin alleles contribute to the outcome of HCV infection by synergizing with polymorphisms at HLA‐B in a population‐specific manner. This polymorphism may be relevant for peptide vaccination strategies against HCV infection. (Hepatology 2013;53:881–889)

Stress and asthma: Hippocrates revisited

Asthma is a complex disease affecting a large proportion of the worlds population,1 but despite decades of intensive biomedical and epidemiological research its aetiology and pathogenesis is still poorly understood. As a consequence, a single target for intervention has not (yet) been identified. Recent epidemiological studies have provided innovative theories of the aetiology of asthma, such as the hygiene hypothesis, which suggests that microbial exposures may reduce the risk of asthma.2 These have considerable potential to guide the development of feasible primary (and secondary) prevention options. However, given the complex gene-environment interactions3 and diverse asthma phenotypes,4 any single type of intervention is unlikely to prevent all, or even a substantial proportion of asthma cases - a ‘one size fits-all’ approach is unlikely to work. The reported link between emotional stress and asthma5 is, therefore, of great interest, as it provides a further candidate for primary (and secondary) prevention. The first report linking emotions to asthma is believed to be by the Greek physician Hippocrates (460-357 BC), who stated that to prevent an asthma attack ‘the asthmatic should guard himself against his own anger’.6 Until the second half of the 20th century this remained the predominant view, that is, asthma was considered to be a psychosomatic disorder in which emotional stress was the key factor in its aetiology; the condition was therefore commonly referred to as ‘asthma nervosa’. For example, Henry Hyde Salter, in his treatise ‘On asthma: its pathology and treatment’ published in 1860, wrote that ‘asthma is essentially, and with perhaps the exception of a single class of cases, exclusively a nervous disease; the nervous system is the seat of the essential pathological condition’.7 With the recognition of causal environmental exposures such as pollen8 and house dust9 in the latter …