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W2462617553 abstract "Omnia non pariter rerum sunt omnibus apta Propertius, Elegies III,9,7 PART 1 – NOT EVERY ALLERGY HAS THE SAME ROOTS Introduction – not everybody's cup of tea Over decades, noncommunicable diseases (NCDs) have become an emergency problem for the developed world. Obesity, cardiovascular diseases, chronic nephropathies, psychiatric disorders and neoplastic diseases top the list of the major global threats and are also increasing in the developing world [1]. These include metabolic diseases, neurodegenerative conditions, autoimmune disorders (type 1 diabetes, chronic inflammatory bowel diseases, thyroiditis, rheumatoid disease) as well as allergic conditions and asthma [2]. Inflammation and immune dysregulation are common features of all these different conditions and they highlight the central multisystem role of the immune system [3]. The increase of respiratory allergy in westernized countries, started 50 years ago, seems to have plateaued at the beginning of this century [4], but a new wave of food allergies has emerged in the last 10–15 years [5,6], in particular in preschool children [7–10]. This ‘second wave’ is particularly evident in countries where respiratory allergy had increased, for example United Kingdom, Australia and United States [5,7,11]. Peanut allergy has more than doubled in the last 15 years and has recently been recorded in 1–2% of children in Australia, Canada, United Kingdom and United States [9]. The reasons for the differences in temporal presentation of various allergic conditions and the intergenerational dissimilarities in the disease profile have not been elucidated; however, as the increase in allergic disease has occurred too rapidly (within one to two generations) to be attributed to genetic changes in the population, it is likely related to environment. The search for environmental causes of allergies and epidemiological trends is a good opportunity to explain the complexity of allergic disease. Whatever the cause(s) of this increase are, they do not act in the same way in different populations, socioeconomic environments and cultural habits; this reflects the situation at the individual level, in which the paediatric allergist knows perfectly that every child has his/her specific allergic condition. Thus, preventive interventions, diagnostic pathways and therapeutic proposals may not be identical in different populations, nor in individuals in the same population. And in an age in which a spate of cutting-edge technology and clinical breakthroughs has substantially altered our vision and practice regarding allergy medicine, it is increasingly clear that all these improvements have their specific applications and, in plain language, may not be everybody's cup of tea. Role of innate immunity in allergy inception Innate immunity is one of the areas of the immunologic research that have substantially modified our understanding of allergic diseases. Cells of the innate immune system have been referred to as ‘the unsung heroes’ by Parham [12] as, with the accruing knowledge in this area, it has become clear that if ‘most people are not perpetually sick, this is tribute to innate immunity squelching most of the infections that we contract’. The innate immunity cell types are specialized in different effector functions: Macrophages are responsible for phagocytosis and activation of bactericidal mechanisms and are major producers of pro-inflammatory cytokines; dendritic cells in addition to releasing abundant pro-inflammatory cytokines, are dedicated to the antigen uptake from peripheral sites (in their immature form) and its presentation to T cells in the lymph nodes (by mature dendritic cells); neutrophils are able to phagocyte and to activate different bactericidal mechanisms; eosinophils act for the killing of antibody-coated parasites; mast cells are able to release granules containing histamine and other active agents; natural killer (NK) cells are able to kill tumor and virus-infected cells and release cytokines, primarily IFN-γ, but also TNF-α and GM-CFS and various chemokines. Thus, innate immunity is highly efficient in dealing with a series of immunologic stimuli and paves the way to the adaptive immunity. To achieve their functions, innate cells act with a series of mechanisms. As an example, NK cells, major players of innate defenses, exert the following functions: Cytotoxicity, including tumor or leukemia cell killing, killing of virus-infected cells, dendritic cells editing, antibody-dependent cell-mediated cytotoxicity (ADCC); Cytokine production, finalized to induce inflammatory responses, regulate adaptive immune responses, regulate hematopoiesis, induce dendritic cells maturation and, in decidual tissues during pregnancy, promote vessels/tissue remodeling and induce Treg; Proliferative capacity. NK cells are essential in tumor surveillance and their activating receptors are engaged by specific ligands frequently overexpressed or expressed de novo upon tumor transformation [13]. However, other events such as cell stress, cell activation, or viral infection can lead to the expression of these ligands, thus resulting in NK cell activation (see Fig. 1). NK cell maturation, witnessed by the expression of particular surface markers as CD161, CD56, CD16, KIR and CD57 and by the downregulation of CD94 and in particular of CD56 [14,15], is accompanied by a progressive decrease in NK cell proliferative potential and an increase in their cytolytic activity [16].FIGURE 1: Schematic representation of the main interactions occurring between normal natural killer (NK) cells (expressing both HLA class I-specific inhibitory receptors and activating receptors) and potential target cells.Given their characteristics, NK have been successfully exploited in the haploidentical hemopoietic stem cell transplantation setting for the treatment of adult and paediatric patients with high-risk leukemias for several years [17,18]. Notably, NK cells are thought to be involved also in the development of allergic diseases. However, up to now the role of NK cells in respiratory allergy has been only marginally investigated. Some studies showed that different cytokines can bias NK cells towards ‘NK-1’ or ‘NK-2’ functional phenotypes, and it has been reported that these polarized NK cell subsets may be unbalanced in asthma [19]. Although, we could not detect NK-1 and NK-2 cell subsets within circulating NK cells, in a recent study [20], we showed that the Th1-polarizing interactions between NK and dendritic cells was significantly altered in patients with respiratory allergy. Remarkably, NK-cell recruitment in tissue and their polarization may be consequent to the effect of infection with different pathogens. Pathogen-associated molecular products (PAMPS) may activate different cell types via Toll-like receptors (TLR), resulting in the release of polarizing cytokines acting on both T and NK cells and leading to their polarization towards Th1 (or NK1) or Th2 (or NK2) profiles. Thus, the particular cytokine microenvironment induced by infection may influence NK cell function, which, in turn, shapes downstream adaptive responses. Notably, NK cells themselves express an array of TLR including TLR3, TLR9, TLR2, TLR7 and TLR8 that allow them to directly sense different pathogens resulting in an increase in cytolytic responses and IFN-γ/TNF-α production [21] references. For example, NK cells display complex interactions with dendritic cells that are amplified by PAMPS interacting with TLR expressed by both cell types. Dendritic cell-derived IL-12 promotes the differentiation of NK towards NK1, able to stimulate Th-1 responses; conversely, the basophil-produced or mast cell-produced IL-4 addresses NK cells towards NK-2, promoting immunologic tolerance or possibly Th-2 induction [22,23]. Regarding the possible role of TLR in allergy, it should be noted that in allergic children, neonatal monocytes are less responsive to lipopolysaccharides (LPSs), dsRNA and bacterial lipopeptides, the natural ligands of TLR2, TLR3 and TLR4 [24]. This is of particular interest considering that: neonatal responses must undergo environment-driven Th1 maturation in the postnatal period [25]; postnatal suppression of Th2 propensity has been attributed to exposure to an increasingly diverse microbial environment during the early years of life; there is now clear evidence that the failure of Th2 suppression in allergic children is related to an underlying disorder of innate microbial recognition pathways; this failure can arise from deviations in innate TLR-mediated responses that have been shown to be preexisting in allergic children [26]. Thus, it appears today that TLR may at least in part be responsible for the differences in allergic predisposition, which appears more likely to emerge in an environment with low microbial burden. The idea of modulating dendritic cells, NK and ultimately Th1/Th2 differentiation through a TLR stimulation is today a seducing possibility for allergy prevention and treatment. In this context, we are aware of both the cellular distribution of different TLR as well as various natural TLR ligands. These include: for TLR1, TLR2 and TLR6, peptidoglycan from gram-positive bacteria, lipoprotein GPI (from trypanosoma cruzi), zymosan (from yeast), mycobacterial lipopeptides, measles and cytomegalovirus proteins; for TLR4, LPS of both gram-negative and gram-positive, lipoteichoic acids (gram-positive), fibronectin and RSV F-protein; for TLR3, ds RNA; for TLR7 and TLR8, ss RNA; for TLR5, Flagellin; for TLR9, unmethylated CpG DNA; for TLR11, uropathogenic bacteria. In conclusion, depending on the type of cytokine(s) released during the early stages of an inflammatory response to infection, NK cells can differently contribute to the quality and magnitude of innate and adaptive immune responses. As NK cells ultimately influence T cell polarization, acting on the deep mechanisms of allergy development in early life creating a ‘positive’ pattern of TLR-induced, dendritic cells and NK-secreted cytokines is more than a theoretical possibility today. Early events in allergy development The unprecedented rise in allergic disease reinforces a pressing need to define the early events responsible, and develop strategies to prevent this. The very fact that the allergic diseases have increased so rapidly and so dramatically in very young children is clear evidence that failure of immune tolerance is a very significant event, and that the developing immune system is vulnerable to modern environmental changes. Equally so, this indicates developmental plasticity of these systems and provides the hope that this can be harnessed for better allergy prevention strategies. It is critically important to consider these issues in the wider context. Modern environmental and lifestyle changes are associated with an unparalleled rise in many chronic inflammatory NCDs. The specific vulnerability of the immune system to recent environmental changes is also reflected in the dramatic increase in virtually all immune diseases. Furthermore, clinical expression of immune disease within the first year of life together with detection of immune dysregulation at birth provides clear evidence of very early effects. Environmental risk factors for early immune dysregulation (dietary patterns, environmental pollutants, microbial patterns and stress) are also recognized risks for many NCDs, highlighting the need for interdisciplinary collaboration focusing on inflammation as a common element and target for NCD prevention. Common risk factors may logically mean that common interventions will have benefits in preventing many NCDs. It is therefore important to consider other health outcomes when designing cohort studies and intervention studies. The growing burden of disease in early life The burden of allergic disease is growing with each generation. The greatest burden of this new epidemic is in young children, who are experiencing the most dramatic increase in food allergy, earlier presentations [7] and increasing persistence [27] of disease. Most recently, food allergy has recently emerged as a substantial public health issue. In developed regions like Australia preschoolers have experienced a five-fold increase in food anaphylaxis over just 10 years [7]. Currently, more than 20% of 1-year-old infants are sensitized to foods and more than 10% have clinical food allergy [6,28]. Many infants go on to develop respiratory allergic diseases [29]. As these younger generations reach adulthood, the burden of allergic diseases is expected to increase even more. Sensitization can be a very early event Previous strategies to prevent food allergy through ‘allergen avoidance’ have not only failed, but have instead been associated with increased risk of disease [30]. This together with other observations in humans and animals suggests that earlier introduction of allergenic foods may be a more logical preventive strategy. On the basis of this, there are several randomized controlled trials (RCTs) worldwide assessing the merits of early introduction of allergenic foods, such as egg and peanut. This includes our own study of healthy infants (n = 1512) at ‘high risk’ of allergic disease, randomized to receive egg powder (or a placebo) daily from when they first introduce ‘solid’ complimentary foods at between 4 and 6 months of age. We are also conducting a smaller pilot study using a similar design in children with eczema. In the course of both studies, we have already noted a significant proportion of clinical reactivity at 4–6 months (at randomization). Specifically, an interim analysis of the eczema study revealed that 22% had early clinical reactions (19/86 infants entering this pilot study), including one case of anaphylaxis requiring treatment with adrenaline (unpublished interim data). This indicates that sensitization has occurred much earlier than when complimentary foods are typically started (4–6 months) and suggests earlier strategies may be needed in some children. Importantly, in all cases there was no previous known history of direct ingestion of the food (egg) by the infant, indicating previous exposure through other routes potentially through breast milk or across the placenta. Although cutaneous sensitization has been proposed in children with eczema, this does not explain rates of reactivity (around 8%) in the study of infants with no eczema (unpublished interim data). Before designing earlier interventions to promote oral tolerance and prevent disease, it is critical to define the underlying immune events, particularly to address the continued uncertainty surrounding questions of allergen ‘dosing’ vs. ‘avoidance’ in pregnancy and lactation. This highlights the need to more fully understand the role and mechanism of early allergen encounter, and how variations in this context can influence the risk of sensitization. It is likely that allergen exposure is a key part of a series of inter-related events that, when functioning normally, lead to appropriate allergen-specific tolerance. Changing environmental conditions are promoting less favourable conditions for tolerance, with these effects beginning before birth and culminating in the early postnatal period. Revisiting concepts of in-utero allergen exposure The role and significance of allergen exposure in utero has been controversial, but needs to be revisited in light of increasing evidence of very early sensitization. There is good evidence that environmental allergens can be detected both in placental tissue [31] and in the fetal circulation [32] from where they could foreseeably interact with the developing immune system. In addition to systemic blood, allergens are also detected in amniotic fluid in animals [33] and in humans [34]. These and other proteins are ingested and hydrolyzed through the gastrointestinal tract after fetal swallowing; another mechanism of potential processing of maternally ingested/derived proteins. Logically, these proteins are also in potential contact with the fetal skin and lungs. Immune responses in utero Human fetal T cells are now known to be in a dynamic balance between activation and quiescence, rather than in a passive state of immature inactivity [35]. Functionally distinct from adult, fetal T cells are highly responsive to activation [36,37], but also more predisposed to Treg differentiation with higher proportions of circulating Treg in fetal life (reviewed in [38]). There is also evidence that the human fetus develops regulatory responses to exogenous antigens (alloantigens [36], microbial antigens [39] and allergens [40]) encountered through the placenta. Although fetal T cells are responsive to allergens [41] as early as 22 weeks’ gestation [42] these responses appear to reflect the promiscuous fetal reactivity of ‘recent thymic emigrants’ [40] rather than ‘conventional adult’ T-cell memory. Utilizing a set of 28 overlapping peptides spanning the Ovalbumin (OVA) molecule, we have previously shown that more than 60% of neonates respond to multiple OVA epitopes, suggesting that these fetal immune responses involve recognition of multiple regions within the molecule and are thus likely to be directed against the native antigen, as opposed to a small number of epitopes in a cross-reacting antigen [41]. Notably, our collaborators have previously shown this initial burst of short-lived OVA responsiveness is limited by parallel activation of suppressive CD4+CD25+regulatory T cells when fetal myeloid cells are cultured for 5 days in the presence of allergen [40], consistent with the recognized fetal predisposition for ‘active tolerance’ [38]. Furthermore, using previously published methods [43], we have demonstrated the presence of OVA-specific CD4+ effector responses in cord blood which were suppressed by addition of fetal CD4+CD25+CD127lo suggesting OVA-specific Treg activity in this cord blood fraction (unpublished data). In-vivo studies also provide evidence that fetal Treg ‘memory’ to other exogenous antigens (alloantigens and microbial agents [39]) crossing the human placenta are long-lived and that these can persist after birth to influence postnatal antigen-specific responses [36,39]. Cord blood levels of food allergens, such as egg (OVA) range between 0.05 and 5.67 ng/ml and correlate directly with maternal levels (r = 0.754, P < 0.001) [44]. Egg ingestion in pregnancy also correlates well with cord blood OVA-IgG levels, which are a better measure of allergen exposure than serum allergen levels probably because of a degree of allergen-trapping in the placenta [31]. As allergen exposure at this age appears to favour regulatory T-cell responses [40], it is perhaps unsurprising that fetal lymphoproliferation to allergens do not correlate with maternal environmental allergen exposures [45,46]. Previous studies using maternal dietary elimination of egg in pregnancy in an attempt to reduce egg allergy have had paradoxical effects. Although egg-elimination achieved a significant reduction in OVA-IgG levels, this was not associated with allergy reduction [47]. Rather a nonlinear (bell-shaped) relationship with subsequent allergy risk has been observed [47]. Specifically, higher levels of OVA-IgG were actually protective against infant allergic disease (as were very low levels) whereas mid-range OVA exposure in pregnancy was associated with the highest risk [47]. This is consistent with aeroallergen studies but still requires further investigation. Other studies suggest that the maternal allergen-specific IgG induced through allergen exposure may have direct allergy suppressive effects in the offspring [48]. We speculate that transplacental allergen encounter induces initial waves of allergen-reactive CD4+ T cells which are preferentially conditioned to differentiate into regulatory populations (as demonstrated in vitro[40]), thereby ‘setting the scene’ for postnatal exposure. The importance of tissue milieu Variations in the local tissue milieu during antigen/allergen encounter play a critical role in determining the pattern of effector responses and the efficacy of regulatory mechanisms [49]. This accounts for both tissue specific differences in immune responses, but also the changes in immune development under different environmental conditions that may alter the local milieu. Accordingly, there is evidence that maternal environmental exposures in pregnancy can specifically modify fetal immune function including dietary patterns [50], cigarette smoke exposure [51,52] and microbial exposure [53–55], through either epigenetic changes or other mechanisms [56]. Variations in the cytokine profiles in cord blood, likely to reflect the milieu in the placenta and fetal tissues, have been associated with allergic predisposition [57]. We have also recently shown that the neonatal thymic milieu also reflects the T helper type 2 (Th2) skewed cytokine milieu of cord blood, with the same age-related postnatal changes [58]. Thymic stromal lymphopoietin (TSLP) produced by thymic epithelial cells in Hassall's corpuscles conditions dendritic cells [59] to induce conversion of reactive CD4+CD25− thymic T cells into CD4+CD25+FOXP3+ Treg [60]. Maturation of thymic Treg cells also requires activation of the TSLPR/IL-7Rα receptor complex by TSLP or IL-7 [61,62]. Of note, we also demonstrated that variations in TSLP in newborn thymic tissue correlate with the capacity to generate Treg, suggesting that there are individual differences in the thymic microenvironment in utero [58]. Moreover, we demonstrated that reduced TSLP and reduced Treg in the first weeks of life was associated with the risk of subsequent sensitization (to foods) at 1 year [58]. It is therefore possible and likely that immune modifying environmental influences in utero could be exerting effects on the milieu in various tissues to promote or protect from allergic disease [49]. The allergen encounter in the early postnatal period Although it is clear that ‘the scene is set’ to some extent in utero, it is also evident that responses are strongly shaped in the early postnatal period. During this period both colonization and breastfeeding provide critical tolerogenic signals in the developing gastrointestinal tract when food allergens are ‘first’ ingested as part of an infant diet. Food allergens secreted in breast milk provide an important early oral exposure [44,63]. However, we have shown in a double-blind RCT of lactating women fed 55 g/day of egg (vs. egg-free placebo) for 21 days that there are individual differences in OVA secretion and that some women (25%) do not appear to secrete OVA in their milk [63]. Our collaborators have also shown that allergen-IgG complexes in breast milk induce antigen-specific Treg cells in the newborn animals [64]. With similar complexes now detected in human milk [65], we speculate that observed differences in maternal milk content could contribute to the efficacy of local tolerance and susceptibility to inflammation. In this context, it is of enormous interest that thymus size is greater in breastfed than formula-fed infants [66] and that animal models show that this may be due to variations in breast milk IL-7 levels. Specifically, IL-7 in maternal milk has been shown to transfer across the neonatal intestine to increase T-cell production in the thymus [67]. Because of the role of IL-7 in generation of thymic Treg this suggests a hitherto unrecognized link between local and systemic tolerance mechanisms, which needs to be investigated further. Transcutaneous exposure to foods is also speculated to be another route for sensitization in the early postnatal period, particularly in children with eczema [68]. Antigen transfer through a defective epidermal barrier is a key mechanism underlying IgE sensitization [69], and epithelial barrier dysfunction has even been proposed as a primary and initiating event in the allergic phenotype (reviewed in [70]). Eczema, frequently the first manifestation of allergic disease (and a recognized risk factor for food allergy) has been clearly associated with epithelial barrier dysfunction and mutations in Filaggrin, a key protein involved in skin barrier integrity [70]. Moreover, children with early-onset (<3 months) and more severe eczema have the greatest risk of IgE sensitization [71]. Clearly, in these children an atopic phenotype (eczema) has been established as a consequence of much earlier events and it is still not clear if food sensitization is a parallel or secondary event. Conclusion Understanding the environmental factors driving this rising predisposition will provide the best hope for reducing the burden of allergic disease through early primary prevention strategies. Emergent differences in immune function of newborns destined to develop allergic disease [26,41] emphasize the need to examine the role of predisposing utero events, as the placenta and the fetus are both vulnerable to exogenous and endogenous maternal influences during this period [72]. Specific maternal exposures, such as microbial exposure, maternal diet, cigarette smoke and other pollutants, can modify fetal immune function and contribute to an increased risk of subsequent allergic disease (reviewed in [72]). These initiating events then appear to be rapidly consolidated in the early postnatal period in the growing proportion of children clinically manifesting an allergic phenotype in the first months of life. The most logical strategies to prevent allergic disease are those that will safely re-establish the more tolerogenic conditions seen in traditional lifestyles, particularly during these critical periods of development. So far this has been focused on specific and isolated interventions such as restoring microbial balance (probiotics), dietary patterns (prebiotics, n − 3 polyunsaturated fatty acids and other supplements) and minimizing adverse exposures including pollutants and stress. However, this may ultimately require a more holistic approach. Likely benefits of lifestyle interventions for the many other chronic inflammatory disorders (NCDs) associated with modern living underscore the need for interdisciplinary collaborations to overcome the rising global burden of these numerous modern conditions. Immune interventions in paediatric asthma: a new beginning Introduction The modern day epidemic of asthma and allergy shows no signs of waning. In order to curb this trend and reduce the prevalence of allergic diseases, we urgently need to find ways of preventing the development of atopy for which, once established, there is no cure and no medications that can alter its natural course. Early environmental exposure of the immature immune system of children is critical in determining allergen sensitization vs. tolerance. There is emerging evidence of an imbalance in both innate and adaptive immunity in those predisposed to atopic disease [26]. In addition, there is evidence of delayed maturity at birth in both Th2 (allergy-favouring) and Th1 (counterbalancing) responses in atopic children [73]. So how do we influence the immune system in children at high risk of atopy to redress this imbalance? A number of strategies could be tried (see Box 1).Fig. 1: no caption available.Reduction in allergen exposure A dose-dependent relationship between allergen exposure and sensitization [74,75] and between sensitization and the development of allergic disease [76] is well established. A number of studies attempted to reduce exposure to allergen in early life as a means of influencing immune development and consequently lowering the risk of asthma and other allergic conditions. The Isle of Wight allergy prevention study was the first to show that a combination of strict avoidance of food and house dust mite (HDM) allergens during infancy has a profound effect on the development of atopy in genetically at risk children. The study showed a significant reduction in the incidence of asthma, atopic dermatitis and atopy in early childhood [77], and a continued effect was observed until later childhood [78]. However, other studies [79–81] using similar, although not the same, allergen reduction strategies met with less success. There may be a nonlinear relationship between allergen exposure and sensitization so that very low and high exposure may lead to tolerance, while a moderate level may cause sensitization [82]. Recent epidemiological observations support the notion of immune tolerance induction, rather than allergic sensitization following early high dose oral exposure to an allergen. Grass pollen immunotherapy in allergic rhinitis may prevent asthma [83]. This led to the hypothesis that high dose orally administered HDM allergen will induce immune tolerance in early childhood. Oral allergen immunotherapy We hypothesized that oral HDM immunotherapy will prevent sensitization to this key environmental allergen and, therefore, prevents the subsequent development of asthma. To test this hypothesis, we are recruiting 120 infants at high risk of atopy in a RCT. Immunotherapy (or placebo) will be administered from 6 months of age for a period of 12 months. Regular assessments with validated questionnaires and allergy tests are carried out at 3 monthly intervals. The results of this trial will be available in 2014. Use of hypoallergenic formulae After a 20 years’ controversy, a systematic review of the National Institute of Allergy and Infectious Diseases (NIAID) Grading of Recommendation, Assessment, Development and Evaluation GRADE panel concluded in 2012 that: patients at risk for developing food allergy are defined as those with a biological parent or sibling with existing, or history of, allergic rhinitis, asthma, atopic dermatitis, or food allergy; the exclusive use of extensively or partially hydrolyzed infant formulas should be considered for infants who are not exclusively breastfed a" @default.
W2462617553 created "2016-07-22" @default.
W2462617553 date "2013-03-01" @default.
W2462617553 modified "2023-09-27" @default.
W2462617553 title "The management of paediatric allergy" @default.
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