Abstract
The prevalence of atopic diseases has increased abruptly in recent years in most Westernized societies, making the question why this happened the topic of a heated debate. The best paradigm available to date to explain this steep rise, the ‘hygiene hypothesis’, supports that it is the excess ‘cleanliness’ of our environments that has led to the decline in the number of infectious stimuli that are necessary for the proper development of our immune system. Recent findings support that it is the combined effect that not only pathogenic, but also non-pathogenic microorganisms, and even their structural components, can exert on the immune system that deters from the development of atopic responses. Adding to these results are intriguing new findings on the effect different gene polymorphisms can have on an individual's predisposition to allergic diseases. The most important linkages produced, to date, include those among the genes for IL-4, IL-13, HLA-DRB, TNF, LTA, FCER1B, IL-4RA, ADAM33, TCR α/δ, PHF11, GPRA, TIM, p40, CD14, DPP10, T-bet, GATA-3, and FOXP3 and allergic disorders. The two parallel research efforts, epidemiologic and genetic, are only recently starting to converge, producing fascinating results on the effect particular gene-environment interactions might have in the development of atopy. The most important lesson learned through this tremendous research effort is that not only a small number but thousands and millions of separate risk factors act in concordance in the production of the allergic phenotype.
Introduction
Over the last 50 years the prevalence of diseases such as hay fever, atopic dermatitis, and allergic asthma has increased significantly in the developed world Citation1–3. The 2002 surveillance for asthma in the United States reported a 76% increase of the estimated annual prevalence of self-reported asthma during the period 1980–1995, its prevalence reaching an impressive 5.5% in 1995 Citation4. Allergic diseases are now epidemic in most Westernized societies, affecting approximately 20%–30% of their populations, and ranking first among the causes of chronic disease in children. Despite the fact that some recent evidence suggests a stabilizing trend of their prevalence Citation5–9, the question why these diseases have spread so rapidly remains hot.
Allergy is an immunological disorder. It is defined as a disease that follows an immune system response towards an otherwise innocuous antigen (Ag) and is usually equated with type I hypersensitivity reaction (immediate type hypersensitivity). The condition that underlies allergic diseases is atopy, which is characterized by raised immunoglobulin E (IgE) levels. Multiple pathways have been identified that can lead to the production of IgE in response to external stimuli Citation10, Citation11.
Key messages
The presence of particular gene variations modifies an individual's likelihood to develop allergic diseases.
Exposure to infections during the maturation of a child's immune response may be crucial to reduce reactivity to innocuous environmental particles.
More than any specific infection, it is the overall microbial burden early in life that seems to protect against the development of allergies.
Mechanisms of IgE production
Most allergens are small, highly soluble, proteins presented to the immune system at very low doses. They seem to induce immune responses that are very similar to those induced by helminthic infections. Several cell types detect allergens and can trigger a response against them ().
Figure 1. The three main pathways of antigen presentation and the effector mechanisms induced during the allergic reaction.
Allergens that end up in local lymph nodes are mostly taken up by dendritic cells which present them to naive CD4+ T cells through their class II major histocompatibility complexes (MHC-II). This signals CD4+ T cells to become activated and differentiate into a predominantly T helper 2 (Th2) phenotype. Th2 cells are thought to be the key organizers of the allergic response from then on. They produce interleukins IL-4 and IL-13 and express costimulatory molecules, like the ligand for the CD40 molecule (CD40L), on their surface. CD40L binds to CD40 on the surface of B cells signaling them to initiate class switching to IgE production Citation12, Citation13. Concurrently, Th2 cells produce IL-5, an activating factor that stimulates eosinophils to release their various inflammatory mediators and toxic proteins. B cells can also take up antigen through their surface immunoglobulin receptors, process it, and present it to T helper cells as peptide-MHC class II complex. This T-B cell interaction promotes the transcription and translation of the IL-4 gene in T cells and in this way the induction of IgE production from B cells Citation11, Citation12.
Both of these pathways depend on the presence of antigen and are referred to as ‘cognate’ (antigen-driven). However, non-cognate pathways also seem to occur. Mast cells and basophils express on their surface FcεRI, the high-affinity receptor for IgE. When the FcεRI-bound IgE antibodies are cross-linked by antigen, CD40L expression and IL-4 secretion are induced signaling B cells to produce IgE. Mast cells and basophils also release vasoactive mediators, chemotactic factors and cytokines which, together with the substances released by eosinophils, trigger the inflammatory cascade that ultimately leads to allergic symptomatology Citation10, Citation14.
Whatever the cell type primarily involved in the initiation of the immune response against an allergen, it seems that the activation of Th2 cells and the consequent B cell signaling are events central to the pathogenesis of atopy. What remains a mystery is why some individuals oversecrete IgE antibodies and overreact to innocuous molecules, while others do not. In order to answer this question one has to examine both the genetic and the environmental factors that can influence the expression of the allergic phenotype.
Genetic factors
Research into genetic factors contributing to an allergic phenotype in humans has proved to be quite complicated. Monozygotic twins are known to be more concordant for any type of allergy than are dizygotic twins. However, even in monozygotic twin pairs (where at least one member is allergic) concordance averages only around 50%–60% Citation15. A second confusing finding is the parent of origin effect. It has been observed that the risk of transmission of an allergic disorder from an affected mother is approximately four times higher than from an affected father Citation16. The mechanisms by which these phenomena occur remain largely unknown.
Allergy is considered to be a genetically determined complex disease, which means it does not obey the classical Mendelian laws of recessive, dominant, or codominant inheritance. The allergic clinical phenotype is not only determined by interactions between multiple major and minor genes but is also modulated by non-genetic factors, like the environment. Adding to this complexity is the fact that under the term ‘allergy’ numerous clinical entities are encompassed, most of which are not very clearly demarcated.
Nevertheless, numerous genetic and genomic studies have been performed to date, already producing a significant number of candidate susceptibility genes. The eight most cited atopy-associated genes until 2003 included the ones encoding for IL-4, IL-13, β2 adrenergic receptor (ADRB2), human leukocyte antigen DRB1 (HLA-DRB1), tumor necrosis factor (TNF), lymphotoxin-alpha (LTA), high-affinity IgE receptor (FCER1B), and the alpha chain of the IL-4 receptor (IL-4RA) Citation17. Apart from these, a number of other genes have received significant attention more recently and are also discussed below.
Allergy susceptibility genes
The MHC class II region shows strong evidence for linkage with allergy in many studies Citation18–21, as this would have been expected since HLA specificities are the ones that restrict the immune response to particular allergens. Associations between several HLA haplotypes and immune responses to specific allergens have been observed Citation22, Citation23. Haplotypes containing the HLA class II DRB1*1501 allele, for example, have been associated to responses against ragweed pollen allergens Citation24. Certain HLA-DQB1*03 alleles, on the other hand, are associated with higher levels of total serum IgE and an increased susceptibility to allergy and asthma Citation25–27 ().
Table I. Major candidate susceptibility genes for allergic diseases discovered to date.
A linkage between specific IgE responses and the T cell receptor α/δ (TCR-α/δ) locus on chromosome 14 has been proved by many researchers as well Citation28–30. It has been shown that allele 2 of the Vα8,1 polymorphism (Vα8,1*2) is associated with higher IgE titers against Der p II, a house dust mite antigenic component Citation29. Certain germ-like elements of the TCR-Va region are even thought to interact with particular HLA-DR types to produce in common a modified response to particular foreign antigens Citation29.
Another candidate for an allergy-susceptibility gene is the tumor necrosis factor gene encoding for TNF, a potent proinflammatory cytokine found in excess in asthmatic airways Citation31, Citation32. Polymorphisms in the gene encoding for TNF have been associated with variation in the expression of TNF-α, in particular, and the presence of asthma. The TNF-308 promoter allele has shown a consistent association with asthma in many studies Citation33–35.
Closely related to TNF, located on band 21 of the short (p) arm of chromosome 6 (6p21), is the gene that encodes for lymphotoxin-alpha (LTα). LTα's main function seems to be to regulate the expression of the TNF gene. As a consequence, polymorphisms in this area have also been linked to the development of asthma. The LtαNcoI polymorphism, in particular, is associated with an increased risk of asthma and bronchial hyperresponsiveness in many studies Citation33, Citation36–38.
Located on band 13 of the long (q) arm of chromosome 11 (11q13), the gene that encodes for the β chain of the high-affinity receptor for IgE (FcεRI-β) is also being associated to atopy in several trials Citation39–42. The FcεRI-β chain stabilizes the receptor's expression on the surface of mast cells and amplifies almost 7-fold its response to activation. Consequently, polymorphisms in this area modify the strength of the immune response against allergens. Allergy, asthma, and bronchial hyperresponsiveness have all been associated with certain FcεRI-β polymorphisms Citation43, Citation44.
Bands 23–35 on chromosome 5q seem to contain multiple allergy susceptibility candidate genes, including IL-4, IL-13, granulocyte-macrophage colony-stimulating factor (GM-CSF) and IL-9. Collectively these genes are known as the cytokine cluster Citation45. IL-4 gene polymorphisms are only weakly linked to asthma Citation46, Citation47, whereas a far stronger link has been established between IL-13 polymorphisms, increased serum IgE levels, asthma and atopy Citation48–51. A second set of genes found in this area is the TIM (T cell immunoglobulin and mucin domain) family genes Citation52. TIM encodes for various surface proteins expressed on CD4+ T cells. In mouse strains, TIM genes have been correlated with the production of IL-4 and IL-13 and the degree of airway hypersensitivity. In humans, certain TIM-1 allelic variants have been associated with protection from atopy, but this protection only seems to be conferred to individuals with a hepatitis A virus exposure history Citation53. This finding is of particular importance since it provides molecular evidence of the hygiene hypothesis theory (discussed in the next section).
On the same area of chromosome 5q, the CD14, ADRB2, and p40 genes are found, all of which are associated with the development of atopic disorders. CD14 encodes for a protein that forms part of the cell surface bacterial lipopolysaccharide (LPS) receptor. Polymorphisms in the CD14 promoter region have been linked to the presence of atopy in some populations Citation54, Citation55, an example being the CD14-159CC genotype which has been associated with an increased risk of early-onset atopy and airway hyperresponsiveness Citation56. The p40 gene, encoding for one of the two subunits of IL-12, has been associated to an increased susceptibility to asthma, atopic dermatitis, and psoriasis vulgaris Citation57–59. Associations between the gene encoding for the β2-adrenergic receptor (ADRB2) and variations in the airway's smooth muscle responsiveness to allergens and asthma have also been reported Citation60–64.
Alpha disintegrin and metalloproteinase-33 (ADAM33) found on chromosome 20p13 is yet another gene that has been linked to atopy. ADAM33 is expressed ubiquitously in muscle cells of every type, particularly in lung smooth muscle cells, and in bronchial fibroblasts. The proteins encoded by ADAM33 have been implicated in processes like proteolysis of extracellular matrix and extracellular communication and signaling. It has thus been suggested that the ADAM33 gene might encode for a protein that plays a role in airway remodeling by fibroblasts and in bronchial smooth muscle contraction. Mutations in the ADAM33 region have been linked to both bronchial hyperreactivity and airway remodeling in asthma Citation65–67.
The DPP10 gene on chromosome 2q14 is also linked to allergy in several studies Citation19, Citation20, Citation68–70. DPP10 encodes for a dipeptidyl peptidase, a peptidase involved in cleaving terminal dipeptides from chemokines and cytokines. Through this process dipeptidyl peptidases can regulate the activity of certain chemokines and cytokines. The exact role of DPP10 proteins is not yet entirely clear, however, some researchers supporting that these proteins are not at all linked with atopy but are in fact associated with type A K+ channels in neurons Citation71.
Associated with asthma as well, the gene for the neuropeptide S receptor 1 (NSR1), also called the G-protein-coupled receptor for asthma susceptibility (GPRA), is located on chromosome 7p15 Citation72, Citation73. Out of the two receptor isoforms encoded by this gene, NSR1-B is differentially expressed in bronchial epithelial and smooth muscle cells of asthmatic individuals compared to healthy controls, suggesting that a dysregulation in NSR1 expression could predispose to asthma Citation73–76.
Another candidate for an allergy susceptibility gene, IL-4RA gene, is encoding for the IL-4 receptor alpha chain that forms a component of, not only the IL-4, but also the IL-13 receptor Citation41, Citation77. Variations in this gene are linked with allergic inflammatory disorders, including hyper-IgE syndrome and atopic dermatitis Citation78, Citation79.
One of the most consistent linkage findings in genetic studies is the one of PHF11 gene on chromosome 13q14, asthma and atopy Citation41, Citation80–82. PHF11 is mainly expressed in the stomach, tonsils, and B lymphocytes, this finding leading to the assumption that PHF11 could be involved in the regulation of lymphocyte activation and immunoglobulin synthesis. The exact functional role of PHF11, however, still remains unclear.
Finally, the transcription factors involved in Th1 and Th2 response polarization and the development of T regulatory (Treg) cells are also thought to be associated with allergy Citation13, Citation83–85. GATA-3, the transcription factor necessary for the development of Th2 cytokine responses and T-bet, and the corresponding transcription factor for Th1 cytokine gene expression have both been implicated in the development of atopy. Since Treg cells are thought to be responsible for controlling the Th1/Th2 response balance, their respective transcription factor, FOXP3, is plausibly linked with atopy as well.
Environmental factors
The fact that the prevalence of allergic disorders has increased rapidly during the last 50 years, and that this increase was primarily experienced in the developed world, both strongly suggest the involvement of environmental factors in their pathogenesis. In an effort to identify these factors it is useful to consider the time window during which atopic diseases most frequently manifest for the first time. The greatest incidence of wheeze occurs in children under the age of 4 years, and it is during the same period that asthma starts in most patients Citation86, Citation87. It is thus logical to assume that atopic sensitization could take place, either during early childhood or, even earlier, during pregnancy. Indeed, T cell responses to common environmental allergens can be detected in almost all newborn babies Citation88.
The probable effect maternal behavior could have on the gestating embryo has been the focus of intense research lately Citation89–92. It is speculated that maternally originating allergenic peptides could be presented to the fetal immune system, either directly, passing inside the fetal circulation, or on the surface of maternal antigen-presenting cells at the maternal-fetal interface Citation88, Citation93. The purpose of this priming could supposedly be to preadapt the fetal immune system to current environmental conditions Citation94, Citation95. Alternatively, maternal exposures might influence directly the genetic profile of the embryo through a process called epigenetic inheritance Citation96, Citation97.
This early sensitization could also contribute to the Th2 cell polarization that is most usually seen in newborn babies Citation88, Citation98, Citation99. The Th2 cell predominance helps reduce the maternal immune system's reactivity against the fetal allograft Citation100; however, at the same time, it confers a predisposing effect for atopic diseases. This is probably the reason why normally, during the first 2 years of life, this Th2 polarization gradually gives way to a Th1 bias. This transition, however, does not seem to happen in atopic children, and they are found to exhibit the Th2 shift for the rest of their lives. Various theories have been proposed to explain why this happens; the most exciting of all and, at the same time, the one that has received the greatest attention is called the ‘hygiene hypothesis’.
The hygiene hypothesis
This hypothesis was formulated about 20 years ago, based on data showing that the prevalence of hay fever and eczema in children is proportional to the number of their younger and older siblings Citation101. What it essentially postulates is that infections during infancy (which purportedly occur more often in larger families) might in fact protect against allergic disorders. At a cellular level, microbial infections might be necessary in order to help shift the Th1/Th2 balance.
Following the development of the ‘hygiene hypothesis’ numerous epidemiologic studies have emerged in support of its main thesis (). Individuals that present with a positive tuberculin response Citation102 or a positive serology to hepatitis A Citation103–105 have been found to possess a lower risk of exhibiting allergic disorders. An inverse relationship between atopy, asthma and allergic rhinitis, and infections of the gastrointestinal tract caused by Helicobacter pylori or Toxoplasma gondii has also been established Citation103, Citation106–108. Measles infection early in life has also been found to be negatively associated with the development of atopy Citation109. Finally, Epstein-Barr virus (EBV), Cytomegalovirus (CMV) and herpes infections have all shown a protective effect against allergy Citation110, Citation111. All these studies essentially support the notion that exposure to pathogens, like hepatitis A virus, early in life helps in the prevention of allergy, probably through a Th1 upregulation mechanism.
Table II. Epidemiologic studies in support of the ‘hygiene hypothesis’. For a more extensive catalogue of relevant epidemiologic studies see reference Citation175.
Using a more indirect approach to support the role of infectious diseases in the prevention of allergy, it has been found that the exposure of young children to older children at home Citation112, Citation113 or to other children at day care Citation114, Citation115 can confer protection against the development of asthma and wheezing. Likewise, living in a farm environment during childhood seems to protect against the development of allergy Citation116–119. Also protective against atopy are those vaccines that process Th1-stimulating properties, like Bacille Calmette-Guérin (BCG) Citation120.
Despite the significant number of studies in support of the hygiene hypothesis, there is an equally high number of studies that has emerged with results that are contradictory to its main thesis. In contrast to other infections, respiratory viral infections early in life have been associated with an increased risk of wheeze Citation121, Citation122. Respiratory syncytial virus (RSV) infection during infancy, in particular, is strongly associated with the development of asthma and allergic sensitization Citation123, Citation124. On the other hand, the protective effect purportedly conferred by measles or hepatitis A infections has been disputed by a number of studies where either no effect or a positive association between these infections and allergy has been found Citation125–129. Children growing up in a farm environment, although having a lower prevalence of atopy, present a paradoxically high prevalence of asthma Citation130, Citation131. Controversial data have emerged on the role mycobacterial infections might have in the development of atopic diseases as well Citation132. Similarly, the protective role of BCG vaccination against atopy has been questioned by some researchers Citation133–136.
The immune regulation theory
The finding that has puzzled scientists the most, however, is that allergies can present in parallel with both helminthic infections and autoimmune diseases in the same individual. The paradox in this is that parasitism with helminths confers a protective effect against allergy, despite the fact that parasitisms are known to provoke a, predominantly, Th2 immune response Citation137–139. It thus seems that the Th1/Th2 paradigm is insufficient to explain this protective effect. In an attempt to explain this paradox and at the same time encompass the conflicting results that different epidemiologic studies have produced, under a single pathogenetic mechanism, van den Biggelaar and colleagues proposed in 2000 an intriguing theory Citation140. What they hypothesized was that parasites could be responsible of inducing the production of IL-10 from T cells that can subsequently downregulate Th2 responses and IgE production. IL-10, mainly produced by CD4+CD25+ regulatory T cell (Treg) populations, is known to be able to dampen immune responses in general. What this theory essentially suggested was that infections with either parasites or with microbial agents might boost those regulatory networks that are necessary to dampen responses as soon as the infection is controlled. These same regulatory responses could be necessary in order to avoid immune reactivity against innocuous environmental particles ().
Figure 2. Schematic representation of the immune-regulation network theory. This network is believed to be responsible for preventing the development of both autoimmune and atopic diseases.
This ‘immune-regulation theory’, apart from explaining the presence of parasitic infections in atopic individuals, can also provide a satisfactory basis for the explanation of the type 1 diabetes/allergy coexistence that is seen in some patients Citation141, Citation142. This coexistence suggests that the root cause for the increase in atopic diseases could also be responsible for the recent rise in the prevalence of autoimmune disorders Citation143, despite the fact that allergy is a Th2- and autoimmune diseases a Th1-associated disease. In this case again, infections by pathogens that induce the production of IL-10 might be responsible for the downregulation of both the Th2 and the Th1 responses that are seen in allergic and autoimmune disorders, respectively. This theory further explains why it is so difficult to generate autoimmune diseases in ‘dirty’ animal colonies Citation143, Citation144.
The role of innate immunity
Based on the above framework it has been proposed more recently that, not only contact with pathogens that manifests themselves clinically, but even contact with non-pathogenic microorganisms, or merely with their components, might be enough to modulate the immune system's reactivity Citation145, Citation146. Attention has mainly focused on the effects that five particular bacterial components might be in a position to exert on the proper education of our immune system. These include the cell wall components LPS (endotoxin), teichoic acid and peptidoglycan, the bacterial DNA component CpG oligonucleotide, and the fungal and helminthic structural constituent, chitin Citation147–149.
Experimental evidence suggests that it is the innate immune system that first comes into contact with these bacterial particles, their recognition relying on pattern recognition receptors, like toll-like receptors (TLRs) and caspase recruitment domains (CARDs). These receptors are mainly found in dendritic cells, and their primary function is thought to be to detect the presence of ‘danger’ signals Citation150. Signaling through TLRs can induce the maturation of dendritic cells into cells that are able to initiate the adaptive immune response cascade. In the absence of these essential ‘danger’ signals, dendritic cells are unable to support the further maturation of responses and, instead, regulatory pathways are activated Citation151. Intermittent contact with microbial particles might, in this manner, be necessary in order to properly ‘educate’ our immune system to become tolerant to non-hazardous particles and allergens. Similarly, chronic infections, like those caused by parasites and Mycobacterium tuberculosis, could be of value to our immune system in that they can provide a constant stimulus for the production of anti-inflammatory cytokines. Indeed, repeated or continuous exposure to an antigen is one of the primary pathways that can lead to the induction of tolerance Citation152, Citation153.
Do we know which is the major source or sources of bacterial stimuli that was present in the past, and that are dramatically reduced in today's developed world? Soil, almost entirely absent from most modern societies, contains a large number of bacteria, including mycobacteria and actinomycetes. Studies performed in North Karelia, Finland and the Republic of Karelia in Russia show a large variation in the prevalence of allergic diseases between these two regions, despite their close geographical proximity Citation154, Citation155. This is attributed to the different environmental exposures that are present among these two populations, including exposure to soil and its products. Even among populations that originate from the same country, large differences in the frequency of atopic symptoms can be found. The large, cross-sectional, PARSIFAL (Prevention of Allergy Risk factors for Sensitization In children related to Farming and Anthroposophic Life-Style) study has recently addressed this particular issue, concluding that exposure to farm environment early in life protects against the development of atopic diseases Citation156–158. Both these studies show that it is not specific infections but rather what urbanization has caused to our environments in general, that has led to the explosion of allergies.
Bacterial populations are also present in large quantities inside our own gut, making them an intriguing candidate for the missing bacterial pool. The molecular ‘signatures’ these bacteria carry allow them to be recognized as weak ‘danger’ signals, thus not inducing proper immune reactions, but triggering the development of regulatory responses Citation151. The role this indigenous bacterial flora plays in the proper development of our immune system is illustrated in trials where the administration of antibiotics early in life has been found to correlate with the frequency of allergic diseases Citation159–161. Antibiotics can disrupt the physiologic gut bacterial flora, thus reducing its influence on the development of our immune system. In support of this view, the patterns of bacterial colonization during early childhood have been found to exhibit significant differences both between the developed and the developing world Citation162 and between allergic and non-allergic children Citation163–165. Reduction of the number of infections occurring early in life could be another way through which frequent antibiotic use might contribute to the development of atopy. In contrast, children from families with an anthroposophic life-style that avoids frequent antibiotic use exhibit a lower prevalence of atopy Citation156, Citation166, Citation167.
Gene-environment and gene-gene interactions
For a disease like allergy that manifests itself in so many different ways and in such diverse populations, it is only natural to assume that it is the combined effect of a constellation of different risk factors that act together in its pathogenesis. It is has recently become clear that these allergy susceptibility factors can interact with each other in many different ways in the production of the allergic phenotype.
In particular, a constantly increasing number of gene-environment interactions are being reported. The CD14-159 polymorphism that was mentioned earlier has been shown to either confer a protective or a predisposing effect to the development of asthma, depending on the levels of LPS present in the environment of the carriers Citation168, Citation169. Other studies have shown that the protective effect this polymorphism confers can only be manifested during mid-childhood, whereas later in life it is lost Citation56. Analysis of a subsample of children that participated to the PARSIFAL study, on the other hand, showed that maternal exposure to a farm environment during pregnancy is not only associated with protection from atopic sensitization, but also with an increased expression of the genes for the microbial receptors TLR2, TLR4, and CD14 in children Citation95.
Different genes have also been shown to be able to interact with each other in the production of a specific phenotypic variant. For example, the combined presence of the 590C allelic variant of the gene encoding for IL-4 together with the Arg551 allele of the IL-4RA gene significantly increases susceptibility to asthma Citation170. Similar interactions have been detected among the IL4RA-S478P and IL13-1111C/T gene polymorphisms, their common presence in an individual increasing susceptibility to asthma by as much as five times Citation171.
Future directions
Owing to the dramatic increase of atopic disorders, research effort has greatly intensified recently, leading to the discovery of fascinating new findings. Despite the tremendous progress achieved, however, large questions on the how and why allergies arise still remain to be answered.
An example is the Th1/Th2 paradigm, which, although providing a basic framework for the molecular mechanisms that might underlie the development of atopy, seems inadequate to explain many of the present experimental findings. The Th2 polarization that is reported to be found in atopic individuals, for example, is primarily detected in peripheral blood, which leaves us the question whether similar imbalances are present in other tissues as well, or whether this phenomenon is restricted there. What is even more unsatisfying about this paradigm is the fact it has been used in the past to explain the pathogenesis of a vast array of entirely different immune disorders. It thus seems more plausible to hypothesize that the Th1/Th2 paradigm must be an oversimplification of the true molecular mechanisms that underlie the development of atopic diseases.
Another area that future studies are expected to shed some light upon is the question of the primary tissue (or tissues) where the protective effect conferred by microorganisms originates. Both the respiratory and the gastrointestinal tract represent plausible candidates. Some evidence in support of the role the latter might play in the development of allergies has already been produced Citation172, although more research on this issue is still necessary.
Finally, one of the greatest issues still unsettled is the issue on the definition of atopic diseases themselves. There is as yet no single instrument to identify asthma, for example, and its diagnosis remains largely clinical. In the past different studies, both genetic and epidemiologic, have used totally different ways in order to define atopic disorders. Even more, a clear distinction on the relationship among atopy and atopic diseases is not yet available, an increasing number of studies suggesting that this relationship might not be as clear-cut as previously thought Citation139, Citation154, Citation173, Citation174. Finally, the distinction among risk factors that are responsible for the onset and those that are responsible for the exacerbation of atopic diseases has not always been obvious in the past and needs to be clarified in future studies.
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