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Keywords:

  • allergy;
  • environment;
  • epigenetics;
  • interferon gamma

Abstract

  1. Top of page
  2. Abstract
  3. The role of epigenetics in the early life immune programming
  4. IFNγ production during early life and the risk of allergic disease
  5. IFNγ gene expression is regulated by epigenetic mechanisms
  6. Microbial exposure and the risk of allergic disease
  7. Does microbial exposure modify demethylation of the IFNγ gene?
  8. Proposed disease pathway
  9. Theoretical and practical issues relevant to investigating these hypotheses
  10. Conclusion
  11. References

The period of immune programming during early life presents a critical window of opportunity for the prevention of allergic diseases. There is mounting evidence that inappropriate immune programming may involve disruption of specific epigenetic modifications (switches) at immune-related genes. This novel area of research has great potential, as epigenetic changes are known to be sensitive to environmental factors and may therefore provide a mechanistic link for the observed association between specific environmental cues, faulty immune development, and the risk of allergic disease. In addition, the dynamic and potentially reversible nature of epigenetic modifications offers potentially novel targets for therapeutic and/or preventative interventions. We review the evidence that (1) failure to up-regulate the interferon gamma (IFNγ) response during infancy is an important determinant of the risk of allergic disease, (2) expression of the IFNγ gene in naïve T-cells is regulated by epigenetic mechanisms, and (3) failure to up-regulate IFNγ gene expression of naïve T-cells associated with low early life microbial exposure. Taken together, these lines of evidence suggest that low microbial exposure during early life increases the risk of allergic disease by reducing demethylation (activation) of the IFNγ gene of naive T-cells.

Allergic diseases have increased in prevalence in many parts of the world and pose a major global health burden (1). Events occurring during the first years of life have the potential to program persisting immunological phenotypes that determine the subsequent risk of allergic disease (2–4). Given that the reversibility of allergic diseases appears to decrease over time after onset, primary prevention strategies targeting this early life ‘window of opportunity’ are a research priority. There is mounting evidence that specific epigenetic modifications (switches) at immune-related genes play a pivotal role in modulation of developing immune responses, and that inappropriate immune programming may involve disruption of these epigenetic modifications. In this article, we present evidence for one specific environment-by-epigenetic hypothesis: that low microbial exposure during early life may increase the risk of allergic disease by reducing demethylation (activation) of the interferon gamma (IFNγ) gene of naive T-cells.

The role of epigenetics in the early life immune programming

  1. Top of page
  2. Abstract
  3. The role of epigenetics in the early life immune programming
  4. IFNγ production during early life and the risk of allergic disease
  5. IFNγ gene expression is regulated by epigenetic mechanisms
  6. Microbial exposure and the risk of allergic disease
  7. Does microbial exposure modify demethylation of the IFNγ gene?
  8. Proposed disease pathway
  9. Theoretical and practical issues relevant to investigating these hypotheses
  10. Conclusion
  11. References

All cells, regardless of tissue type, contain essentially the same genetic material, but express this material differently. Epigenetic modification (independent of primary DNA sequence) of genes is the principal mechanism by which differential gene expression is regulated (5). Specific inhibitory chromatin (DNA wrapped around the cylinder-like histone core) modifications facilitate the compaction of DNA, to prevent interaction of a subclass of DNA-binding proteins necessary for transcriptional initiation, whereas alternative epigenetic modifications that result in a ‘relaxed’ chromatin state are compatible with gene transcription. A rapidly expanding body of in vitro evidence indicates that epigenetic activation or silencing of immune-related genes during early life may play an important role in immune programming (2, 6–9). The epigenetic changes that cytokine loci undergo when naive T-cells differentiate into T-helper 1 (Th1) or Th2 effector cells an extensively studied model of cell-lineage-dependent epigenetic changes (10). The kinetics and balance of naïve T-cell differentiation into Th1 or Th2 effector cells is critical, as delayed maturation of the Th1 response may predispose to a relatively Th2-skewed state, and an increased risk of allergic disease (11). Importantly, epigenetic processes are influenced by environmental factors such as diet, tobacco smoke, lifestyle, and microbial infections (12–14). Therefore, the epigenetic determinants of naïve T-cell differentiation may provide a novel framework for understanding the mechanisms by which environment alters the risk of allergic disease.

IFNγ production during early life and the risk of allergic disease

  1. Top of page
  2. Abstract
  3. The role of epigenetics in the early life immune programming
  4. IFNγ production during early life and the risk of allergic disease
  5. IFNγ gene expression is regulated by epigenetic mechanisms
  6. Microbial exposure and the risk of allergic disease
  7. Does microbial exposure modify demethylation of the IFNγ gene?
  8. Proposed disease pathway
  9. Theoretical and practical issues relevant to investigating these hypotheses
  10. Conclusion
  11. References

IFNγ is produced in response to viral or intracellular bacterial infection and functions to activate macrophages, increase major histocompatibility complex molecule expression and exert direct antiviral activity on infected cells. Reduced IFNγ during early life is a consistent and central finding in the pathogenesis of allergic disease. We and others have found reduced IFNγ at birth in infants who subsequently develop eczema, and delayed postnatal maturation of IFNγ responses in atopic children (11, 15–21). In utero, uncontrolled IFNγ production at the fetal/maternal interface is a common cause of fetal loss (22). As a result, IFNγ gene transcription is suppressed during gestation (22). Following birth, there is upregulation of the IFNγ response capacity of CD4+ T-cells (17, 18). This upregulation may be induced by microbial exposure (19); and several markers of early life microbial exposure (farming, house dust endotoxin, and household pets) have been shown to both increase early IFNγ production (Th1 response) and decrease the risk of allergic disease(23). Delayed postnatal development of the capacity for IFNγ production increases the risk of subsequent allergic disease (2). This may be because diminished negative regulation of Th2 cell differentiation by IFNγ during early life immune responses to allergens favours the development of atopy-associated Th2-memory cells (11).

IFNγ gene expression is regulated by epigenetic mechanisms

  1. Top of page
  2. Abstract
  3. The role of epigenetics in the early life immune programming
  4. IFNγ production during early life and the risk of allergic disease
  5. IFNγ gene expression is regulated by epigenetic mechanisms
  6. Microbial exposure and the risk of allergic disease
  7. Does microbial exposure modify demethylation of the IFNγ gene?
  8. Proposed disease pathway
  9. Theoretical and practical issues relevant to investigating these hypotheses
  10. Conclusion
  11. References

Induction of IFNγ has unequivocally been linked with decreasing methylation of specific cytosine-phosphate-guanine (CpG) dinucleotides in the IFNγ gene (6, 24). This has been shown to be the ultimate regulator of IFNγ expression as opposed to transcription factor levels (6, 24). Of specific relevance, it has been shown that as naïve T-cells are pushed down a Th1 pathway there is progressive CpG demethylation of the IFNγ gene promoter and an increase in the IFNγ response capacity (25).

Microbial exposure and the risk of allergic disease

  1. Top of page
  2. Abstract
  3. The role of epigenetics in the early life immune programming
  4. IFNγ production during early life and the risk of allergic disease
  5. IFNγ gene expression is regulated by epigenetic mechanisms
  6. Microbial exposure and the risk of allergic disease
  7. Does microbial exposure modify demethylation of the IFNγ gene?
  8. Proposed disease pathway
  9. Theoretical and practical issues relevant to investigating these hypotheses
  10. Conclusion
  11. References

More than 80 studies have provided supportive evidence for the hypothesis that the risk of allergic disease is reduced by higher microbial exposure during early life (the ‘hygiene hypothesis’). It has been shown that the risk of allergic disease is reduced by exposure to a larger number of siblings, daycare environments, relatively contaminated water, pets, and farms with livestock (26–30). The importance of the total microbiological environment is being increasingly recognized, rather than early life infections alone (30, 31). Recent evidence also suggests that the diversity of faecal microbiota during early life may be important (32). The contribution of microbial exposure may be very significant. For instance, in 2002 a review concluded that even factors linked to sibling number alone had a population attributable fraction of 38% for atopic sensitization (33). That is, factors associated with sibling number alone could account for over a third of atopic disease at a population level.

However, data regarding the central mechanisms underlying the hygiene hypothesis remain inconclusive and our understanding of the pathways involved is strikingly inadequate. Consequently, we are yet to translate data regarding the hygiene hypothesis into improved health outcomes. A greater focus on the mechanisms involved in the modifying effect of microbial exposure is required. Mechanisms that may be shared by a wide range of exposures, such as modification of IFNγ expression, are of particular interest.

Does microbial exposure modify demethylation of the IFNγ gene?

  1. Top of page
  2. Abstract
  3. The role of epigenetics in the early life immune programming
  4. IFNγ production during early life and the risk of allergic disease
  5. IFNγ gene expression is regulated by epigenetic mechanisms
  6. Microbial exposure and the risk of allergic disease
  7. Does microbial exposure modify demethylation of the IFNγ gene?
  8. Proposed disease pathway
  9. Theoretical and practical issues relevant to investigating these hypotheses
  10. Conclusion
  11. References

While it is clear that microbial exposure may induce IFNγ expression by CD4+ T-cells (19), there is currently no direct evidence that microbial exposure induces demethylation (activation) of the IFNγ gene in CD4+ T-cells. However, in general terms, infection with viral (34), (35), bacterial (36–38), and parasitic (39, 40) agents have each been shown to induce methylation events within host DNA. More specifically, there are examples of microbial factors modifying IFNγ gene transcription via changes in IFNγ gene methylation. For instance, the Human Immunodeficiency virus evades the immune system by inducing hypermethylation (silencing) of the IFNγ gene in CD8+ T-cells (41). Conversely, infection with lymphocytic choriomeningitis virus results in demethylation (activation) of the IFNγ gene in naïve CD8 T-cells (35). Similarly, in Burkitt’s lymphoma (an Epstein-Barr virus-transformed B cell line) the IFNγ gene shows hypomethylation with associated increasing levels of IFNγ production (42). It has also been shown that prostaglandin E2 inhibits demethylation of the IFNγ gene during differentiation of naive T-cells. As such, it is plausible that microbial agents may exert an effect on IFNγ gene methylation during the process of naive T-cell differentiation via their effect on prostaglandin E2, or other inflammatory cytokines.

Proposed disease pathway

  1. Top of page
  2. Abstract
  3. The role of epigenetics in the early life immune programming
  4. IFNγ production during early life and the risk of allergic disease
  5. IFNγ gene expression is regulated by epigenetic mechanisms
  6. Microbial exposure and the risk of allergic disease
  7. Does microbial exposure modify demethylation of the IFNγ gene?
  8. Proposed disease pathway
  9. Theoretical and practical issues relevant to investigating these hypotheses
  10. Conclusion
  11. References

We propose that low early life microbial exposure is associated with persisting methylation (silencing) of the IFNγ gene in naive T-cells, resulting in a diminished IFNγ response capacity, and in turn, an increased risk of allergic disease. Microbial exposure may modify the methylation/demethylation ratio of naive T-cells at one of two stages in naive T-cell to development. The first possibility is that microbial stimuli act at the stem-cell level in the thymus (either on pre-T-cells, thymic nurse cells, or thymic dendritic cells)(Fig. 1). If this were the case, then one would anticipate that microbial exposure should decrease the ratio of recent thymic emigrants (RTEs) vs mature naive T-cells released from the thymus into the peripheral circulation during early postnatal life. RTEs are an immature form of naive T-cell in which the IFNγ gene is highly methylated (43). Recent thymic emigrants form the major proportion of the CD4+ T-cell compartment in cord blood; they have a high rate of apoptosis, and are gradually replaced by mature naive T-cells. A testable hypothesis might be: that following birth microbial exposure accelerates the rate at which RTEs are replace by mature naive T-cells in the peripheral circulation.

image

Figure 1.  Proposed disease pathway one: microbial exposure during early life may decrease the risk of allergic disease by inducing demethylation of the interferon gamma gene of naive T-cell precursors in the thymus. This would result in a decrease in the ratio of recent thymic emigrants (RTEs) (in which the IFNγ gene is highly methylatated) to mature naive T-cells (in which the IFNγ gene is less methylated) in the peripheral circulation. RTE, recent thymic emigrants; IFNγ, interferon gamma.

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The second possibility is that microbial exposure acts downstream to influence the methylation/demethylation balance of naive T-cells during post-thymic differentiation into T-helper cells (Fig. 2). If this were the case, the logical targets for microbial stimuli would be the antigen presenting cells (APCs), which control the process of naive T-cell differentiation. Indeed, the true targets may be the bone marrow precursors, which give rise to APCs in the periphery. The possibility that microbial exposure effects post-thymic naive T-cell differentiation is in keeping with the observation that the deficiency in the capacity of neonatal T-cells to produce IFNγ involves independent maturational defects in both T-cells and APCs (44). A testable hypothesis would be that following birth, microbial exposure is associated with demethylation of the IFNγ gene of naive T-cells during the process of differentiation into T-helper cells.

image

Figure 2.  Proposed disease pathway two: microbial exposure during early life may decrease the risk of allergic disease by inducing demethylation of the interferon gamma gene of naive T-cells during the process of differentiation into T-helper cells in the peripheral circulation. IFNγ, interferon gamma.

Download figure to PowerPoint

Theoretical and practical issues relevant to investigating these hypotheses

  1. Top of page
  2. Abstract
  3. The role of epigenetics in the early life immune programming
  4. IFNγ production during early life and the risk of allergic disease
  5. IFNγ gene expression is regulated by epigenetic mechanisms
  6. Microbial exposure and the risk of allergic disease
  7. Does microbial exposure modify demethylation of the IFNγ gene?
  8. Proposed disease pathway
  9. Theoretical and practical issues relevant to investigating these hypotheses
  10. Conclusion
  11. References

Several scientific and logistic issues are relevant to an investigation of this model. First, total IFNγ expression level within specific cells is regulated by both underlying genetic and epigenetic profile, acting independently and/or synergistically. Therefore, any polymorphisms that result in between-individual variation in expression of the IFNγ gene need to be identified and functional consequences quantified before the overlying contribution of epigenetic modification of the locus can be accurately determined (45, 46). Second, the measurement of microbial exposure is currently fraught, as it relies on various proxy markers (sibling number, farming environment, etc). What we really require is a direct summary measurement that would allow us to quantify the extent of microbial exposure at various time points. Quantification of gut microbiota diversity using PCR techniques appears to be a promising new technique that may be valuable in this context (32). Finally, it is important to recognize the changing composition of the naive CD4+ T-cell compartment during early life. The cord blood CD4+ T-cell compartment is largely composed of RTEs (43). During postnatal life, RTEs demonstrate high levels of apoptosis, and are gradually replaced by mature naïve CD4+ T-cells. It would be impossible to interpret variations in IFNγ demethylation within the naïve CD4+ T-cell compartment without knowing the proportion of RTEs vs mature naïve T-cells. Techniques to identify RTEs on the basis of T-cell receptor excision circles (by-products of the genetic rearrangements involved in the production of the mature T-cell receptor) have been developed (47), but are relatively novel.

Conclusion

  1. Top of page
  2. Abstract
  3. The role of epigenetics in the early life immune programming
  4. IFNγ production during early life and the risk of allergic disease
  5. IFNγ gene expression is regulated by epigenetic mechanisms
  6. Microbial exposure and the risk of allergic disease
  7. Does microbial exposure modify demethylation of the IFNγ gene?
  8. Proposed disease pathway
  9. Theoretical and practical issues relevant to investigating these hypotheses
  10. Conclusion
  11. References

An improved understanding of the environment-by-epigenetic pathways involved in the pathogenesis of allergic disease may provide a novel and important framework to inform disease prevention strategies. There is mounting evidence for the hypothesis that low early life microbial exposure is associated with persisting methylation (silencing) of the IFNγ gene of naive T-cells, and that this in turn is associated with an increased risk of allergic disease. Microbial exposure may alter the methylation/demethylation balance of the IFNγ gene of naive T-cells at either the thymic (stem cell) level, or downstream, during post-thymic differentiation into T-helper cells. Studies combining early life epidemiological data with an investigation of the kinetics of IFNγ demethylation in naive T-cells, whilst logistically scientifically challenging, are a promising line of future inquiry.

References

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  2. Abstract
  3. The role of epigenetics in the early life immune programming
  4. IFNγ production during early life and the risk of allergic disease
  5. IFNγ gene expression is regulated by epigenetic mechanisms
  6. Microbial exposure and the risk of allergic disease
  7. Does microbial exposure modify demethylation of the IFNγ gene?
  8. Proposed disease pathway
  9. Theoretical and practical issues relevant to investigating these hypotheses
  10. Conclusion
  11. References
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