ASK AN EXPERT Immune system over-reactivity – are allergens the real aggressors? Who is to blame?

considerable in healthcare management and medicine. This presents the thoughts and opinions of those who spend their lives studying these issues from di ﬀ erent perspectives. The immune system is a dynamic and versatile defence system capable of differentiating pathological molecules (or antigens) from harmless ones and forming appropriate responses. This system evolves in response to environmental changes and adapts to counter perceived threats. However the recent and rapidly changing profiles of these environmental exposures in the Western world may have led to the maladaptive responses seen in allergic (atopic) diseases. These increasing diseases include asthma, allergic rhinitis, food allergies and eczema which result from inappropriate responses to otherwise benign proteins or allergens. All allergens stimulate immune activation; non-allergic individuals form active immune tolerance, the appropriate adaptive response. In those with allergies, however, allergens induce proliferation and differentiation of CD4 T-cells into the TH2 phenotype which produces cytokines IL-4, IL-5, IL-9 and IL-13(1). These cytokines, in turn, can induce reactive airways and stimulate a B-cell switch to produce allergen-specific antibodies of the IgE class. IgE then binds to receptors on effector cells, including mast cells. (2). Allergen contact subsequently leads to IgE cross-linking, activation of the effector cells and the release of mediators such as histamine and tryptase (2). The rapid release of these mediators results in symptoms including hives, eczema, rhinitis, asthma, and anaphylaxis (2).


Clinical Director, Clinical Immunology Laboratory (MCH), Head of Immunology, Special Interest Section-CSACI and Research Director, Meakins-Christie Laboratories MUHC-Research Institute
The immune system is a dynamic and versatile defence system capable of differentiating pathological molecules (or antigens) from harmless ones and forming appropriate responses. This system evolves in response to environmental changes and adapts to counter perceived threats. However the recent and rapidly changing profiles of these environmental exposures in the Western world may have led to the maladaptive responses seen in allergic (atopic) diseases. These increasing diseases include asthma, allergic rhinitis, food allergies and eczema which result from inappropriate responses to otherwise benign proteins or allergens. All allergens stimulate immune activation; non-allergic individuals form active immune tolerance, the appropriate adaptive response. In those with allergies, however, allergens induce proliferation and differentiation of CD4 T-cells into the TH2 phenotype which produces cytokines IL-4, IL-5, IL-9 and IL-13(1). These cytokines, in turn, can induce reactive airways and stimulate a B-cell switch to produce allergen-specific antibodies of the IgE class. IgE then binds to receptors on effector cells, including mast cells. (2). Allergen contact subsequently leads to IgE cross-linking, activation of the effector cells and the release of mediators such as histamine and tryptase (2). The rapid release of these mediators results in symptoms including hives, eczema, rhinitis, asthma, and anaphylaxis (2).
Activation of TH2 immunity appropriately occurs in response to threats such as parasitic infections. In the absence of these and other immune stimulators, genetically susceptible individuals may respond to allergen exposure with skewed activation of TH2 cells (3). Environmental influences such as increased hygiene and a reduction in exposure to complex antigenic environments and infection which collectively reduce overall immune stimulation may be causatively linked to the disproportionately increased frequency of allergic disease in the western world. This hygiene hypothesis, first proposed as an explanation for this burgeoning frequency of atopy, was based on observations that farm children experienced less atopy than their urban raised peers (4) and children of lower birth order also developed fewer allergies compared with elder siblings.
The microbiome hypothesis, a refinement of this concept, suggests that exposure to complex microbial flora, both pathogenic and commensal, results in the development of appropriate immune-regulation to allergens (3). The microbiome is the sum of symbiotic microbial species present in an individual, estimated to be over 100 billion in the GI tract alone (5). Evidence suggests that balanced immune regulation depends upon a healthy microbiome. In germ-free mice with no microbiome, T-cell dysregulation toward TH2 (6) and higher susceptibility atopic disease (7) is shown. Colonization of the germ-free mice with Bacteroides fragilis restored appropriate T cell balance (8).
In humans, alterations in the microbiome have been associated with increased atopy. One study showed lower numbers of total commensal microorganisms, including notable decreases in Bacteroides species, in food sensitive children compared with a control group (9). In asthmatic adults alterations in the pulmonary microbiome, including increased Proteobacteria and decreased Bacteroides

Christine McCusker, MSc, MD, FRCP 1 & Adam Byrne, MSc, MD, FRCPC
species, has been demonstrated (10). Events linked to altered gut microbiota including Caesarean section delivery, perinatal antibiotic use, and bottle feeding are also associated increased atopy (9). As such reducing infectious disease spread and external modulation of the microbiome through increased hygiene, antibacterial wipe use, and antibiotic use may be promoting the development of atopy in at risk individuals.
The practice of recommending food avoidance for pregnant and breastfeeding mothers, coupled with delayed introduction of "allergenic" food in infants, may also be contributing to the increase in food allergies. One study examining peanut allergy prevalence in genetically similar populations in Israel and England found a marked increase in peanut allergy in English children. They identified the key major lifestyle difference in peanut allergic versus non allergic children as delayed age at first introduction to peanuts (11). In the subsequent, randomized control trial there was a significant decrease in peanut allergies in children encouraged to consume peanuts early (between the ages of 4-11 months) as compared to those avoiding until 2 years of age (12). These results suggest that the development of tolerance to foods may be achieved with early introduction in the diet although the optimal timing and form of these introductions remain to be confirmed.
In summary current evidence suggests that promoting the formation of appropriate immune responses to allergens depends on the development of complex microbiota and introduction of complex antigens early in infant development. Allergens are otherwise harmless proteins.
Promoting the formation of immunotolerance and targeting TH2 pathways will be the keys to reduction and prevention of atopic diseases.¾