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    Figure 1.

    Aggregated overview of multiple studies on the helminth/allergy interface. The areas shaded black indicate increased prevalence of allergic reactivity in the presence of helminth infection, the areas shaded white indicate decreased prevalence, and those in gray indicate no change in prevalence on clinical outcome (left circle), skin prick test (SPT; middle circle), and aeroallergen-specific IgE (asIgE; right circle).

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Human Helminths and Allergic Disease: The Hygiene Hypothesis and Beyond

Helton C. SantiagoDepartamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.

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Thomas B. NutmanLaboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland.

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There is much debate about the interaction between helminths and allergic disease. The “Hygiene Hypothesis,” a very popular concept among scientists and the lay public, states that infections, especially during childhood, can protect against allergic diseases. Indeed, helminth infections are known to induce regulatory responses in the host that can help the control of inflammation (including allergic inflammation). However, these infections also induce type-2-associated immune responses including helminth-specific IgE that can cross-react against environmental allergens and mediate IgE-driven effector responses. Thus, it is the delicate balance between the parasites' anti- and pro-allergenic effects that define the helminth/allergy interface.

The immune system has evolved, in large part, through its interaction with microbes and parasites, an interaction that drives specific or specialized immune responses to deal with the widely varying groups of microorganisms. For example, parasite-derived induction of interleukin (IL)-4, IL-5, and IL-13 coordinate the prototypical responses to metazoan helminth pathogens,1 whereas viral- and bacterial-specific induction of Type 1 and Type 2 interferons are required for control of these types of infections.1 Interestingly, these responses (broadly inflammatory in nature) themselves, if uncontrolled, can harm the host by causing allergic diseases (Th2-associated inflammation) or autoimmune/inflammatory disorders (typically Th1- and/or Th17-associated). Typically, on the heels of such inflammation come anti-inflammatory networks that are required to prevent long-standing tissue damage.2

These regulatory (or anti-inflammatory) processes triggered during infection underlies the “Hygiene Hypothesis”3 that states that infections, especially during childhood when immune responses are being “educated” and the T- and B-cell memory pool is being created, protect against inflammation-associated disorders4 because they modulate or limit immune-mediated effector responses. Indeed, the presence of helminth infections has been associated (to a small degree) with modulation of the severity of inflammatory bowel disease,5 diabetes,6 and arthritis79 to cite just a few examples.

There is little consensus among the many studies that have examined the interaction between helminth infection and atopy (Table 1). This lack of consensus is most likely related to the differences in outcome measures/definitions used in the many studies that have used a variety of outcomes including: 1) the severity or frequency of asthma, rhinitis, or eczema; 2) the frequency of allergen sensitization by skin prick tests (SPTs); or 3) the levels of allergen-specific IgE (asIgE) levels in the blood. Other causes for the disparate results relate to variation among the species of infecting helminths and differences in the age of the populations being studied. To attempt to reconcile these differences, meta-analyses have been performed; these, too, have not been conclusive. For example, while Ascaris lumbricoides was found to be a risk factor for the development of asthma, hookworm infection was associated with a protective effect.60 Infection with other parasites such as Trichuris trichiura, Enterobius vermicularis, and Strongyloides stercoralis had no effect on the outcome of asthma.60 Conversely, the presence of A. lumbricoides was found to lower the frequency of atopy (measured by SPT) to at least one environmental allergen in most studies61 (Table 1), but not to the perennial allergens, cockroach or house dust mite (HDM).61 Hookworm infection has also been associated with protection from atopy to some allergens, but not to HDM or to cockroach extract.61 Interestingly, the majority of the published studies demonstrate that while helminth infection decreases the frequency of SPT positivity, these infections are associated with increased allergen-specific IgE (asIgE) (Figure 1).

Table 1

Detailed list of human studies examining the influence of helminth infection on atopy

First author, year Country N Helminth Allergen(s) Clinical evaluation SPT asIgE§
Parasites* Assessed Outcome Effect Prevalence
Authors concluded that helminths offer protection against allergies
 Hagel, 199310 Venezuela 89 Al Not informed ND  
 van den Biggelaar, 200011 Gabon 520 Sh HDM ND   ND
 Araujo, 200012 Brazil 175 Sm HDM, mold ND   Trend ↓
 van den Biggelaar, 200113 Gabon 520 Sh HDM ND  
 Nyan, 200114 Gambia 429 Al Various Wheeze No change ND
 Scrivener, 200115 Ethiopia 604 Hkw, Al HDM Wheeze No change No change
 Huang, 200216 Taiwan 3,107 Ev Not informed Asthma, rhinitis ND ND
 Cooper, 2003a17 Ecuador 4,433 Al, Tt Various Wheeze, rhinitis, rash No change ND
 Cooper, 2003b18 Ecuador 2,865 Various Various ND    
 Dagoye, 200319 Ethiopia 563 Al HDM, CR Wheeze No change  
 Wahyuni, 200520 Indonesia 466 Bm HDM ND   Trend ↓
 Flohr, 200621 Vietnam 1,601 Hkw, Al HDM, CR ND   ND
 Rodrigues, 200822 Brazil 1,055 Al, Tt Various ND    
 Endara, 201023 Ecuador 3,901 Al, Tt Not informed Eczema ND
 Supali, 201024 Indonesia 441 Bm CR ND    
 Rujeni, 201225 Zimbabwe 672 Sh HDM ND  
 Kanobana, 201226 Cuba 958 Tc, Al, Hkw Not informed Asthma ↑ (Tc) ↓ (Hkw) ND ND
 Alcantara-Neves, 201227 Brazil 1,445 Various Various Asthma/wheeze No change No change
 Mendonça, 201228 Brazil 1,148 Tc HDM, CR ND  
 Manuel, 201229 Malaysia 170 Tc Not informed Rhinitis    
 Oliveira, 201430 Brazil 91 Sm HDM, CR, mold ND   ND
 
Authors found mixed or no association or took no conclusions
 Davey, 200531 Ethiopia 7,649 Various HDM, CR Wheeze No change  
 Ponte, 200632 Brazil 113 Al HDM Asthma No change No change No change
 Calvert, 201033 South Africa 3,322 Al HDM EIB No change
 Vereecken, 201234 Cuba 1,285 Al, Tc, Hkw HDM, CR Asthma No change
 Souza, 201435 Brazil 20 Al HDM ND   ND No change
 Alcantara-Neves, 201436 Brazil 1,271 Al, Tt, Tc Various ND   No change
 Hamid, 201537 Indonesia 623 Al, Tc HDM, CR Wheeze, eczema No change ↑ (Tc)
 Wordemann, 200838 Cuba 1,320 Ev, Hkw, Al Various Asthma, rhinitis, AD ↑ (Ev, Hkw) ↓ (Al) No change ND
 Obeng, 201439 Ghana 1,385 Sh, Al, Tt Various Asthma/wheeze No change ↓ (Sh) ↑ (Tt) NE
 
Authors concluded that helminths are a risk factor for allergies
 Kayhan, 197840 Turkey 100 Al Not informed Asthma ND ND
 Joubert, 198041 South Africa 259 Al Various ND
 Alshishtawy, 199142 Egypt 105 Sm HDM, pollen Asthma ND
 Buijs, 199743 Netherlands 1,379 Tc HDM, cat, dog Asthma  
 Lynch, 199744 Venezuela 89 Al HDM Asthma
 Dold, 199845 Germany ∼2,300 Al Various Asthma, rhinitis
 Palmer, 200246 China 2,164 Al Various Asthma ND
 Benicio, 200447 Brazil 1,132 Al, Tt Not informed Wheeze ND ND
 Daschner, 200548 Spain 135 As AsE Chronic urticaria ND ND
 Obihara, 200649 South Africa 359 Al(IgE) HDM Asthma
 Bahceciler, 200750 Istanbul 1,018 Ev Various Wheeze, rhinitis No change ND
 Pereira, 200751 Brazil 1,011 Al Various Wheeze/asthma  
 Hagel, 200752 Venezuela 470 Al AlE, HDM Asthma ↑ (Al-IgE) ND
 Hunninghake, 200753 Costa Rica 439 Al HDM, CR Asthma
 Alcantara-Neves, 201054 Brazil 682 (IgE)Tt, Al Various Wheeze ND
 Walsh, 201155 United States 12,174 Tc NE Asthma ND ND
 Choi, 201156 Korea 1,116 Cs Various Asthma, rhinitis No change
 Moncayo, 201257 Ecuador 376 Al AlE, HDM, CR Wheeze No change
 Buendia, 201558 Colombia 313 Al HDM Asthma
 Webb, 201659 Uganda 2,316 Various Various Wheeze

Al = Ascaris lumbricoides; As = Anisakis simplex; Bm = Brugia malayi; Cs = Clonorchis sinensis; Ev = Enterobius vermicularis; Hkw = hookworm; Sh = Schistosoma haematobium; Sm = Schistosoma mansoni; Tc = Toxocara canis; Tt = Trichuris trichiura.

AlE = Ascaris lumbricoides extract; AsE = Anisakis simplex extract; CR = cockroach; HDM = house dust mite.

SPT = skin prick test.

asIgE = aeroallergen-specific IgE; AD = allergic dermatitis; EIB = exercise-induced bronchorreactivity; ND = not determined.

Figure 1.
Figure 1.

Aggregated overview of multiple studies on the helminth/allergy interface. The areas shaded black indicate increased prevalence of allergic reactivity in the presence of helminth infection, the areas shaded white indicate decreased prevalence, and those in gray indicate no change in prevalence on clinical outcome (left circle), skin prick test (SPT; middle circle), and aeroallergen-specific IgE (asIgE; right circle).

Citation: The American Society of Tropical Medicine and Hygiene 95, 4; 10.4269/ajtmh.16-0348

The concept that helminth infection modulates allergic diseases emerged in the 1970s6264 and has been debated ever since.40,6570 As depicted in Table 1, it has often been observed that helminth infections commonly reduce the frequency of SPT reactivity and increase the levels of asIgE (Table 1 and Figure 1). This apparent dichotomy was felt to reflect the expansion of polyclonal IgE-secreting B cells, an expansion that would lead to high levels of IgE with multiple specificities leading to an inability to trigger a mast cell or basophil response. It was thought that allergens, in such conditions, could not physically cross-link the asIgE bound to the high-affinity Fc epsilon (FcɛRI) because of the multiple differing IgE antibody specificities on proximal FcɛRIs. Although theoretically possible, this concept has largely been discarded based on studies that suggest that the ratio of polyclonal to antigen-specific IgE needed to prevent basophil or mast cell degranulation rarely is achieved in vivo since it requires only cross-linking a few hundred FcɛRIs on cell membranes to trigger activation.71,72 More recent data allow us to propose other mechanisms at work in helminth infection that drive asIgE in helminth-infected populations (e.g., cross-reactive IgE) or modulate SPT positivity (e.g., IL-10) as discussed below.

Because chronic helminth infections often induce both IgE and IgG isotypes, especially IgG4 antibodies, it has been proposed that IgG can also contribute to the modulation of type I hypersensitivity responses. IgGs are usually induced in quantities 1,000- to 10,000-fold greater than those of IgE, and as such, the IgG antibodies bind antigen prior to the antigen being available to trigger an IgE-mediated effector response. This so-called “blocking phenomenon” has been explored, and two mechanisms have been identified: physical73,74 and inhibition of target cells by FcγRIIb activation by IgG complexed to antigens.7476 Although other IgG isotypes have been implicated in physical IgE blocking, IgG4 seems to play a major role.77 It has been demonstrated that IgG can intercept allergen before it binds to IgE present on membranes of mast cells and basophils,74 and that allergen-IgG complexes can deactivate target cell by activation of the inhibitory Fc receptor (FcγRIIb), that in turn activates phosphatases in the molecular cross-linking regions of IgE shutting down FcɛRI signaling.78,79

A more unifying explanation suggests that IL-10, a primarily T-cell–derived cytokine commonly induced in chronic helminth infection,8082 may underlie the protection from SPT positivity.11,83 Indeed, it is believed that the IL-10 modified Th2 response may be responsible for the parasite-antigen-specific tolerance imprinted on the host by helminth infection.80,84,85 Parasite-induced IL-10 or other regulatory mechanisms—that can involve cell populations such as Tregs81,86 and Bregs8789—can increase the IgE-induced activation threshold of basophils,90 regulate T-cell91,92 and B-cell activation,92 promote IgG class switch,93 and IgG4-producing B-cell differentiation and proliferation.94 Moreover, IL-10 has been shown to drive down the production of IgE while at the same time induce isotype switching to IgG4.95,96

Despite the regulatory responses that helminth infections can induce in the host, these may not be sufficient to counteract the Th2-associated processes that mediate many allergic diseases. This puts into a framework the concept that a very delicate balance between pro- and anti-allergenic effector responses is required to maintain homeostasis. It is widely known that helminth parasites are associated with antigen-driven expansion of Th2 cells9799 along with polyclonal T-cell activation.9799 Interestingly, allergen extracts and helminths excretory/secretory products often share similar properties that can lead to Type 2-associated responses. For example, both are rich in proteases100 that can promote Th2 differentiation through protease-activated receptor 2101103 directly on T cells102 or indirectly by inducing IL-33 or thymic stromal lymphopoietin production by tissue cells104,105 or IL-13 production by macrophages.106 In addition, both allergens and helminths are known to increase numbers and activity of type 2 innate lymphoid cells107110 that license dendritic cells to promote Th2 priming in lymph nodes.111

Along with this strong, specific, and polyclonal Th2 activation induced by helminth infection, these infections also induce both polyclonal- and antigen-specific IgE production.112 Whether a result of this Th2-associated response or of some other type of response (e.g., Treg, IL-10, transforming growth factor-β), it has been observed that helminth infection causes decreases in IgG responses to parenterally-administered vaccines113 and increases in IgE responses to bystander antigens.114117 This IgE bystander effect has been suggested to be one of the reasons that helminth parasites can promote allergic reactivity through mechanisms that include: B-cell IgE polyclonal activation; IgE potentiation in which infection creates an environment that will favor IgE production to other nonparasite antigens; and IgE cross-reactivity among parasite antigens and environmental allergens.

There has been increased interest in IgE cross-reactivity involving helminth parasites and allergens as well.116128 We have demonstrated that helminth infection can be associated with increased IgE responses to many different allergens, especially those structurally related to parasite antigens.116 Individuals infected with filarial parasites were shown to have higher levels of IgE against HDM and cockroach extracts (that have several major allergens with homologues in filarial parasites) but not against timothy grass extract, an allergen extract with just a few minor allergen homologues in helminths.116

In more detailed studies, cross-reactivity among allergens and parasite molecules has been well described for tropomyosin,120,122,129 considered a pan-allergen.130 Tropomyosins are highly conserved across many species and cross-reactivity is not surprising from the structural point-of-view. This allergen has dominated discussions about helminth-allergen cross-reactivity, and many reviews have already discussed its implications in detail.131,132 However, studies on allergen and parasite protein sequences have found that huge numbers of allergens have both linear133 and conformational134 epitopes with significant similarity to homologous helminth proteins. The structural basis for this “allergenicity” has been inferred from bioinformatic analyses, in which it has been shown that the level of identity conservation between allergens and parasite proteins were negatively correlated with IgE prevalence to that allergen.133 Furthermore, most of the major allergens with homologues in helminth parasites show medium to low levels of conservation with helminth proteins (amino acid identities ranging from 20% to 40%),133 levels of identity deemed unlikely to be subject of antibody cross-reactivity. Nevertheless, evidences of cross-reactivity among less-conserved pairs of antigens have been demonstrated recently,116,117,120,123,133 suggesting that this may be a broader phenomenon than previously appreciated. It was noticed that extracts of the cockroach Blatella germanica (Bla g) can inhibit the binding of IgE to several Anisakis simplex allergens.118 Similarly, IgE binding to several Ascaris allergens can also be inhibited by Dermatophagoides pteronyssinus (Der p) or Blomia tropicalis (Blo t) extracts, including glutathione-S-transferase (GST).120

GSTs are major allergens of HDM,119 cockroach,135 mold,136,137 and parasites.138,139 Among the 13 classes of canonical GSTs, there are many that show very little amino acid conservation.140 Even with the small degree of sequence conservation, cross-reactivity among parasite and allergenic GST has been demonstrated formally.123 There was found to be a significant positive correlation of antiallergenic (Bla g 5, Der p 8, and Blo t 8) and antiparasite (Ascaris and filarial) GST-specific IgE levels in humans.123,138 In addition, experimental models have corroborated these findings. For example, Heligmosomoides polygyrus infection induced IgE anti-cockroach GST,123 and immunization studies with Ascaris antigens induced IgE and Th2 cells against HDM extract.117 Despite helminth protein and allergen cross-reactions leading to cross-sensitization in humans are possible,58,141144 formal proof has not, to date, been demonstrated, especially for poorly conserved allergen-helminth proteins pairs.

Thus, the interface between helminth infection and allergic disorders reflects the delicate balance between the regulatory responses and the pro-allergenic effects of the parasites. Despite the relatively consistent finding that the presence of an active helminth infection results in lower prevalence of SPT to common environmental allergens, the fact that these same helminth infections markedly increase levels of antigen-specific IgE suggest that the complex interplay among this antigen- and allergen-specific IgE, the high affinity FcɛRI on effector cells, the regulatory and effector cytokines, and the cells at barrier sites must be studied in concert to truly understand this very complex interaction.

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