The tropics, helminth infections and hygiene hypotheses

ABSTRACT

The Tropics is very appropriate to test the hypotheses raised to explain the increasing trends of allergy and other inflammatory diseases worldwide. The absence of parasite infection as a possible cause of the increase of allergic diseases was proposed by J. Gerrard a long time ago; however, the idea that helminth infections, which induce a strong Th2 could reduce allergy symptoms seems counterintuitive; but the fact is that they have a dual effect: they increase the Th2 responses but also exert immunosuppression and both effects influence the symptoms of allergy. Basic experimentation has provided valuable information about the mechanisms of allergic inflammation and more recently, about its control by helminth induced immunomodulation, discovering helminth molecules with anti-inflammatory properties that are meant to replace the live helminth therapeutic approaches. The immunosuppressive power of helminths makes them excellent candidates to be considered in the hygiene hypotheses. Future comprehensive studies evaluating simultaneously the role of microbial infections, helminth infections, microbiota, pollution and biodiversity will help to elucidate the causes of the increasing trends of allergic disorders. Doing this in the tropics, where all these variables are still present could be difficult but no doubt that will be more informative.

KEYWORDS:

• Allergy
• allergic diseases
• cystatins
• helminths
• hygiene hypothesis
• the tropics

1. Introduction

The tropics is a very appropriate zone to test in real time the evolution of the hypotheses raised to explain the increasing trends of allergy and other chronic noncommunicable inflammatory diseases worldwide. In this region, there are contrasting and changing levels of socioeconomic development, urbanization, Western lifestyle, and a great biodiversity that includes almost all known infectious organisms. Several environmental and sanitary conditions that were part of the history of current affluent societies are occurring now in tropical developing countries. Therefore, in the tropics, the analyses cannot be simplified assuming that the prevalence of allergic diseases is low or claiming that conditions potentially preventive of allergy are missing. Indeed, in this zone, all factors whose absence or presence are supposed to determine the increase of allergy concur; however, the increasing frequency trends of asthma and rhinitis are also observed [1]. Here the roles of helminth infections on these trends are analyzed, taking for granted that several factors should be considered under the umbrella of more than one working hypothesis. Since more comprehensive reviews present data from several helminths influencing autoimmunity [2] and allergy [3], this editorial will be focused on Ascaris spp., a widely distributed parasite whose immunomodulatory properties are increasingly studied at the experimental level.

2. The hypotheses

The role of parasite infections as potential modifiers of the prevalence of chronic inflammatory diseases was first proposed by B. Greenwood to explain the low prevalence of autoimmune diseases in Nigeria [4] and then by J. Gerrard to explain the higher frequency of asthma, eczema, and urticaria in the white than in the Metis populations in Canada [5]. Several years later, D. Strachan suggested that infections in early childhood could prevent allergic diseases, but parasites were not mentioned [6]. From an evolutionary point of view, the alteration of our ‘old friends’ (parasites and microbiota) by modern living styles was proposed by G. Rook as partially explaining the decrease of immunomodulation and increase of inflammatory diseases [7]. An historical analysis of the allergy epidemic highlights the role of helminth control as one of the explanations of the trends from 1870 to 2010 [8]. These hypotheses, although controversial, have been supported by a great number of epidemiological studies and experimental work using both animal models and ex vivo human cells; in addition, interesting mechanisms for the preventive action of the appropriate environment have also been proposed [9]. However, the relative role of each of the claimed intervening factors and their potential relationships remain to be evaluated under a more global approach; in fact, there are emerging interesting data regarding the influence of helminths on microbiota [10].

3. The dual effect of helminth infections

The idea that helminth infections, which induce a strong Th2 response similar to that observed in allergy, could reduce allergy symptoms seems counterintuitive; but actually they have a dual effect: they increase the Th2 responses but also exert immunosuppression and both effects influence the symptoms of allergy. These properties, especially the downregulation of the immune responses, have been extensively supported by experimental animal models. Which effect predominates in a particular human population depends on the concurrence of several factors, among them intensity of the infection [11], which in turn is probably determined by genetic factors controlling the strength of the protective immunity and the degree of susceptibility to parasite immunomodulation [12].

Positive associations between asthma and helminthiases are expected not only in some urban populations of middle-income countries where they are partially controlled and deworming programs are permanent [13], but also in developed countries where these infections are still present [14].Therefore, it is neither surprising nor contradictory to find some studies showing positive associations between helminth infections and allergy [15] and others detecting negative associations. Moreover, both effects have been found in the same population equally exposed to helminths, suggesting among other aspects, an important role of host genetic background controlling the severity of infection [16]. These contrasts are easily identifiable in the tropics because of the unequal and combined level of development observed in different countries, which can alter the equilibrium between the pro- and anti-inflammatory effects of helminthiases [17].

In the tropics, a gradient can be detected from rural communities, heavily parasited and exhibiting less allergic symptoms [18], to urban settings less exposed and light parasited where the effect of the helminthiases is predominantly IgE/Th2 enhancer [19] and allergic diseases are as frequent as in industrialized societies and have even increased during the last decade [1]. An additional relationship between helminth and allergy is found in developed wealthy countries where there is no parasite-derived immunoregulation [12]. In general, urbanization has been shown to influence allergy sensitization [20] and one of the reasons could be the decreased (but not totally eradicated) presence of helminthiases. Therefore, helminth infections may explain not only why poor hygiene conditions are associated with low allergy frequency but also why the increasing trends in the prevalence of allergies is more general and not restricted to affluent countries.

4. Helminth-driven immunomodulation

Helminth-induced immunomodulation in humans is now a well-known phenomenon that depends on several factors such as intensity and chronicity of infection, host genetic background, type of parasite, and probably polyparasitism [21]. The immunosuppressive effects of chronic, heavy helminth infections have been found stronger than any described immunomodulatory phenomenon accompanying bacterial or viral infections excepting that by human immunodeficiency virus. This supports Gerrard’s idea that the declining of parasitic infections could be related to the increase of allergic diseases, but more important it has opened new perspectives for treating allergy and other immune-mediated inflammatory disorders, to the point that there are currently therapeutic anti-inflammatory strategies using live helminth intended to ameliorate these conditions in humans [22,23]; however, contradictory results and concerns have appeared, among them the relative high number of failures of clinical trials with helminth therapy [3] and the possibility that these findings could interfere with parasite control programs [24].

For a long time, basic experimentation on immunoparasitology has provided valuable information about the mechanisms of allergic inflammation and more recently, about its control by helminth-induced immunomodulation [9]. These basic experimental works have discovered numerous helminth molecules with anti-inflammatory properties that are meant to replace the live helminth therapeutic approaches [12,23]. These molecules are part of the variety of mechanisms of parasite evasion from the host immunity as a result of a long process of adaptation during the coevolution with vertebrates. They have different mechanisms of action [23] and have been obtained from several helminths, including Ascaris lumbricoides.

According to the Ascaris suum genome, Ascaris species have more than 15 potentially immunomodulators. The mechanisms of the immune downregulatory effects of A. suum infection have been recently explored in LPS (Lipopolysaccharide)-induced inflammatory responses in mice [25], finding that infection suppressed secretion of pro-inflammatory cytokines (IL-1β, TNF-α, and IL-6) and induced high levels of IL-10 and TGF-β as well as CD4+CD25highFoxp3+ T cells in the mesenteric lymph nodes. This has also been investigated in pigs using transcriptomic analysis, showing that chronic A. suum infection induces suppression of inflammatory pathways in the intestinal mucosa, downregulating genes encoding cytokines and antigen-processing and co-stimulatory molecules. This effect was reproduced by A. suum body fluid in human dendritic cells (DCs) in vitro [26]. However, few of the immunomodulatory molecules found in excretory/secretory products of these species have been characterized, among them PAS-1 has been extensively studied [27]. The recent analysis of the anti-inflammatory properties A. lumbricoides cystatin (rAl-CPI) [28] started a new phase of research on the immunosuppressive side of this nematode. Cystatins, a family of cysteine protease inhibitors, have been obtained from Onchocerca volvulus, Acanthocheilonema viteae, Brugia malayi, and Nippostrongylus brasiliensis, being filarial cystatins and especially AvCystatin the most studied [29].

rAl-CPI was able to ameliorate the inflammation in a mouse model of DSS-induced colitis. Treatment with this molecule significantly reduced disease activity index, myeloperoxidase activity, and inflammation score without toxic effects. Also, IL-10 and TGFB gene overexpression was observed together with reduction in IL-6 and TNFA expression. rAl-CPI also induced the production of IL-10 and TGFB by macrophages [28] and further work in an animal model of airway inflammation has confirmed its IL-10-associated anti-inflammatory activity showing the induction of regulatory T cells as well as the production of IL-10 by human monocyte-derived DCs [30]. In addition, since some helminth products could be potential inducers of adverse allergic reactions, several tests for allergenic activity have been done to rAl-CPI, finding that it binds IgE but it does not have allergenic activity [31]; therefore, this A. lumbricoides-derived immunomodulator seems promissory for treating immune-mediated inflammation of intestine and lung.

5. Conclusion

During the last years, epidemiological, clinical, and experimental evidence has supported the role of helminth infections modifying allergic diseases. The immunosuppressive power of these parasites makes them excellent candidates to be considered in the hygiene hypotheses; however, investigating only few potential risk factors limits the research scope. Future comprehensive studies evaluating simultaneously microbial infections, helminth infections, microbiota, pollution, and biodiversity will help to define their relative role and potential interactions under the framework of the hygiene hypotheses. Doing this in the tropics, where all these variables are still present could be difficult but no doubt more informative.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Acknowledgments

Funded by Colciencias, Grant 590-2013 and the University of Cartagena.

Additional information

Funding

The authors have been funded by Colciencias, grant 590-2013 and the University of Cartagena.