Over recent decades, several epidemiologic studies performed in different parts of the world have demonstrated a significant increase in the prevalence of atopy and have consequently demonstrated an increase in the probability of type I allergic diseases involving asthma, hay fever, atopic dermatitis, or allergic gastroenteritis.1
The reason and mechanism by which allergy and parasitism have consistent overlaps that allow them to be studied under a similar framework begins with the formulation of the “hygiene hypothesis,” as well as the immunological basis supporting this hypothesis.
The “hygiene hypothesis” was originally postulated to explain the outbreak of allergy, which has presently expanded to an epidemic proportion.2
The hypothesis postulates that a lack of early exposure to different germs or parasites (clean environments) could have a direct relationship with the development of allergic diseases. It seems that an idle immune system is more prone to an inappropriate immune response, leading to immunopathological effects such as allergy or autoimmunity depending on the type and nature of the antigens to which exposure occurs.3,4
The “hygiene hypothesis” has been a subject of disagreement ever since the term was first proposed.5
The text suggests that allergic diseases (hay fever and eczema) are less common in children from larger families because they are exposed to more infectious agents through their siblings than are children from families with only one child, where transmission of infectious agents is more limited.
The “hygiene hypothesis” was interpreted as an explanation for the increased prevalence of allergic diseases in Western countries, with the assumption that opportunities for infection were reduced through the higher standards of hygiene achieved in those countries.
Improved hygiene is believed to mediate its effect through decreased exposure to infectious agents in early life. Recent studies highlight the importance of the gastrointestinal microbial environment in the development of allergic diseases. In particular, infection with hepatitis A, Helicobacter pylori
, and Toxoplasma
in individuals living in temperate climates, and geo-helminths in those living in endemic areas, have been shown to be associated with a reduced-risk of atopic manifestations.6 Because the hygiene hypothesis has significant gaps, other concepts have been proposed in an attempt to create new descriptions to reduce these gaps. In particular, the “microbiome hypothesis” and the “biodiversity hypothesis” have emerged.
Current studies suggest that features of the home, medical practices, and cleanliness behaviors are all involved in the hygiene effect in some way. Traditional markers associated with the protective microbial environment have been supplanted by “culture-independent microbiome science,” distinguishing the characteristics of potentially protective microbiomes from pathologic features.3
Rapidly declining biodiversity may contribute to the rapidly increasing prevalence of allergies in urban populations worldwide. According to the “biodiversity hypothesis,” reduced contact between people and natural environmental features and biodiversity may adversely affect the human commensal microbiota and its immunomodulatory capacity.7
Cohabitation with different allergenic sources in early life, such as pets, several sources of microbial infections, and other domestic animals could have an additive protective effect on the development of allergies and asthma via similar and shared mechanisms. Revisiting the “hygiene hypothesis” using more accurate descriptions based on the preventive microbe intervention platforms, termed the “microbiome theory,” it is possible to reinforce and reformulate the “hygiene hypothesis.”3
There is evidence that exposure to some infections can promote either allergy development or allergy protection, depending on several external and internal factors. The chemical or biological products of the environment, the type of microbiota existing in each place, the timing and bioburden of infectious agents, the characteristics of the intestinal flora, the parasitic infections or the genetic susceptibility of the host can all play an important role in the future development of atopy and allergic diseases.8
These relationships are the starting point that allow an introduction to immunology and molecular biology to better understand all of these apparently interrelated phenomena.
Translating the “hygiene hypothesis” into immunological terms, and on the basis of the aforementioned aspects related to this theory, it can be suggested that these processes begin in uterus and during prenatal life, as well as in early postnatal developmental stages, and could represent an opportunity for allergy-preventing environmental factors. The current knowledge of the cellular and molecular mechanisms used to explain the events of the hygiene hypothesis includes changes in the fine balance between the Th1, Th2, and regulatory T cell responses. These responses can become activated or not depending on the way of activation and the activation status of the innate immune cells.9
T cell-mediated immunity is an adaptive process of developing antigen-specific T lymphocytes to eliminate viral, bacterial, or parasitic infections, as well as malignant cells. This type of immunity can also be involved in the aberrant recognition of self-antigens leading to autoimmune inflammatory diseases, or some special antigens defined as “allergens” which lead to allergic diseases.
In fact, T cell-mediated immunity is the central element of the adaptive immune system and includes a primary response by naïve T cells, effector functions by activated T cells, and the persistence of antigen-specific memory T cells. Moreover, T cell-mediated immunity is a key part of a complex and coordinated response that includes other effector cells such as macrophages, natural killer cells, mast cells, basophils, eosinophils, and neutrophils.
Initially, two major functional T helper subpopulations were distinguished by their cytokine profiles: Th1 cells enhance proinflammatory cell-mediated immunity and were shown to induce delayed-type hypersensitivity (DTH) and mediate the response to some protozoans such as Leishmania
and Trypanosoma. Th2 cells promote noninflammatory immediate immune responses and have been shown to be essential in B cell production of IgG, IgG-4,10 IgA, and IgE.
Undoubtedly, the introduction of the Th1/Th2 paradigm to the natural and adaptive immune response was a tipping point to better understand the evolution of the immune response against different pathogens and their possible immunopathological effects.11
However, additional cellular T cell subsets have been defined in recent years, contributing to a better understanding of different immunopathological facts not explainable by Th1/Th2 cell interactions.
Naïve T cells are the most homogenous representatives of unactivated CD4+ (T helper) and CD8+ (T cytotoxic) subsets. Once their activation occurs, they can be distinguished by their cytokine profiles. Thus, activated T helper cells can be subdivided into Th1, Th2, Th17, and Treg subsets based on the profile of cytokines they produce. In addition, there are subsets of regulatory T (Treg) cells that add complexity to T cell heterogeneity.
2.1. Allergens as cause of sensitization
According to the World Health Organization/European Academy of Allergy and Clinical Immunology (WHO/EAACI) allergy definitions, allergens are defined as “antigens that cause allergy.” Most allergens reacting with IgE and IgG antibodies are proteins, often with carbohydrate side chains, but in certain circumstances, pure carbohydrates have been postulated to be allergens. In rare instances, low molecular weight chemicals, such as, isocyanates and anhydrides acting as haptens are still referred to as allergens for their capacity to induce IgE antibodies. In the case of allergic contact dermatitis, the classical allergens are low molecular weight chemicals, such as, chromium, nickel, and formaldehyde, which react with T cells.12
Other definitions have also used that incorporate new parameters into the mentioned definition. Chapman et al.13
defined allergens as “environmental agents that induce IgE-mediated immediate hypersensitivity,” which includes the term “environment.”
However, the potential for environmental and food allergens to become allergens would be restricted to those proteins that are structurally related to a limited range of metazoan parasite proteins and should be sufficiently different from the host proteins as to display an IgE response and its dependent effector mechanisms.14
Fitzsimmons and Dunne14
used another definition that includes the term “nonparasitic”: “Allergens are nonparasitic antigens capable of stimulating a type I hypersensitivity reactions in atopic individuals”; the reference to parasitism is included in this definition.14
2.2. Allergens as type I allergies’ diagnoses and treatment tools
The worldwide prevalence of allergic diseases is rising dramatically in both developed and developing countries. The WHO estimates that 10–40% of the global population, depending on the countries, is atopic and is at risk of suffering some type of allergic disease, such as, asthma, hay fever, allergic conjunctivitis, allergic gastrointestinal disorders, or allergic dermatitis.15
To date, the only specific treatment applied in this type of disease has been hyposensitization with allergen extracts, which has been used empirically since the early 20th century.
However, despite the time elapsed after its implantation, it remains unclear which factors are involved in the action of these treatments and how they induce tolerance to allergens leading to type I hypersensitivity. This type of tolerance, which does not always occur consistently, is discussed in the context of different types of medicine.
With the recent application of genomics and proteomics methods, the knowledge about individual, well-characterized allergens has increased the expectations of the diagnosis and the specific treatment of allergic diseases mediated by IgE.16–24
These advances have also improved the availability of well-characterized tools to study the mechanism of action for how these treatments induce allergen tolerance.25–28
First, characterizations of allergenic sources have greatly improved. The development of specific tools to detect and quantify individualized allergens in biological products that are made of complex, antigenic mosaics has allowed for the detailed study of allergen compositions.29–30
Second, individualized allergens themselves, their hypoallergenic variants, or relevant peptides may constitute the therapeutic products.18
Starting in 2001, a consortium (CREATE Project) involving basic and clinical researchers, biotechnological industries that produce allergens, and regulatory agencies was created to standardize the materials and methods used to develop these products. The aim of this work was the production of recombinant allergens to use as universal references, after they were compared with their homologous native forms and to define the most appropriate methods for quantifying individualized allergens.31
In recent studies on the molecular basis of allergy, contrary to traditional thinking, most allergens have a narrow range of functionality. These allergens are found in a restricted number of protein families.32
The biochemical classification system for protein families reveals more than 12,000 protein families, and approximately only 200 families contain allergenic proteins.
2.3. The biological function and nature of allergens
According to the data included in the Allergome database,33
there are now approximately 2500 allergenic sources that are well-defined as allergens, and the number of these well-identified allergens (excluding isoforms and epitopes) is just over 3000. From a molecular taxonomy perspective, the Database of Allergen Families34
shows that of the 12,273 existing protein families (March, 2011), only 186 families include allergens. There are approximately 1000 allergens that could be assigned to a specific protein family, and only 10% include allergens with unknown or unidentified biological functions. Only a few families such as the prolamins, polcalcines, profilins, tropomyosins, cupins, and PR10-related proteins include 26% of the aforementioned 1100 allergens. The allergens that belong to these few families are a highly homogeneous group of proteins. They are present in many different allergenic sources that form the most important group of allergens to cause the cross-reactivity phenomenon. Conversely, there are species-specific or family-specific allergens in more phylogenetically restrictive protein families. Some of these allergens such as the major allergen from Alternaria alternata
(Alt a 1), define a new family of proteins.32,35–37
Most allergens are proteins. The intrinsic properties of proteins make them undistinguishable from the proteins that stimulate other immunoglobulin isotypes (IgA, IgG, or IgM), which constitute the conventional antigens.
As mentioned previously, within the substantial heterogeneity of the existing protein families, only a few contain allergenic proteins, and, of all the protein domains, only 2.1% include allergenic proteins.33 If so, apart from the classic factors that influence antigenicity, such as the molecular size, concentration, solubility, stability, biochemical activity, and phylogenetic proximity, what would cause a protein to become an allergen? Or put in another way, what makes an allergen?
It is clear that the answers to these questions lie in how the immune system responds to different antigens that are capable of stimulating the immune system and in the strategies that are used to respond to interactions with each antigen.
Because allergenicity cannot be defined by the common rules for allergen-IgE binding sites, a complete set of old and new concepts related to answering the question, “What makes an allergen?” should be formulated in the future.
2.4. Defining the concept of allergens
Taking into account that the immune response against helminthic infections are predominantly Th2, which mainly involves cytokines, such as IL-3, Il-4, IL-10 and IL-13, which are implicated in the increased levels of IgE antibodies, eosinophils, basophils, and mast cells, and that the allergic phenotype has a very similar pattern of immune response, several authors have suggested that both immunological processes could have the same or a similar origin.10,38–42
On the other hand, Fitzsimmon et al.43
in their excellent review reported homologous protein families between allergen proteins and some metazoan parasite proteins. Some of the top 10 allergen families (tropomyosins, PR-1, lipocalins, profilins, and serine-proteases) have members in helminth species, and many of them have IgE-binding ability. Other proteins included in this top-ten list, such as prolamins and expansins, have not been identified in helminth species to date.
Currently, all available data about the structure, biochemical, and biological functions of the different allergens allow the clustering of these factors into allergen families, and certainly, these characteristics should be part of the definition of allergens.44
The phylogeny of allergen sources and allergen taxonomic markers can also contribute to a better understanding of the allergen concept.45,46
Currently, it is very difficult to discriminate between allergenic and non-allergenic proteins, considering the classic concepts of major, minor or non-allergenic proteins. In previous years, increasing knowledge about the innate immune system has modified our understanding about the protein allergenicity concept.
Pathways of innate immune activation appear central to the contribution of allergenicity. The intrinsic properties of allergens seem to activate both the innate and adaptive immune system. Recently, it has been demonstrated that some allergens possess intrinsic adjuvant properties to stimulate innate immunity. The adjuvant properties appear to contribute to the allergic sensitization in atopic or sensitized individuals.44,46,47
These adjuvant properties are mainly mediated by protease activity, carbohydrate residues, and lipids, which interact with the innate immune system to promote allergic Th2 responses.
The question, “What makes an allergen? ” can be answered by not only characteristics defined by the protein itself and other adjuvant components capable of activating Th2 responses, but also the origin and evolution of the immune response to these proteins in each form of parasitism. Allergenicity in susceptible subjects is a complex and multifactorial phenomenon that can be explained only by the combination of all of the aforementioned factors.
3. Helminth parasites and allergy
“Helminth” is a nontaxonomic general term meaning “worm.” In Helminthology, associated with medical health, two major phyla of parasitic worms are recognized: the Nematoda (round worms), which are subdivided into two main classes, Adenophorea and Secernentea; and the Platyhelminthes (flatworms), which are subdivided into two main classes, Cestoda (tapeworms) and Trematoda (flukes).
Among the helminthiasis, the most common human infections are those caused by geohelminths (intestinal parasites also known as soil-transmitted helminths). Highly prevalent parasites such as Ascaris lumbricoides
, Trichuris trichura
and hookworms belong to this family. Recent global estimates indicate that approximately 3.5 billion people are infected with one or more of these common nematode parasites.48
Other important helminth parasitosis includes Schistosomiasis, which are transmitted by cercariae swimming in water, and Filariasis, which are transmitted by arthropods, although both of these have a more restricted distribution.
Fluke infections are also important helminthiasis transmitted by metacercariae in water or foods. Their adults are established in the bile ducts, the lungs or the intestine, depending on the species.
is a liver fluke that causes Fascioliasis, a zoonotic infection that affects approximately 50 million people worldwide; over 180 million are at risk of infection in both developed and undeveloped countries.49
Despite the fact that “immunity against helminths” and “parasites and allergy” are subjects that have been exhaustively reported in the literature, only a limited number of references about the “parasitic origins of the allergic response” can be found, even in discussions on the evolutionary relationship of allergens.14
It is unanimously accepted that the immune response to helminth parasites and the immunological basis of allergy occur under the same rules.
Most allergen or helminth antigen-specific CD4+ human T cell clones have a Th2 phenotype, whereas the majority of T cell clones specific to microbial antigens or antigens responsible for type IV hypersensitivity exhibit a Th1 phenotype.
The selective or preferential activation of CD4+ T cell subsets secreting a defined pattern of cytokines is the key to defining the means by which the immune response shifts towards protection or towards immunopathology.50,51
However, the Th1/Th2 paradigm cannot adequately explain the development of certain inflammatory responses. A new subset of T cells called Th17 cells represent another independent group of T cells with specific functions that can eliminate certain extracellular pathogens, which are presumably not adequately handled by Th1 or Th2 cells. The major function of Th17 cells has been described in the induction of autoimmune tissue inflammation.
Recently, Th9 cells were also proposed as a subset that develops under the influence of IL-4 and TGF-β to produce IL-9. There are now several subsets that may have the potential to produce immunological disease.
Th9 cells participate in the lesions of many diseases, such as allergic inflammation, tumors, and parasitic infections.52
The current understanding of the contribution of Th9 cells to both effective immunity and immunopathological disease could provide important support for the future development of treatments for allergic and autoimmune diseases.53
In summary, although the evidence for the polarized cytokine secretion profiles of Th1 and Th2 is indisputable, several recent studies have shown a more complex pattern of cytokine interactions in different models of the immune response, including autoimmune models that are inconsistent with the simple dichotomy paradigm (Table 8.1
Differentiation of Effector T Cells Subsets
|Th Cell Subset|
|Profile Cytokine Secretion|
• Macrophage activation
• Cell-mediated immunity
• Phagocyte-dependent protective responses
|Pathogenesis of organ-specific autoimmune disorders, Crohn’s disease, Helicobacter pylori-induced peptic ulcer, acute kidney allograft rejection, and unexplained recurrent abortions|
|IL-4, IL-5, IL-10, IL-13|
• Antibody production
• Eosinophil activation
• Inhibition of several macrophage functions (providing phagocyte-independent protective responses)
Helminth infection immune responses
|IL-17, IL-17F, IL-21, IL-22|
• Clearing extracellular pathogens
• Tissue inflamation
|Autoimmune tissue inflammation|
|IL-9, IL-10, IL-21|
• Mast cells activation with effects on the epithelial cells of the lung and gut
• Direct effect on regulatory T (Treg) cells, T helper 17 (Th17) cells, and antigen presenting cells (APCs).
Nematode infection immune response
• Maintenance of peripheral tolerance
• Down-modulation of the amplitude of an immune response
• Prevention of autoimmune diseases
Treg participate in all cell-mediated immune responses, directly affecting Th1, Th2, Th17, CTL, and B cell reactions against “self” and “foreign” Ag.
a Treg can be divided into different subsets based on the expression of FoxP3 and/or the production of IL-10, TGF-β, and IL-35.
Additional knowledge of the IgE- mediated response common to allergy and helminths and the immune response and a comparison between immunogens from parasites and allergenic sources targeted by IgE or those involved in the activation of the innate and adaptive immune responses, could provide additional keys to how the host–parasite relationships evolved to induce, suppress, and regulate these interactions. Furthermore, which tools the parasites are using to escape and how the hosts apply immunological resources to achieve a more effective defense against parasite infections remain unanswered questions.
Answers to these questions would undoubtedly be keys for success in the study of immune regulation in response to allergic phenomenon through parasite immune modulators in addition to studying the immunologic origin of allergic diseases. As Fitzsimmons and Dune14
cite, “parasitology could help to introduce the evolution into the allergy.”
Helminth infections have immunomodulatory effects on antiparasite inflammatory responses in humans, but the results are not conclusive. Helminth infections have been associated with reduced as well as increased prevalence of atopic diseases in different populations, depending on the helminth species,57
epidemiology and distribution,58
and parasite burden. High levels of parasites may induce down-regulation while low burdens may have the opposite effect.61,62
There is evidence that some helminths are associated with atopy and/or risk factors for asthma. Thus, Ascaris, Anisakis,
and asthma have a strong positive association, but others such as Trichuris
There is also evidence that Schistosoma mansoni
and hookworm infections induce a protective effect to allergic asthma by decreasing the immune response to allergens and clinical manifestations of asthma.66,67
One of the most remarkable characteristics of the many human helminth infections is the preponderance of asymptomatic infections as a positive co-evolutionary result of the host–parasite relationship. This situation is the primary cause of the development of parasite-mediated immune regulation.38,67–69
Several studies have shown that helminth infections induce a complex immune regulatory network that involves dendritic cells, Treg cells and systematic elevated levels of IL-10 and possibly TGF-β, B reg cells and activated macrophages14,38,43,65,67
to achieve chronic asymptomatic conditions.
Several clinical studies have found that certain helminth infections (Trichuris suis
or Necator americanus
) protect against the development of aberrant inflammation, but it is clear that the final objective is to identify the parasite-derived immunomodulatory components responsible for protective effects.65–69
These components are a complex array of antigens/allergens, adjuvants and different immunomodulators capable of activating the pathway through innate immune cells (DC subsets) by recognition of the various families of receptors (PRR: pattern recognition receptors) such as Toll-like (TL) receptors, Nucleotide-binding Oligomerization Domain (NOD)-like receptors, pattern recognition (RIG)-like receptors, and C-type lectin receptors that allow the recognition of a great variety of pathogens though their characteristic components.70
Understanding the mechanisms by which helminths regulate inflammation may potentially lead to the development of strategies focused on the control of undesirable inflammation in allergic and autoimmune diseases.