Asthma is one of the most common chronic diseases in the world. It is estimated that around 300 million people in the world currently have asthma . Asthma has become more common in both children and adults around the world in recent decades. The increase in the prevalence of this disease has been associated with an increase in atopic sensitization, and is paralleled by similar increases in other allergic disorders such as eczema and rhinitis . The rate of asthma increases as communities adopt western lifestyles and become urbanized. With the projected increase in the proportion of the world's population that is urban from 45% to 59% in 2025, there is likely to be a marked increase in the number of asthmatics worldwide over the next two decades . Nevertheless the prevalence of asthma in rural developing countries has been under estimated for many years . In many areas of the world persons with asthma do not have access to basic asthma medications or medical care and are not included in any statistical survey . Increasing the economic wealth and improving the distribution of resources between and within countries represent important priorities to enable better health care to be provided. The burden of asthma in many countries is of sufficient magnitude to warrant its recognition as a priority disorder in government health strategies. Particular resources need to be provided to improve the care of disadvantaged groups with high morbidity. Resources also need to be provided to address preventable factors [1, 2]. It is estimated that asthma accounts for about 1 in every 250 deaths worldwide. Many of the deaths are preventable, being due to suboptimal long-term medical care and delay in obtaining help during the final attack. The economic cost of asthma is considerable both in terms of direct medical costs (such as hospital admissions and cost of pharmaceuticals) and indirect medical costs (such as time lost from work and premature death) . Therefore there is a greater understanding of the factors that cause asthma which may lead to novel public health and pharmacological measures to reduce the prevalence of asthma seems to be a worldwide priority.
Among the many factors influencing the prevalence of asthma in developing countries from the tropics are geo-helminthic infections , including those caused by
2. Immunological aspects of asthma
It is well accepted that asthma is a chronic inflammatory disorder of the bronchial mucosa . The symptoms include chest tightness, wheeze, and cough, and often variable obstruction of airflow through the bronchi. The clinical manifestation of asthma is the result of three events within the airways: reversible obstruction, airway hyper-reactivity and inflammation. Among these factors, airway inflammation is believed to play a major role in the development of the disease .
The bronchial inflammation process of asthma is stimulated by cells of the innate immune system (dendritic cells, mast cells, eosinophils, neutrophils, macrophages and NK-cells) and of the adaptive immune system (CD4 + T-lymphocytes, and antigen-specific IgE secreting B-lymphocytes). The innate and adaptive cells are of Th2 class, secreting the cytokines IL-13 and IL-4 prominently or responding to these cytokines through their transduction molecule STAT6 [12, 13]. Thus, the input of these cells into the bronchus and the release or secretion of many mediators (e.g. heparin, reactive lipids or eicosanoids, and enzymes including tryptase and chitinase) lead to increased permeability of blood vessels and consequent edema, increased mucus production, and exaggerated smooth muscle contraction  causing airflow obstruction and the symptoms described above. Also, continued inflammation results in remodeling of the airway in which it is thought that TGF-β cytokine may drive the metaplasia of the epithelium, increased vascularity, thickening of the basement membrane, and muscular hypertrophy, leading to lasting airflow obstruction and breathlessness [14, 15].
The induction of adaptive immunity requires antigen-presenting cells (APCs). It is well known that dendritic cells (DCs) are the main type of APC involved in the induction of Th2 responses to allergens in asthma . In the lung, DCs can be found throughout the conducting airways, interstitium, vasculature and pleura and in bronchial lymph nodes. Lung DCs express many receptors, including Toll-like receptors, Nod-like receptors and C-type lectin receptors up regulate the expression of several co-stimulatory molecules (such as CD80 and CD86) and chemokines (such as CCL17 and CCL22) that attract T cells, eosinophils and basophils into the lungs[16-19]. In humans, monocyte-derived conventional DCs promote Th2 responses by secreting pro-inflammatory cytokines and up-regulating the expression of co-stimulatory molecules after antigen stimulation suggesting that lung DCs are necessary for Th2 cell stimulation during airway inflammation.
As mentioned above, various inflammatory cells, such as basophils, eosinophils and mast cells are recruited to airways after allergen challenge. Although the main focus in asthma has been on their roles as inflammatory cells, increasing data suggest that these cells also function as APCs to initiate or enhance Th2 responses. Basophils, which are circulating granulocytes that express the high-affinity IgE receptor FcεRI, amplify immediate hypersensitivity responses by releasing histamine-containing granules and by producing large quantities of IL-4 . Moreover, several studies have highlighted a crucial previously unknown role for basophils as APCs that drive Th2 responses through their expression of major histocompatibility complex (MHC) class II and co stimulatory molecules . Also it has been proposed that MHC class II- dependent interactions between basophils, which are prominent at sites of allergic inflammation, and CD4+ T cells may have an important role in the induction of Th2-mediated inflammation [22, 23]. Another circulating granulocyte that is prominent at sites of allergic inflammation is the eosinophil. After being stimulated, eosinophils have an important pro-inflammatory role by producing leukotrienes, as well as Th1 cytokines (interferon-γ and IL-2) and Th2 cytokines (IL-4, IL-5, IL-10, IL-13 and TNF-α which contribute to airway inflammation . In addition, eosinophils, like basophils, can also function as APCs . Other relevant components of airway inflammation are the mast cells which express FcεRI and c-Kit and reside in tissues near mucosal surfaces and blood vessels. Mast cells can initiate immediate hypersensitivity reactions by de-granulating in response to both adaptive (IgE-mediated) and innate immune signals. For example, mast cells can be activated through cross-linking of antigen-specific IgE bound to FcεRI  or in response to Toll-like receptor agonists, or to cytokines such as IL-33 . In addition to producing histamine and leukotrienes, mast cells produce cytokines (IL-1, IL-3, IL-4, IL-5, IL-6, IL-8, IL-10, IL-13, IL-16, tumor necrosis factor and transforming growth factor-β) and chemokines (such as IL-8, lymphotactin, CCL1 (TCA-3), CCL5 (RANTES), CCL2 (MCP-1) and CCL3 (MIP1-α).
An important mediator of airway inflammation is Nitric Oxide (NO) which it is a diffusible gas that can activate biochemical process either on the same cell that produced it or on neighboring cells . NO is synthesized from L-arginine by enzyme nitric oxide synthase (NOS), of which there are three isoforms : NOS I or neuronal NOS (nNOS) was originally isolated from rat and porcine cerebellum; NOS II or inducible NOS (iNOS) from activated macrophages; NOS III or endothelial NOS (eNOS) from endothelial cells . High NO levels could be harmful for asthmatic patients because at elevated concentrations, NO lead to the formation of reactive nitrogen species (RNS) and subsequent oxidation and nitration of proteins, which negatively affect protein functions that are biologically relevant to chronic inflammation in the asthmatic bronchial tissues [28,29]. In asthmatic patients, NO is mainly produced by iNOS expressed in bronchial epithelial cells and some inflammatory cells . NO is also produced by neutrophils and macrophages in response to IFN-γ and a second signal provided by a PAMP ligand or TNF-α. iNOS expression is induced by these signals, this enzyme promotes the oxidation of the guadino nitrogen of L-arginine, resulting in the production of NO and citruline . In addition, other mechanisms have been associated with NO production. It has been demonstrated that the ligation of CD23 (low affinity receptor for IgE FcεRII) on human macrophages is a strong inducer of NO . Indeed, the cross-linking of CD23 by IgE, (IgE -immune complexes or by specific monoclonal antibodies) induces pro-inflammatory response, including NO production . Therefore, allergic sensitization inside the lower airways may account for NO production. In this context, it has been reported that aeroallergen sensitization correlated with exhaled NO (eNO) in mild to moderated asthmatic subjects . Also, the late-phase influx of eosinophils may contribute to NO production at the respiratory mucosa.
3. Stimulation of airway inflammation by helminths parasites
It is important to point out that there are close similarities between the allergic inflammatory responses stimulated in the host by environmental allergens (described above) with the immune responses elicited by parasite antigens. Gut inflammation stimulated by intestinal nematode also include innate (mastocytes, basophils and eosinophils) and adaptive cells of Th2 class which secret preferentially IL-13 and IL-4 cytokines. Pro- inflammatory cells like mastocytes and eosinophils stimulated by these cytokines may release many mediators (heparin, reactive lipids or eicosanoids, and enzymes including tryptase and chitinase) leading to increased permeability of blood vessels, increased mucus production and smooth muscle contraction . Also, inflammation induced by most helminths in the host is associated with NO production through somatic and excretory-secretory antigens of adult worm and larvae [36- 40]. These mechanisms may contribute to make a hostile microenvironment in the gut for the parasites promoting worm expulsion.
The capacity of helminths, to stimulate inflammatory responses has been well documented and they are probably related to the complex lifecycle and the antigenic composition of this nematode. For example, there is evidence that after penetration of the intestinal mucosa
The mechanisms by which these parasites induce airway inflammation are still not well elucidated. High levels of polyclonal and specific IgE against adult stages of the parasite are a characteristic of
Regardless of the intrinsic allergenic potential of these parasites, there are evidences that active infection can potentiate the allergic response to non-related antigens. For example, it has been shown that antigenic extracts of
4. Epidemiological studies showing a positive association between helminthic infections and asthma
Human immune response to infections with helminths parasites may differ according to the profile of the infection. As mentioned above, acute or seasonal infections may include primary infections and repeated or intermittent infections without long period of continuous infections and may result from infrequent short exposures or intermittent exposure after treatment in endemic areas [3, 5]. It has been proposed that mild, seasonal helminthic infections stimulate preferentially inflammatory Th2 type immune responses among parasitized populations [3, 81] characterized by the production of high levels of serum specific IgE and allergic reactivity toward parasite soluble antigens  which may lead to the development of bronchial hyper reactivity and asthma [83, 84] particularly among atopic individuals . This situation may be reflected on the increased prevalence of asthma and allergic diseases observed in many low and middle-income countries [86, 87] undergoing parasite eradication programs [5, 6]. For example, epidemiological studies carried out in different rural communities in China, have shown a strong association between Ascaris lumbricoides infection and the development of asthma . These early results are consistent with a meta-analysis of many of studies investigating the association between the presence of geohelminth eggs in stool samples and asthma providing some evidence for parasite-specific effects . In this work in which thirty-three studies were taken in account,
5. The other side of the coin: Chronic helminthic infection may suppress allergic manifestation and the development of asthma
Because parasites are in constant attack by a range of effective immune mechanisms, they have developed effective evasion mechanisms which may vary from simple avoidance to a more active modulation of the immune response in order to establish a non inflammatory environment that allows the parasite to survive. Nematode parasites may enhance survival by directing the immune response to that of a less appropriate type. For example interference with the Th1/-Th2 response balance, the production of high levels of regulatory cytokines such as IL-10 and TGF- β which may lead to a general suppression of T and B cell responses and also mimicry of host proteins which direct the immune response to tolerance have been reported . It has been proposed that because these suppressing mechanisms are not parasite- specific, they may affect the development of allergic reactions in chronically exposed populations [94, 95]. It has been proposed that the effect of geo-helminths on the suppression of atopy is more important early in life causing a deviated Th2 immune phenotype that is not changed later in life, after elimination of the infection . Moreover, there is evidence that maternal helminthic infections could affect infant immunity [97, 98] raising the possibility that the immunologic effects of infection start in the fetus. Further, the inverse association between chronic helminthic infections and allergic disorders among school children from different rural populations from Venezuela, Gambia, Ethiopia, Taiwan, Ecuador and Ghana has been well documented .
The exact mechanisms by which these parasites dampen allergic responses are probably multiple. Chronic helminthic infections may protect against allergic disease because of their profound suppression of the host immune system, leading to a general T-cell hypo responsiveness that is facilitated by the activity of regulatory T (Treg) and B cells and the modulation effects of innate immune cells such as macrophages, dendritic cells (DCs) and local stromal cells, resulting in an anti-inflammatory environment characterized by increased levels of interleukin (IL)-10 and transforming growth factor (TGF)-β . In humans, several studies have shown that Treg cell activity (both by natural CD4+CD25+FoxP3+ and adaptive CD4+IL10+ Tr1 cells) protects against allergic disease [100,101, 102]. Indeed, successful allergen specific immunotherapy in humans which leads to a reduction in allergic symptoms has been associated with the emergence of IL-10–producing Treg cells which may be involved in the increase in IgG4 and IgA responses and a simultaneous decrease in IgE . Several studies carried out in distinct experimental models have revealed a number of active molecules in extracts of helminths that can modulate the immune system of the host. Early work conducted by Itami et al  have demonstrated that high molecular weight components purified by gel filtration chromatography from an
6. Future challenges and research perspectives
As mentioned above, the prevalence of asthma in rural developing countries has been under estimated for many years and in many areas of the world in which persons with asthma do not have access to basic asthma medications or medical care and are not included in any statistical survey. Thus adequate control of asthma in developing countries would require improvements in health care and the development of technologies to obtain the information needed to identify high-risk groups (disease mapping) . This goal would be difficult to achieve if countries do not allocate resources to enable better health care. On the other hand, since many years several global efforts have been made to address the health effects of human parasitism by helminths which results from poverty and exert a well known detrimental impact on the health status of children continuously exposed to these parasites. The World Health Assembly (WHA) has adopted several resolutions calling for the control or elimination of these diseases, and for the implementation of a number of large-scale control and elimination programs. However, despite such WHA/WHO resolutions, the control of morbidity and the elimination of these infections are still a big challenge for global health programs. Some of the identified obstacles include the current scarcity of tools for updated disease mapping, the development of new anthelmintic drugs and vaccines, the improvement of sensitive diagnostic tools and the monitoring of the progress of control interventions and quantification of changes in incidence of infection and disease . However and according to the WHA/WHO resolution, mass chemotherapy have been widely implemented in rural areas of many developing countries in which sanitary limitations are far to be overcome . Under these conditions, this approach would reduce worm burdens without elimination of the infection in endemic areas, which gradually will change the profile of the infection from a chronic pattern, with moderate to heavy worm burdens  to a more mild and seasonal pattern , thereby disrupting the regulatory, anti-inflammatory effect of chronic infections on the immune response, allowing allergic sensitization in atopic parasitized individuals [117, 118]. Thus, the development of diagnosis protocols facilitating rapid identification of atopic individuals among rural populations is an immediate challenge to achieve control of parasites without affecting the health status of a significant proportion of these populations. On the other hand, the presence of respiratory symptoms as a consequence of inflammation due to the parasite migratory phase in non atopic individuals  must also be considered. For these purposes, large birth cohort studies designed according to specific epidemiological objectives and based on results from cross-sectional studies, small longitudinal and pilot intervention studies would help to elucidate the role of the many parameters involved in host- parasite interactions contributing to the pathogenesis of asthma. Also, the identification of conserved features of helminth products that interact with innate immune cells to co-ordinate adaptive anti-parasite responses as well as of potent parasite derived allergens is a key challenge to improve the technology used in the diagnosis and monitoring of allergic diseases in the tropics. Noteworthy is the cross-reactivity of helminth antigens with environmental allergens which may explain the high prevalence of IgE sensitization to invertebrate allergens leading to the development of asthma and other allergic diseases . Finally, the identification and characterization of individual helminth-derived immunomodulatory molecules that selectively induce regulatory immune responses will provide potential candidates for immunotherapy  and must be the subject for future research programs.