The specific environmental Nivolumab risk factors leading to the remarkable differences in allergy prevalence between rural and urban communities remain unclear (76–78). The hypothesis that the immunomodulatory effects of parasite infections in rural settings explains it should

be properly investigated. In addition to the downregulation of allergic responses detected during some nematode infections (more evident and better studied in schistosomiasis than in ascariasis (79)), a strong IgE response dominates in human infections by A. lumbricoides, a phenotype that, for a long time, has been interpreted as potentially pro-allergenic and probably related to the complex lifecycle and the antigenic composition of this nematode. Also, high total IgE levels are typical of helminthiasis, which seems to be result of polyclonal B-cell stimulation by parasite products (80,81). The role of such

nonspecific antibodies in immunity to parasites is unknown. Some authors have found that they may prevent cell sensitization by specific IgE (82), but there is evidence that a polyclonal IgE response does not prevent allergic reactions mediated by an actively produced IgE antibody (83,84). Therefore, other mechanisms, probably the immunomodulation on the effector phase of response, are currently considered when analysing the associations of helminth infections and skin tests with environmental allergens. After penetration of the intestinal mucosa, A. lumbricoides larvae Tyrosine Kinase Inhibitor Library clinical trial migrate to the liver, inducing the formation of granulomas, extensive inflammation

and tissue injury. Surviving larvae reach the lungs and generate an inflammatory infiltrate in the airways dominated by severe peri-alveolar eosinophilia (85,86). Antibody production is induced by larvae, and high levels of polyclonal and specific IgE are a hallmark of the infection and, in humans and pigs, immunity is determined by the generation of parasite-specific IgE antibodies against larvae and adult worms (87,88). Experiments show that Ascaris induces sensitization and asthmatic symptoms in humans and infected animals, Loeffler’s syndrome, and IgE-mediated asthma, Celecoxib including immediate-type cutaneous reactivity and airway responses after aerosol challenge with parasite extract (16,89–92). For example, Hagel et al. found that specific IgE levels to A. lumbricoides and positivity of skin test with the nematode extracts were associated with bronchial hyper-reactivity in children from a rural area of Venezuela. Also, the percentage of forced expiratory volume in 1-s (FEV1) predictive values correlated inversely with anti-A. lumbricoides IgE levels. In contrast, in urban children, the same associations were with specific IgE to D. pteronyssinus (16). As already mentioned, epidemiological investigations detected positive associations between A. lumbricoides infection and allergic phenotypes including mite sensitization (13–18).