Effects of helminth co-infections on atopy, asthma and cytokine production in children living in a poor urban area in Latin America

Abstract

Background: Helminths are modulators of the host immune system, and infections with these parasites have been associated with protection against allergies and autoimmune diseases. The human host is often infected with multiple helminth parasites and most studies to date have investigated the effects of helminths in the context of infections with single parasite or types of parasites (e.g. geohelminths). In this study, we investigated how co-infections with three nematodes affect markers of allergic inflammation and asthma in children. We selected Ascaris lumbricoides and Trichuris trichiura, two parasites that inhabit the human intestine and Toxocara spp (Toxocara canis and/or T. cati), intestinal roundworms of dogs and cats that cause systemic larval infection in humans. These parasites were selected as the most prevalent helminth parasites in our study population.

Results: 36.4% of children were infected with one parasite; 12.7% with 2 and 5.2% with 3. Eosinophilia>4% and >10% was present in 74.3% and 25.5% of the children, respectively. Total IgE>200 IU/mL, sIgE≥0.70 kU/L and SPT positivity were present in 59.7%, 37.1% and 30% of the children, respectively. 22.7% had recent asthma (12.0% non-atopic and 10.7% atopic). Helminth infections were associated in a dose-dependent way to decrease in the prevalence of SPT and increase in eosinophilia, total IgE, and the production of the regulatory cytokine IL-10 by unstimulated peripheral blood leukocytes. No association with asthma was observed.

Conclusions: Helminth co-infections in this population were associated with increased markers of the Th2 immune response, and with a host immune regulatory phenotype that may suppress allergic effector responses such as immediate hypersensitivity reactions in the skin.

Figure 1

Geometric means (pg/mL) and standard deviation (SD) of IL-10 production by non-stimulated blood cells in the IL-10 responder children, by number of of helminth infections. Kruskal-Wallis test (P = 0.0001).

Figure 2

A hypothesis to explain the pattern of cytokine production observed in cultures of peripheral blood leukocytes from individuals who had been infected with multiple helminths, specifically spontaneous production of IL-10 in the absence of exogenous antigen (i.e. in unstimulated cultures); and the presence of a Th2 recall response, but not an IL-10 recall response, to A. lumbricoides antigens. (1) Multiple helminth infections could lead to stimulation of the immune system by hundreds of different antigens, including antigens that are cross-reactive with self antigens. (2) Strong helminth-specific and nonspecific polyclonal Th2 immune responses, with the differentiation and expansion of memory cells, would result from such infections. The Th2 immune response could lead to helminth-specific and non-specific polyclonal IgE production, to eosinophil expansion and activation, and to inflammation. The high levels of polyclonal IgE could theoretically inhibit mast cell activation, by competition with allergen-specific IgE for FcϵRI receptors on mast cells, causing inhibition of immediate hypersensitivity skin test to allergens). (3) A consequent differentiation and expansion of helminth-specific Tregs, some of them cross-reactive with self antigens (and some perhaps only autoantigen-reactive, as a consequence of tissue damage by inflammation) could occur (for the sake of clarity, only cross-reactive and helminth-specific Tregs are shown). (4) The cross-reactive/self antigen-specific Tregs would be maintained in a steady state of activation by self antigens, and would release low levels of regulatory cytokines, including IL-10. The spontaneous production of elevated levels of IL-10 could suppress mast-cell degranulation. Because these Tregs could be maintained through continuous stimulation to self antigens in vivo, they would not be further stimulated by helminth antigens in vitro. TLR- toll-like receptor.