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      Hookworm-related cutaneous larva migrans in patients living in an endemic community in Brazil: Immunological patterns before and after ivermectin treatment

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          Abstract

          Hookworm-related cutaneous larva migrans (Hr-CLM) is caused by animal hookworm larvae migrating in the human epidermis where they elicit an inflammatory response. This study describes the immunological profile in Hr-CLM patients.

          In 77 Hr-CLM patients from Manaus, Brazil, peripheral eosinophils were counted, and serum concentrations of total immunoglobulin E (IgE) and selected cytokines were determined by ELISA before and after treatment with ivermectin. Controls included patients’ household members (endemic controls), non-endemic Brazilian and Japanese individuals.

          Eosinophil counts and total IgE in Hr-CLM patients were higher than in controls and correlated with disease severity. Concentrations of interleukin (IL)-4, IL-5, IL-6, and IL-10 were higher in Hr-CLM patients than in endemic controls ( p < 0.001) while no differences were detected for interferon (IFN)-γ, tumor necrosis factor (TNF)-α, IL-1β, IL-2, or transforming growth factor (TGF)-β. Following ivermectin treatment, numbers of eosinophils and concentrations of IL-4, IL-5, and IL-10 decreased whereas IgE, IFN-γ, and TGF-β concentrations increased. The IL-5/IFN-γ ratio declined from 5.9 (interquartile range [IQR] 0.8–31.6) before to 0.1 (IQR 0.05–0.2; p = 0.001) after treatment.

          Thus, although an impact of other infections on the immune parameters determined cannot be excluded, Hr-CLM in endemic areas is associated with eosinophilia and elevated cytokine levels, particularly of IL-5 and IL-10, which decrease following ivermectin treatment.

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          Most cited references36

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          Interleukin-4- and interleukin-13-mediated host protection against intestinal nematode parasites.

          Intestinal worm infections characteristically induce T-helper 2 cell (Th2) cytokine production. We reviewed studies performed with mice infected with either of two intestinal nematode parasites, Nippostrongylus brasiliensis or Trichinella spiralis, that evaluate the importance of the Th2 cytokine interleukin-4 (IL-4) and IL-13 in protection against these parasites. These studies demonstrate that while IL-4/IL-13 protect against both parasites by activating signal transducer and activator of transcription 6 (Stat6) through IL-4 receptor alpha (IL-4Ralpha) ligation, Stat6 activation protects against these parasites through different mechanisms. Stat6-dependent gene transcription promotes expulsion of N. brasiliensis solely through effects on non-bone marrow-derived cells that may include enhancement of intestinal smooth muscle contractility, changes in intestinal epithelial cell function, and increased intestinal mucus secretion. In contrast, Stat6 signaling promotes immunity to T. spiralis both through effects on bone marrow-derived cells that can be reproduced by treating mice with IL-4 or IL-13 and through effects on non-bone marrow-derived cells. The former effects appear to include T-cell-dependent induction of intestinal mastocytosis, while the latter sensitize non-bone marrow-derived cells to mast cell-produced mediators. We argue that a limited ability of the host immune system to distinguish among different nematode parasites has led to the evolution of a stereotyped Th2 response that activates a set of effector mechanisms that protects against most intestinal nematode parasites.
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            Interleukin-5 (IL-5) augments the progression of liver fibrosis by regulating IL-13 activity.

            Eosinophils are frequently found in increased numbers in a variety of chronic fibrotic diseases; however, their role in the development of hepatic fibrosis has not been dissected in vivo. Here, we used interleukin-5 (IL-5) knockout (KO) mice to determine whether eosinophils contribute to the progressive liver fibrosis that develops in response to chronic Schistosoma mansoni infection. Although infection intensities were similar in C57BL/6 and IL-5 KO mice, the average size of granulomas was significantly smaller in both acutely and chronically infected IL-5 KO mice. Their granulomas were also completely devoid of eosinophils. In addition, the knockout mice displayed over a 40% reduction in hepatic fibrosis by week 16 postinfection. The reduced fibrosis was associated with increased production of the antifibrotic cytokine gamma interferon. Moreover, although IL-13 production did not decrease consistently in the absence of IL-5, IL-13-triggered responses were substantially reduced in the granulomatous tissues. This was confirmed by analyzing the expression of several genes associated with alternative macrophage activation, including arginase 1, Fizz-1, and YM-1. Importantly, all of these IL-13-regulated genes have been linked with the mechanisms of wound healing and fibrosis. In addition to IL-5 polarizing the antigen-specific CD4+ Th2 cell response, we found that granuloma eosinophils were themselves a significant source of IL-13. Thus, by producing profibrotic mediators and polarizing the Th2 response, these findings illustrate both direct and indirect roles for eosinophils and IL-5 in the pathogenesis of schistosomiasis-induced liver fibrosis. Thus, inhibiting the activity of IL-5 or eosinophils may prove effective for a variety of chronic fibrotic diseases.
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              Chronic intestinal helminth infections are associated with immune hyporesponsiveness and induction of a regulatory network.

              Helminth infections have been associated with protection against allergy and autoimmune diseases. We investigated the effects of chronic infections with Ascaris lumbricoides and Trichuris trichiura (measured twice over a 5-year period) on cytokine and antibody responses. We collected blood from 1,060 children aged 4 to 11 years living in a poor urban area of Brazil and measured Th1 (gamma interferon [IFN-gamma]) and Th2 (interleukin-5 [IL-5] and IL-13) cytokines and the regulatory cytokine IL-10 in unstimulated and stimulated (with mitogen or A. lumbricoides antigens) cultures of peripheral blood leukocytes and levels of total IgE and anti-A. lumbricoides IgG4 and IgE in serum. Intestinal helminth infections were associated with an increased proportion of children producing IL-5 in response to A. lumbricoides and producing IL-10 spontaneously, especially among coinfected and chronically infected children. Helminth infections were associated with a generalized suppression of cytokine responses to mitogen. Levels of total IgE and anti-A. lumbricoides IgG4 and IgE were especially elevated in chronically infected children. In conclusion, intestinal helminth infections were associated with a typical Th2 immune response profile and with the induction of immune hyporesponsiveness that was associated with greater frequencies of the production of spontaneous IL-10.
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                Author and article information

                Journal
                1886
                122234
                European Journal of Microbiology and Immunology
                EuJMI
                Akadémiai Kiadó, co-published with Springer Science+Business Media B.V., Formerly Kluwer Academic Publishers B.V.
                2062-509X
                2062-8633
                1 December 2013
                : 3
                : 4
                : 258-266
                Affiliations
                [ 1 ] Department of International and Environmental Parasitology, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan
                [ 2 ] Institute of Microbiology and Hygiene, Charité - Universitätsmedizin Berlin, Campus Benjamin Franklin, Hindenburgdamm 27, 12203, Berlin, Germany
                [ 3 ] Foundation for Tropical Medicine in Amazonia (FMT-AM), Av. Pedro Teixeira 25, Manaus, 69040000, Amazonas, Brazil
                [ 4 ] Institute of Tropical Medicine and International Health, Charité - Universitätsmedizin Berlin, Spandauer Damm 130, 14050, Berlin, Germany
                Author notes
                [* ] +49-163-674 37 07, +49-4181-36943, hermann.feldmeier@ 123456charite.de
                Article
                4
                10.1556/EuJMI.3.2013.4.4
                c5772fa6-48c5-419c-b731-7f038dd1a040
                History
                : 7 October 2013
                : 14 October 2013
                : 14 October 2013
                Categories
                Original Article

                Medicine,Immunology,Health & Social care,Microbiology & Virology,Infectious disease & Microbiology
                treatment,cytokine,cutaneous larva migrans,immunological profile,ivermectin

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