Balic, A., Harcus, Y., Holland, M. J. & Maizels, R. M. Selective maturation of dendritic cells by Nippostrongylus brasiliensis-secreted proteins drives TH2 immune responses. Eur. J. Immunol. 34, 3047-3059

Institute of Immunology and Infection Research, University of Edinburgh, Edinburgh, UK.
European Journal of Immunology (Impact Factor: 4.03). 12/2004; 34(11):3047-59. DOI: 10.1002/eji.200425167
Source: PubMed


Helminth infections at mucosal and tissue sites strongly polarize towards Th2 immune responses, following pathways which have yet to be elucidated. We investigated whether dendritic cells (DC) exposed to gastrointestinal nematodes induce Th2 differentiation and, if so, whether this outcome reflects the absence of DC activation (the default hypothesis). We studied secreted proteins from the parasite Nippostrongylus brasiliensis, which induce Th2 development in vivo without live infection. Murine bone marrow-derived DC pulsed with N. brasiliensis excretory/secretory antigen (NES) can, on transfer to naive recipients, prime mice for Th2 responsiveness. Heat inactivation of NES abolishes both its ability to drive Th2 responses in vivo and its capacity to stimulate DC for Th2 induction. NES, but not heat-inactivated NES, up-regulates DC maturation markers associated with Th2 promotion (CD86 and OX40L), with little change to CD80 and MHC class II. Moreover, DC exposed to NES readily produce IL-6 and IL-12p40, but not IL-12p70. LPS induced high IL-12p70 levels, except in DC that had been pre-incubated with NES. These data contradict the default hypothesis, demonstrating that a helminth product (NES) actively matures DC, selectively up-regulating CD86 and OX40L together with IL-6 production, while blocking IL-12p70 responsiveness in a manner consistent with Th2 generation in vivo.

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    • "In this context, what stands out is the observation that pLL on its own induces, in vitro and in vivo, the upregulation of CD86. Selective upregulation of CD86 among major costimulatory molecules was also reported in DCs exposed to the excretory-secretory products of the nematode Nippostrongylus brasiliensis (49). However, in contrast to our experimental system, this was accompanied by secretion of IL-6 and IL-12/23p40, suggesting that exposure to the N. brasiliensis extract caused some NF-κB activation. "
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    • "Ruyssers et al. [25] and Cancado et al. [26] recently demonstrated the therapeutic potential of excretory/secretory (ES) products from adult hookworms, Ancylostoma caninum and A. ceylanicum, on experimental colitis in mice, predominantly through the down-regulation of Th1 and Th17 cytokines. Although helminthic ES products could directly modulate dendritic cells (DC), suppress the expression of co-stimulatory MHCII and produce anti-inflammatory cytokines [20], modulation of the immune system by ES products derived from different helminth species or developmental stages may act differently [27], [28], [29], [30]. T. spiralis is one of the most widespread zoonotic parasitic nematodes in the world. "
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    • "Future work should give valuable insights into the mechanisms of suppression of Th2 responses against both parasites and bystander antigens both at the level of Th2 induction (by administering parasite products with the OVA sensitisation), and established anti-parasite Th2 responses (by administering parasite products at OVA-airway challenge). A possibility that should be considered is whether helminth molecules induce a competing Th2 response, as many parasite products themselves induce potent Th2 responses in vivo (Balic et al., 2004; Dowling et al., 2011; Zaccone et al., 2011) and in the case of administration of NES products, an allergic-type response developed to the ES antigens themselves (Trujillo-Vargas et al., 2007). "
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