It has been proposed that infections with helminths can protect from the development of allergic diseases. However, epidemiological and experimental studies have yielded conflicting results. Therefore we investigated if an infection with Nippostrongylus brasiliensis influenced the development of allergen-induced Th2 cell responses in mice. We found a decrease in allergen-induced airway eosinophilia and Eotaxin levels in the airways when mice were infected with the helminths 8 weeks, and especially 4 weeks, but not 1 or 2 weeks before ovalbumin (OVA)-airway challenge. While OVA-specific IgG1 and IgE serum levels and cutaneous hypersensitivity reactions were not reduced by the helminth infection, there was a reduction in OVA-specific IgG1 and IgE levels in bronchoalveolar lavage fluid of mice. Suppression of allergen-induced airway eosinophilia and reduction of Eotaxin production was not observed in IL-10 deficient mice. In addition, we found that helminth-induced airway eosinophilia and Eotaxin production was strongly increased in IL-10 deficient mice infected with the helminths in comparison to control mice. Taken together, these results show that infection with N. brasiliensis suppresses the development of allergen-induced airway eosinophilia and that this effect may be mediated by IL-10. Our results support the view that helminth infections can contribute to the suppression of allergies in humans.

Most infections with respiratory viruses induce Th1 responses characterized by the generation of Th1 and CD8+ T cells secreting IFN-γ, which in turn have been shown to inhibit the development of Th2 cells. Therefore, it could be expected that respiratory viral infections mediate protection against asthma. However, the opposite seems to be true, because viral infections are often associated with the exacerbation of asthma. For this reason, we investigated what effect an influenza A (flu) virus infection has on the development of asthma. We found that flu infection 1, 3, 6, or 9 wk before allergen airway challenge resulted in a strong suppression of allergen-induced airway eosinophilia. This effect was associated with strongly reduced numbers of Th2 cells in the airways and was not observed in IFN-γ- or IL-12 p35-deficient mice. Mice infected with flu virus and immunized with OVA showed decreased IL-5 and increased IFN-γ, eotaxin/CC chemokine ligand (CCL)11, RANTES/CCL5, and monocyte chemoattractant protein-1/CCL2 levels in the bronchoalveolar lavage fluid, and increased airway hyperreactivity compared with OVA-immunized mice. These results suggest that the flu virus infection reduced airway eosinophilia by inducing Th1 responses, which lead to the inefficient recruitment of Th2 cells into the airways. However, OVA-specific IgE and IgG1 serum levels, blood eosinophilia, and goblet cell metaplasia in the lung were not reduced by the flu infection. Flu virus infection also directly induced AHR and goblet cell metaplasia. Taken together, our results show that flu virus infections can induce, exacerbate, and suppress features of asthmatic disease in mice.

Our results suggest that helminths suppress the development of asthma by secreting substances that modulate allergic responses without affecting the generation of helminth-specific Th2 immunity. The identification of these products may lead to the design of novel therapeutic intervention strategies for the treatment of asthma.

Most Bcl-2 family members can localize to intracellular membranes via hydrophobic sequences within their C-terminal portion. We found that the C terminus of the anti-apoptotic family member A1 did not function as a membrane anchor. Instead, this stretch of the protein rendered A1 highly unstable by mediating its polyubiquitination and rapid proteasomal degradation. Moreover, the domain did not only function independently of its position within the A1 protein but when transfered could even destabilize unrelated proteins like enhanced green fluorescent protein and caspase-3. A1 was, however, much more stable in the presence of the Bcl-2 homology-only protein BimEL, suggesting that direct interaction of A1 with pro-apoptotic members of the Bcl-2 family strongly reduces its rate of turnover. We further show that the C-terminal end of A1 also contributes to the anti-apoptotic capacity of the protein. In conclusion, our data demonstrate that the C terminus serves a dual function by controlling the stability of A1 and by amplifying the capacity of the protein to protect cells against apoptosis.Apoptosis plays a critical role in tissue development and homeostasis. This is witnessed by the fact that a number of mammalian pathologies, including cancers and autoimmune and degenerative disorders, arise as a consequence of apoptotic processes going awry (1). Many apoptotic pathways converge at the mitochondria where they induce permeabilization of the outer mitochondrial membrane and subsequently the release of death-inducing factors such as cytochrome c (2, 3). The stability of the outer mitochondrial membrane is controlled by members of the Bcl-2 family (4), which are characterized by the presence of between one and four conserved regions termed Bcl-2 homology (BH) 4 domains (5). The Bcl-2 family consists of both pro-and anti-apoptotic members. The pro-apoptotic members can be further subdivided into those that possess multiple (two or three) BH domains, such as Bax and Bak, and those that possess only the short BH3 domain, such as Bim, Bad, Bid, and Noxa. The "BH3-only" proteins are thought to serve as sensors for different apoptotic stimuli and are stringently regulated at both the transcriptional and post-translational levels (6). The "multidomain" members, which are also referred to as "Bax/Bak-like" proteins, function downstream of their BH3-only relatives and are responsible for the formation of pores in the outer mitochondrial membrane (7). The antiapoptotic Bcl-2 proteins, of which Bcl-2 is the prototype, appear to protect the integrity of the outer mitochondrial membrane by sequestering and thereby neutralizing the pro-apoptotic family members (8 -10).Current models of apoptosis posit that the fate of a cell exposed to an apoptotic stimulus will depend on the balance between the pro-and anti-apoptotic Bcl-2 family members (11). One well recognized mechanism for regulating protein levels is via ubiquitin-mediated proteasomal degradation (12). Levels of Bim, for example, are normally kept low as a consequence of con...

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