Mycobacteria and the Nramp1 gene in asthma

Abstract

Allergic diseases, such as allergic asthma, are steadily increasing in developed countries. Most likely, the cause of the rise in allergic diseases must be sought in environmental factors. In this respect, the suggestion that a change in the level and the kind of early childhood infections would be factor influencing the development of allergic diseases has drawn most attention and discussion. This suggested relationship between hygiene and allergic disease is called the “hygiene hypothesis”. Basically, this hypothesis states that improved hygiene in industrialized societies, with improved public health measures and the use of vaccines and antibiotics has reduced the incidence of infections that normally stimulate the immune system in some way that mitigates against asthma. In line with the hygiene hypothesis it has been suggested that mycobacteria can be used as an “anti-asthma” vaccine. In this thesis, the potential of a heat-killed preparation of M. vaccae (SRL172) was evaluated. First, in chapter 2 to 4, it was shown that administration of M. vaccae suppresses allergic and asthmatic responses in a mouse model during, but also after, the onset of allergic disease. Importantly, M. vaccae must be administered during allergen exposure to be effective in our model. This may have important implications for the application of M. vaccae in humans. The contradictive results in clinical trails using M. vaccae, but also BCG, may be due to the duration and/or the level of exposure to allergens during the treatment period. Secondly, in chapter 5, we hypothesized that genes controlling the resistance to bacterial infections can influence the development of allergic diseases as well. The Nramp1 gene is one of the best characterized genes controlling resistance to intracellular infections. Therefore, it was studied whether Nramp1 alleles, that determine resistance to intracellular bacteria, affect the sensitivity to the induction of allergic asthma as well. It was demonstrated that the Nramp1 gene affects the development of allergic, but not the development of asthmatic manifestations in a mouse model. In our opinion, Nramp1 may now be considered as a potential locus for susceptibility for allergy and allergic disease. Moreover, Nramp1 could provide a link between genes, the (bacterial) environment and the development of allergy. Finally, it was investigated in chapter 6 whether Nramp1 may be involved in treatment of allergic disease with heat-killed M. vaccae as well. It was demonstrated that Nramp1 indeed affected the efficacy of M. vaccae in reducing the allergic and asthmatic response. In addition, Nramp1 affected the macrophage activation after M. vaccae treatment and maybe as a result, Nramp1 affected T cell-mediated immune response to M. vaccae. In summary, this thesis shows that the macrophage, which function is determined by Nramp1, may play a crucial role in the downregulation by mycobacteria of allergic and asthmatic responses. The macrophage, whose activation is regulated by Nramp1, seems to be a key cell connecting innate, natural immunity with the adaptive, cellular immunity, and therefore might be an important target for the treatment of asthma.