If you appreciate unusual scientific results then these two recent papers are for you to read. One paper by David Hill et al. (1), was published in Nature immunology, and another one by Olszak and An et al. (2), was published in Science. Both papers are trying to explain how hygiene hypothesis might work by showing how early exposure to commensial bacteria-derived signals educates immune system so it can control allergic responses later on. What is interesting, however, is that fact that both papers reached similar conclusions by examining different arms of immune system.
In paper by David Hill et al., the authors observed an increase in basophils and IgE in germ-free mice or in mice treated with broad-spectrum antibiotics. Using house dust mite allergen or papain allergy model, the authors showed that microbial flora-deficient mice display exaggerated inflammatory response and produce more IgE promoting cytokine IL-4. This increase in basophil numbers however did not occur in either T and B cell-deficient mice or IgE-deficient mice, indicating that IgE promoted basophil accumulation. Direct injection of IgE supported this conclusion. Mechanistically, IgE driven basophil accumulation was shown to be mediated through increase of basophil differentiation from its precursors via augmentation of sensitivity to IL-3. In addition, B-cell specific MyD88 signaling was shown to play a role in limiting IgE production. In short, this paper explained hygiene hypothesis based on B cells-MyD88/IgE/ basophil axis.
In paper by Olszak and An et al., however, authors reached similar conclusion regarding protective effect of microbial flora by examining biology of NKT cells in germ-free mice. The authors showed that germ-free mice had more tissue NKT cells (I wonder how authors of other papers could miss this fact). Using chemically-induced colitis model or allergen-induced asthma model, the authors showed that blocking CD1d molecule by specific antibody inhibited allergic-prone response in germ-free mice (reduced tissue eosiphilia and IgE accumulation), indicating that NKT cells are involved. This conclusion was supported by NKT-specific deficient mice. Crucially, the authors showed that early, but not late life exposure to microbes could protect germ-free mice from allergy. Mechanistically, accumulation of NKT cell in germ-free mice was linked to CXCL16 over-production as a result of microbial-deficiency. It was MyD88 independent effect.
While both paper shed some new lights into hygiene hypothesis, it also highlight how narrow scientific research has become. Each group looked at germ-free mice and observed only what made more sense to them. We know that NKT cells can drive IgE response and I can even argue that NKT cell activation in germ-free mice helps B cells to switch to IgE production. So in a way these two paper complement each other. However, the point is that we still don't understand why absence of microbial signals should lead to IgE response in general. Does it mean that IgE response is somehow helpful in protecting tissue against insults of non-microbial origin? Why? How?
David
