Tuesday, September 8, 2015

Dirt exposure could prevent asthma development in mouse

Allergic or exaggerated response to mostly innocuous antigens is a Terra Incognita in our understanding of how immune system really works. First question that comes to mind is why is there even such molecule as IgE that causes nothing but allergic reaction when combined with antigen? A hypothesis proposed by immunologist, Ruslan Medzhitov, suggests that the evolutionary role of IgE was to defend the body against toxins. But IgG could do that too? 

Another hypothesis commonly referred as hygiene hypothesis explains that allergic responses are, in fact, out-of-control type II immune reactions (highly skewed Th2-IgE-IL-13 axis) due to absence of "normal" education of immune system by reduced exposure to infections or infectious materials (bacteria, dirt, dust, fungi, dander, etc.) during early life (that supposed to induce Th1-IFNγ axis balancing Th2 response).

First, the authors showed that compared to control, mice pre-exposure to LPS before HDM application were protected from developing features of airway hypersensitivity (the most important figure is 1D).

Since LPS pre-exposure induced A20 up-regulation in lung epithelial cells, the authors tested mice with lung epithelial specific deletion of A20 (tnfaip3 KO). Indeed, beneficial effect of LPS exposure was abolished in these A20 deficient mice (tnfaip3 EC-KO).

Finally, the authors speculated that asthmatic individuals may be deficient for A20 in their lung epithelial cells. However, for some reason, contrary to the authors hypothesis, lung cells from severe asthmatics expressed more A20 molecules compared to lung epithelial cells from mild asthmatics (see figure below). The authors did not discuss this contradiction.

There are several weaknesses in this article. For one, most data are presented as bars rather than scatter plot with individual data points. 2nd, for some unknown reason, the authors decided not to show lung hypersensitivity assay with LPS pre-exposure from mutant mice, as it was done with wild-type mice in Fig. 1D. This assay is clinically the most relevant. This is a Science paper, to remind you.

So, in summary, while I do think that exposure to dirt during early life is relevant for human asthma development, based on results from this paper I am not convinced that expression of A20 in lung epithelial cells play a role here.  

David Usharauli

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