IL-4R mutation drives IL-17 dominant asthma phenotype

Asthma represents a dysregulated immune response to antigens that normally do not produce clinically-detectable immune responses. Ordinarily asthma response was regarded as classical Th2 class response with dominant IL-4/IL-13/eosinophil axis. However, for past 10 years, since the discovery of Th17 cells, scientists started to find a separate subtype of asthma dominated by IL-17/neutrophil axis. 

New paper in Nature Medicine pinpointed one molecular mechanism that underlie Th2→Th17 switch in asthma. It showed that a single amino acid mutation in IL-4Rα introduces instability in regulatory T cell lineage leading to Th17 induction.

Initially, the authors observed that mice with a glutamine (Q)-to-arginine (R) substitution at amino acid residue 576 of IL-4Rα (Il4ra^R576 mice) develop more severe experimental asthma in response house dust mite allergen.

In vitro culture of conventional or induced regulatory T cells derived from mice on Il4ra^R576 background showed exaggerated IL-17 expression in response to TGFβ1 and IL-4.

Lineage tracing analysis revealed instability of regulatory T cell lineage and their differentiation into IL-17 producing cells (ex-Tregs).

Indeed, when Tregs were rendered incapable to differentiate into IL-17 producing cells in Foxp3^YFPCreRorc^Δ/Δ mice, severity of asthma was reduced.

In summary, this study showed that genetic mutation in IL-4Rα introduces instability in Treg lineage and leads to IL-17 dominant asthma phenotype. Such asthma conversion is expected to be sensitive to anti-IL6 therapy.

David Usharauli

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).

The new paper in journal Science is another example for such immune "balancing" act in support of hygiene hypothesis. Here, the authors reported that pre-exposure to low dose of LPS (endotoxin, a part of gram-negative bacteria) could raise the threshold for lung airway epithelial sensitivity to house dust mite (HDM) extract via modulation of NF-kb activity via up-regulation of A20 (Ubiquitin-editing protein).  

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

Two distinct, mutually exclusive immune signatures, TH2 and TH17, determine therapy responsiveness in asthma

Asthma is a chronic condition manifested in episodes of airway hypersensitivity (inflammation, smooth muscle constriction) to innocuous signals that ordinarily would cause no tissue response in average individual. Eventually this chronic state leads to tissue remodeling and reduction of oxygen-rich air available for lung. 

Classical, allergic asthma episodes are driven by type 2 (TH2) immune response dominated by IL-4 and IL-13. However, more recently another category of asthma characterized by TH17 signature has been described. It appears that TH17 signature asthma may be more resistant to current asthma therapy.

The new study in Science Translational Medicine provided additional support for asthma stratification based on immune signature. This Genentech study showed that asthma immune profile can be stratified into mutually exclusive, non-overlapping TH2^high and TH17^high signatures.

This is a short paper. Basically, the authors analyzed airway gene signature from 51 asthma patients. They found that asthma patients' immune signature fall in 2 categories: either TH2^high or TH17^high. There is additional double negative category but its immune signature is not known.

Interestingly, both TH2^high and TH17^high signatures were associated with eosinophil infiltration.

Since current asthma therapies mainly target TH2 signature, the authors tested the outcome of α-IL-4/IL-13 blockade on animal asthma model (house dust mite antigen sensitization). As expected, dual blockade of TH2 cytokines significantly reduced airway inflammation.

However, TH2 cytokine blockade also induced TH17 signature, as would have been expected from in vitro studies (though it is not entirely clear from the data if this shift to TH17 pathway induced any clinically-relevant airway inflammation here).

Finally, the authors showed that blockade of both TH2 and TH17 pathways may be necessary to avoid inverse increase in TH2-driven airway hypersensitivity during anti-IL-17 therapy.

In summary, this study suggests that clinical trial design for α-IL-17 target therapy in asthma patients may need modification based on this findings. For example, α-IL-17 therapy alone may be not sufficient or that eosinophil signature could not be used as a exclusion factor for α-IL-17 therapy.

David Usharauli