Wednesday, August 3, 2016

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 (Il4raR576 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 Il4raR576 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 Foxp3YFPCreRorcΔ/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

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