Interleukin-4 (IL-4) plays a major role in immunoglobulin E (IgE) production. Its signal is conferred to effector cells through binding to the alpha chain of the IL-4 receptor (IL-4Ralpha). We present further evidence for polymorphisms in the IL-4Ralpha gene having an effect on IgE regulation. For two of four common polymorphisms, S503P and Q576R, we found an association with lowered total IgE concentrations (P=0.0008 if occurring together). The polymorphism S503P has not yet been described and is located within the I4R motif of the receptor. In vitro analyses using synthetic peptides of this region showed that the tyrosine kinase Janus kinase 1 (JAK1), as well as IRS-1 and IRS-2 bind to the I4R motif irrespective of the polymorphism or a tyrosine phosphorylation. In vivo immunoassays using T cells of four different groups of individuals (S503/Q576; P503/Q576; S503/R576; P503/R576) revealed that only in case of both polymorphisms the phosphorylation of IRS-1 and IRS-2, but not JAK1 was increased. We found no binding of STAT6 to the I4R synthetic peptides; however, the phosphorylation was reduced in the presence of any of the two polymorphisms, including P503 alone. We discuss possible conformational changes of the receptor leading to the observed effects on the phosphorylation status of IRS-1, IRS-2 and STAT6, in addition to previous findings that Q576R alters STAT6 binding. We conclude that P503 and R576 influence the signal transduction pathways through the IL-4Ralpha, an effect that is magnified by the presence of both polymorphisms. This could explain the observed association effects with lowered total IgE concentrations.

In conclusion, the present study clearly shows that SAV leads to an inhibition of the S-FAP needed to obtain optimal T cell activation at the low allergen concentrations present in vivo. This novel mechanism may explain the increased allergen threshold levels found in allergen provocation tests and the reduction of late-phase reactions observed after SAV.

To evaluate the tolerability and efficacy of specific immunotherapy with mite extracts, we performed a double-blind, placebo-controlled immunotherapy study in 30 patients with proven allergy to mite allergens. The specific immunotherapy with standardized extracts of Dermatophagoides pteronyssinus and D. farinae by a clustered rush protocol was well tolerated. After 1 year of treatment, the actively treated group showed a significant improvement compared to their starting value as well as to the placebo-treated patients with regard to skin prick test, conjunctival provocation test, and subjective rhinitis score. The subjective asthma score and bronchial hyperreactivity, measured by the methacholine provocation test, was improved in comparison to the starting value, but not to the placebo group, after 12 months. However, a further, open comparison of the placebo- and verum-treated groups at 18 months revealed a significant reduction. The drug intake was not increased in the verum-treated group. Exposure to mite levels was constant throughout this time period, as revealed by antigen measurement. We conclude that specific immunotherapy in perennial, mite-allergen-induced asthma may reduce not only immediate, IgE-mediated symptoms but, after a rather long time period of 12-18 months, also the inflammatory component of bronchial asthma, thus leading to a reduction of unspecific hyperreactivity.

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This study demonstrates that apart from T-cell epitopes of rBet v 1, many other crossreactive or Bet v 1 isoallergen-specific epitopes exist. This indicates that isoallergenic variation plays an important role in the induction of Bet v 1-specific and crossreactive T-cell responsiveness to allergens.