Abstract
We hypothesized that the scarcity of N-nucleotides might contribute to the inability of the neonate to mount a robust allergic immune response. To test this, we used terminal deoxyribunucleotidyl Transferase deficient (TdT−/−) mice, which express “fetal-like” T cell receptor and immunoglobulin repertoires with largely germline-encoded CDR3 regions. Intraperitoneal sensitization was followed by aerosol provocation with either PBS or the allergen OVA in both TdT−/− mice and wild-type mice to develop allergic respiratory inflammation. The effects of this procedure were investigated by lung function test, immunological analysis of serum and brochoalveolar lavage. The local TH2 cytokine milieu was significantly attenuated in TdT−/− mice. Within this group, the induction of total IgE levels was also significantly reduced after sensitization. TdT−/− mice showed a tendency toward reduced eosinophilic inflow into the bronchial tubes, which was associated with the elimination of respiratory hyperreactivity. In conclusion, in a murine model of allergic airway inflammation, the expression of fetal-like antigen receptors was associated with potent indications of a reduced ability to mount an asthma phenotype. This underlines the importance of somatically-generated antigen-receptor repertoire diversity in type one allergic immune responses and suggests that the fetus may be protected from allergic responses, at least in part, by controlling N addition.
Highlights
We hypothesized that the scarcity of N-nucleotides might contribute to the inability of the neonate to mount a robust allergic immune response
Allergic sensitization is described as a misled classical affinity-driven immune response associated with an imbalance towards a TH2 milieu3,4. TH2-cell derived cytokines such as interleukin 4 (IL-4) promote B cell isotype switching to immunoglobulin E (IgE) which plays a key role in allergic asthma by acting as a link between an allergen and the mast cell to which the IgE is attached by its constant domain to membrane-bound Fcε receptors[5,6,7]
We found that in a murine model of allergic airway inflammation terminal deoxynucleotidyl transferase (TdT−/−) deficient mice, which express “fetal-like” antigen receptor repertoires without N-nucleotides[21], give substantial indications to develop an impaired immune response
Summary
We hypothesized that the scarcity of N-nucleotides might contribute to the inability of the neonate to mount a robust allergic immune response. Intraperitoneal sensitization was followed by aerosol provocation with either PBS or the allergen OVA in both TdT−/− mice and wild-type mice to develop allergic respiratory inflammation. In a murine model of allergic airway inflammation, the expression of fetal-like antigen receptors was associated with potent indications of a reduced ability to mount an asthma phenotype. This underlines the importance of somatically-generated antigen-receptor repertoire diversity in type one allergic immune responses and suggests that the fetus may be protected from allergic responses, at least in part, by controlling N addition. In atopic dermatitis the circulating IgE repertoire reflects superantigen like activation[12]
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