Evert Nijhuis

Gene expression in CD4+ T-cells reflects heterogeneity in infant wheezing phenotypes

Although a marked increase in the reporting of wheezing symptoms since the mid-1970s has been described, the underlying immunopathology of the different wheezing phenotypes has not been clarified. Since differences in gene expression might be involved, the objective of the present study was to identify gene expression profiles in CD4+ T-cells from two distinct infant wheezing phenotypes. The gene expression profiles of peripheral CD4+ T-cells were compared by means of microarray analysis of six transient wheezers, six persistent wheezers and seven healthy controls. The differentially expressed genes were subsequently validated by RT-PCR. The differential gene expression profiles reflected common immunological pathways involved in apoptosis or proliferation of T-cells. Furthermore, both wheezing phenotypes showed decreased expression of the complement component 5 receptor 1 gene, a gene involved in the regulation of bronchial responsiveness. Moreover, differences in gene expression profiles were found in genes involved in the immune response against respiratory syncytial virus, such as those encoding signal transducer and activator of transcription 1 and an inflammatory mediator showing enhanced production in asthma (prostaglandin E2 receptor 2). The present findings suggest that clinical symptoms of wheeze are reflected in common immunological pathways, whereas differences between wheezing phenotypes are, in part, reflected in distinct gene expression profiles.

Modulation of Lymphocyte Function In Vivo via Inhibition of Calcineurin or Purine Synthesis in Patients with Atopic Dermatitis

are indispensable for PG transporter activity, such as the missense mutations c.763G4A (p.Gly255Arg) and c.1668G4C (p.Gln556His) identified. Both changes are nonconservative, affect evolutionarily highly conserved amino acids (Figure 2), and were predicted in silico by all bioinformatic tools of pathogenic relevance (Supplementary Table 1 online). The pathogenic character of c.763G4A (p.Gly255Arg) and the impact of the glycine residue at position 255 is further strengthened by the fact that the same codon was mutated (c.764G4A; p.Gly255Glu) in a patient described by Zhang et al. (2012). To corroborate these data, we constructed molecular models of wild-type and mutated SLCO2A1 proteins to visualize changes of protein folding and structure (Meng et al., 2006; Bordoli et al., 2009; Yang et al., 2011). Both mutations are located in a transmembrane domain and considerably affect the protein structure (Figure 2), which was additionally confirmed by Ramachandran plots (Supplementary Figure S1 online). In this report, we show that SLCO2A1 is a frequent cause of autosomal recessive PHO, confirming the data recently published by Zhang et al., 2012. Although most patients harbor mutations in HPGD and SLCO2A1, further genetic heterogeneity is likely, and candidate approaches targeting other PG-signaling components seem promising. CONFLICT OF INTEREST JB, VF, NB, HB, and CB are employees of Bioscientia, a member of Sonic Healthcare.