Analysis of cytokine signaling in patients with extrinsic asthma and hyperimmunoglobulin E.
BACKGROUND
Recent data suggest that the regulation of class switching to IgE by cytokines is mediated by STAT transcription factors. The induction of IgE by IL-4 and IL-13 occurs through the activation of the intracellular signal-transducing protein Stat6, whereas the inhibition of IgE class switching by interferon-y (IFN-gamma) occurs through the activation of Statl.


OBJECTIVE
We hypothesized that in extrinsic asthma or in cases of markedly elevated IgE (ie, hyperimmunoglobulin E [HIE]) increased levels of IgE may be associated with alterations in the cytokine levels or the activation of Stat6.


METHODS
PBMCs and sera from 8 patients with extrinsic asthma (mean IgE, 285+/-100 IU/mL), 3 patients with HIE (mean IgE, 7050+/-1122 IU/mL), and 14 nonatopic control subjects (mean IgE, 112+/-28 IU/mL) were analyzed.


RESULTS
The mean IL-4 level detected by ELISA was much greater in patients with HIE than control subjects (88.6+/-11.5 pg/mL vs 11.5+/-7.1 pg/mL, P = .005), and increased IL-4 levels among patients with both asthma and HIE correlated with the increased IgE levels. In contrast, IL-13 levels were not elevated. Levels of Stat6 protein present in PBMCs did not differ in the patients and control subjects. Examination of Stat6 DNA-binding activity demonstrated no activation of IL-4 signaling in patients with either HIE or acute asthma. Interestingly, evidence for the presence of B cells that have already switched to IgE was seen in PBMCs of several patients with asthma or HIE.


CONCLUSIONS
These results indicate that (1) IgE production in asthma and HIE usually is associated with elevated levels of IL-4, but not IL-13, in the peripheral blood; (2) the increased sera IL-4 levels in asthma and HIE are not sufficient to induce Stat6 activation in PBMCs; and (3) evidence of switch recombination to epsilon may be detected in isolated cases of elevated IgE. This implies that high levels of IgE in these patients either results from B cells that have already undergone class switching, from Ig class switching that is localized to target tissues, or both.
Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
R L
RL
Miller
T M
TM
Eppinger
D
D
McConnell
C
C
Cunningham-Rundles
P
P
Rothman
D000328:Adult; D001249:Asthma / Q000097:blood*; D016207:Cytokines / Q000097:blood / Q000502:physiology*; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D006942:Hypergammaglobulinemia / Q000097:blood*; D007073:Immunoglobulin E / Q000096:biosynthesis* / Q000097:blood; D007134:Immunoglobulin Switch Region / Q000502:physiology; D007371:Interferon-gamma / Q000097:blood; D018793:Interleukin-13 / Q000097:blood; D015847:Interleukin-4 / Q000097:blood; D050800:STAT6 Transcription Factor; D015398:Signal Transduction / Q000502:physiology*; D018418:Th2 Cells / Q000378:metabolism; D015534:Trans-Activators / Q000502:physiology
D016207:Cytokines; D018793:Interleukin-13; D050800:STAT6 Transcription Factor; C494101:STAT6 protein, human; D015534:Trans-Activators; D015847:Interleukin-4; D007073:Immunoglobulin E; D007371:Interferon-gamma