Dear Editor,
CD4+ T helper 2 (Th2) cells play a key role in
progression of allergic rhinitis (AR). Traditionally T-cells acquire the
characteristics of Th2 cells in the presence of IL-4, a process that may
be influenced by engagement of co-stimulatory factors expressed by
antigen-presenting cells1. Notch is a co-stimulatory
pathway for CD4+ T-cells, and the importance of Notch
for generation of Th2 cells and the development of allergic rhinitis has
been suggested in animal studies2,3. However, its
potential role in the advancement of allergy in humans remains unknown.
Our group has previously demonstrated that neutrophils and nasal
epithelial cells promote allergic mucosal inflammation by interacting
with T-cells. Based on these findings, we hypothesized that neutrophils
and epithelial cells in allergic nasal mucosa induce Notch signaling in
CD4+ T-cells, promoting allergic inflammation. The
present study analyzed Notch ligand expression on primary nasal
epithelial cells and neutrophils along with Notch receptor expression on
CD4+ T-cells in patients with pollen-induced AR off
season and compared with healthy control (HC). In the appendix of this
article information regarding patient characteristics and methods is
supplemented.
Expression of Notch1-4 on T-cells was assessed by FACS. The fraction of
CD4+ T-cells expressing Notch1,4 in mucosa was
significantly higher in AR compared to HC (Fig 1B). No differences in
Notch expression were detected in blood derived CD4+T-cells (Fig 1A). In animal models of allergic rhinitis, JAG1-Notch1,4
signaling has been demonstrated to polarize T-cell responses towards
Th2, promoting an allergic inflammation3,4. Against
the backdrop of our findings in CD4+ T-cells, it is
tempting to suggest that the increase in Notch1,4 in allergic mucosa
might be a sign of increased Th2 cell polarization and that Notch
signaling maintain TH2 inflammation and consequently AR progression. In
the present study no difference in the expression of Notch was detected
on CD4+ T-cells in peripheral blood. However, this
study was performed outside the pollen season, and it cannot be excluded
that a similar signal can also be seen in the blood in patients with
pollen induced symptoms. Further the expression of JAG1, JAG-2, DLL-1,
and DLL-4 was also assessed with FACS. The fraction of epithelial cells
expressing JAG-1 and DLL-1 was significantly elevated in AR compared to
HC. (Fig 2A). The increased expression of JAG-1 and DLL-1 among patients
with AR could be further corroborated by analyzing median fluorescence
intensity (MFI) (Fig 2B,C). Although significant, the expression levels
of DLL-1 on the surface of epithelial cells were notably lower than the
corresponding expression levels of JAG-1. (Fig 2B,C). There are
conflicting theories regarding in what way Notch signaling regulates
T-cell functions. However, there are evidence for an instructive model
where JAG-Notch1,2 interaction initiates Th2 cell differentiation, and
DLL-Notch3 promotes T helper 1 (Th1) cell
differentiation5. Our result illustrates a
JAG-1>>DLL signaling gradient by epithelial
cells supporting a Th2 outcome (Fig 2B,C). Further, the fraction of
neutrophils expressing JAG-1 was significantly increased in AR compared
to HC, in samples derived from mucosa and blood (Fig 2D,G). In addition,
the expression levels of JAG-1 as measured by MFI, were significantly
increased on neutrophils from AR compared to neutrophil from HC, in
samples derived from mucosa and blood (Fig 2E,F and H,I).
Together with our previous report of antigen-presenting epithelial
cells, our data suggest that the increased expression of JAG-1 in
epithelial cells in allergic mucosa induce a sustained Th2 polarization
of Notch1 and Notch 4 expressing T-cells. In analogy, neutrophils have
also been shown to present antigens to T-cells6.
Hence, it might be that neutrophils in AR mucosa present antigen to
T-cells promoting a Th2 polarization in CD4+ T-cells
by increased expression of JAG-1.
Wk 600
Increased expression of
jagged-1, Notch-1 and Notch-4 in nasal mucosa of patients with allergic
rhinitis
Eric
Hjalmarsson1, Marianne Petro1,
Susanna Kumlien Georén1, Ola
Winqvist2, Lars Olaf Cardell1,3
1. Division of ENT Diseases,
Department of Clinical Science, Intervention and Technology, Karolinska
Institutet, Stockholm, Sweden
2. ABClabs, Biomedicum, Stockholm Sweden
3. Department of Otorhinolaryngology, Karolinska University Hospital,
Stockholm, Sweden
Corresponding author:
Professor Lars Olaf Cardell
Division of ENT Diseases, Department of Clinical Science Intervention
and Technology, Karolinska Insitutet, Stockholm, Sweden
Phone: +46 (0) 8 585 814 53
E-mail: lars-olaf.cardell@ki.se