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Increased presence of dendritic cells and dendritic cell chemokines in the sinus mucosa of chronic rhinosinusitis with nasal polyps and allergic fungal rhinosinusitis.

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ORIGINAL ARTICLE
Increased presence of dendritic cells and dendritic cell chemokines
in the sinus mucosa of chronic rhinosinusitis with nasal polyps and allergic
fungal rhinosinusitis
Chris M. Ayers, MPH1 , Rodney J. Schlosser, MD1,2 , Brendan P. O’Connell, MD1 , Carl Atkinson, PhD3 ,
Ryan M. Mulligan, MS1 , Sarah E. Casey, MS3 , Benjamin S. Bleier, MD1,4 , Eric W. Wang, MD1 ,
Eugene R. Sansoni, BS1 , James L. Kuhlen, MD1 , Jennifer K. Mulligan, PhD1
Background: The aim of this study was to determine if there
is a link between local dendritic cells (DCs) and various subtypes of chronic rhinosinusitis (CRS): CRS with nasal polyposis (CRSwNP), CRS without nasal polyposis (CRSsNP),
and allergic fungal rhinosinusitis (AFRS). Once DC presence was established we considered possible mechanisms
for DC recruitment to the sinuses.
Methods: Biopsy specimens were taken from the osteomeatal complex during endoscopic sinus surgery in patients with AFRS (n ≥ 5), CRSsNP (n ≥ 6), and CRSwNP
(n ≥ 6). Control patients (n ≥ 5) were undergoing either tumor resection or repair of cerebrospinal fluid leak and had
no radiographic or endoscopic evidence of inflammatory sinus disease. Tissue samples were immunohistochemically
stained for DC marker, CD209, costimulatory molecules,
CD80 and CD86, and chemokine receptors, CCR2 and
CCR6. Sinus tissue lysates were examined for levels of
the DC chemoaractants, chemokine ligand 2 (CCL2) and
CCL20.
Results: Analysis of sinus tissue from AFRS and CRSwNP
revealed elevated numbers of cells staining positive for
CD209, CD80, CD86, CCR2, and CCR6 compared to controls. CCL2 and CCL20 levels were elevated in AFRS
1
Department of Otolaryngology–Head and Neck Surgery, Medical
University of South Carolina, Charleston, SC; 2 Ralph H. Johnson VA
Medical Center, Charleston, SC; 3 Department of Microbiology and
Immunology, Medical University of South Carolina, Charleston, SC;
4
Massachusetts Eye and Ear Infirmary, Harvard Medical School,
Boston, MA
Correspondence to: Jennifer K. Mulligan, PhD, MSC 550, 135 Rutledge Ave.,
Charleston, South Carolina 29425; e-mail: konopa@musc.edu
Funding sources for the study: American Academy of Otolaryngic Allergy
(to B.O.C.) and the Flight Attendant Medical Research Institute (to R.J.S.
and J.K.M.).
Potential conflict of interest: None provided.
Received: 20 September 2010; Revised: 26 November 2010; Accepted: 14
December 2010
DOI: 10.1002/alr.20046
View this article online at wileyonlinelibrary.com.
and CRSwNP compared to controls, similar to increases
in their receptors, CCR2 and CCR6, respectively. While
there were trends toward increases in all markers in
CRSsNP, none was statistically significant compared to
control.
Conclusion: AFRS and CRSwNP have increased numbers of
DCs displaying costimulatory molecules, DC chemoaractants, and their corresponding receptors in the sinus mucosa compared to controls. These differences represent a
possible mechanism for increased numbers of DCs with a T
helper 2 (Th2)-skewed profile seen in CRSwNP and AFRS.
C 2011 ARS-AAOA, LLC.
Key Words:
allergic fungal rhinosinusitis; chemokine; chronic rhinosinusitis without nasal polyps; chronic rhinosinusitis; dendritic cells
How to Cite this Article:
Ayers CM, Schlosser RJ, O’Connell BP, et al. Increased
presence of dendritic cells and dendritic cell chemokines
in the sinus mucosa of chronic rhinosinusitis with nasal
polyps and allergic fungal rhinosinusitis. Int Forum Allergy
Rhinol, 2011; 1:296–302
T
he immune system, in healthy adults, rests in a state
of equilibrium between T helper 1 (Th1) and Th2,
prepared to mount an immune response toward either in
the presence of an immune challenge1 ; however, in various
disease states, including chronic rhinosinusitis (CRS), this
balance is disrupted. CRS with nasal polyps (CRSwNP),
including those with allergic fungal rhinosinusitis (AFRS),
display a Th2-skewed immune phenotype.2 Conversely,
CRS without nasal polyps (CRSsNP) has elevated Th1
and Th2 mediators with a mixed neutrophilic, eosinophilic
infiltrate.3–5 The clinical significance of this upregulation
of Th2 cytokines is that they can further drive many of the
physical symptoms associated with CRSsNP and CRSwNP,
including stimulation of mucus production.6
International Forum of Allergy & Rhinology, Vol. 1, No. 4, July/August 2011
296
Increased DCs in CRSwNP and AFRS
Although these diseases are closely related, the mechanism driving the observed differences in Th1/Th2 skewing
remains largely unknown. One possible means by which
this may be occurring involves dendritic cells (DCs). DCs
play a significant role in a number of human diseases including systemic lupus erythematosus, head and neck squamous cell carcinoma, Crohn’s disease, rheumatoid arthritis, chronic obstructive pulmonary disease, and asthma.7,8
DCs are highly efficient antigen-presenting cells capable
of directing T-cell responses toward either a Th1 or Th2
response.9 Upon extracellular antigen capture, DCs undergo phenotypic maturation, thereby upregulating cell
surface expression of major histocompatibility (MHC) IIpeptide complexes and costimulatory B7 molecules such
as CD80 and CD86.10,11 Studies conducted in a murine
asthma model suggest that expression of CD80 and CD86
is crucial for the initiation of Th2 responses associated with
asthma.12 In murine and human models of allergic rhinitis,
nasal provocation with allergen was capable of stimulating
increased expression of the DC costimulatory molecules in
the nasal turbinate and mucosa.13,14 Although an increased
presence of DCs has been shown in other respiratory diseases including allergic rhinitis13 and asthma,15 their role in
CRSsNP and CRSWNP or in AFRS is less defined. A study
by Rampey et al.16 suggests that there are both an increased
number of antigen-capturing DCs as well as mature DCs in
the mucosa of patients with eosinophilic nonatopic nasal
polyposis and AFRS.
DCs can be upregulated in tissues primarily through 2
main mechanisms: recruitment of immature DCs or monocytes that are differentiated to DCs in situ. DCs express
numerous chemokine receptors and are highly responsive
to a large number of chemokines. For example, exposure of
respiratory epithelial cells to allergens can induce production of chemokine ligand 20 (CCL20), thereby recruiting
immature DCs expressing its respective ligand CCR6.17 Additionally, CCL2, another potent DC chemoattractant, can
be detected in high levels in bronchoalveolar lavage fluid
following endobronchial allergen challenge.18 In addition
to their role in immune cell recruitment, CCL2 and CCL20
have also been suggested to initiate Th2 skewing.19–22 In
the upper airway CCL223 and CCL2021 have been detected
in the nasal mucosa; however, the role of these factors in
sinusitis remains unclear. Therefore, in the current study,
we investigated if there were alterations in the number of
DCs and DC migratory products in the sinus mucosa of
CRSsNP, atopic and nonatopic CRSwNP, and AFRS.
Patients and methods
Clinical evaluation and tissue preparation
The Medical University of South Carolina Institutional Review Board granted approval prior to initiation of the study
and informed written consent was obtained from all participants. Biopsy specimens were taken from the osteomeatal
complex (uncinate and anterior ethmoid tissue) during en-
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International Forum of Allergy & Rhinology, Vol. 1, No. 4, July/August 2011
doscopic sinus surgery. Control patients (n ≥ 5) were undergoing either tumor resection or repair of cerebrospinal
fluid leak and had no radiographic or endoscopic evidence
of inflammatory sinus disease. CRSwNP patients (n ≥ 6)
were diagnosed through clinical and radiographic examinations that revealed inflammatory sinus disease with nasal
polyposis and no subjective history of atopy and did not
meet the criteria for AFRS. CRSsNP patients (n ≥ 6) were
diagnosed similarly without frank nasal polyposis. Atopic
status was determined by either positive skin prick testing
or modified radioallergosorbent (RAST) testing. AFRS patients (n ≥ 5) met the classic Bent and Kuhn criteria24 with
immunoglobulin E (IgE) hypersensitivity to fungi demonstrated by either skin testing or elevated serum IgE. Patients
using systemic steroid or antifungal medications within
1 month of study enrollment were excluded. Patient demographics are summarized in Table 1.
Immunohistochemistry
Biopsy specimens collected during surgery were placed
R
O.C.T. medium (Sakura Finetek, Torin Tissue-Tek
rance, CA), snap-frozen in liquid nitrogen, and stored at
−80◦ C until use. A Leica CM 1850 cryostat (Wetzlar,
Germany) was used to cut tissue specimens (8-μm thickness) that were then affixed to Vectabond-coated (Vector
Labs, Burlingame, CA) slides. The sections were frozen and
stored at −20◦ C until processing.
Tissue specimens were fixed using acetone for 6 minutes
at room temperature. The slides were then subjected to
10% hydrogen peroxide for 2 hours to quench endogenous
peroxidase activity. Tissue specimens were treated with
5% swine serum for 20 minutes to block nonspecific antibody staining and subsequently incubated with commercially available antibodies. DCs were identified by staining
for CD80 (1:10), CD86 (1:20), or CD209 (1:20). Sinonasal
expression of the DC chemokine receptors, CCR2 (1:200)
and CCR6 (1:100), were also examined (Abcam, Cambridge, MA) or matched with isotype control for 1 hour.
Following this, slides were subjected to biotinylated secondary antibody (Dako, Carpinteria, CA) for a period of
25 minutes. Next, streptavidin-horseradish peroxidase
(Dako) was added to the slides and allowed to incubate
for a period of 25 minutes. The specimens were then subjected to NovaRED (Vector Labs) substrate solution for
5 minutes, after which the tissue was counterstained with
hematoxylin (Dako).
A Nikon Eclipse E600 microscope was used to take photomicrographs from 3 random sections on each slide. The
photographer was blinded to patient diagnosis and took
3 random photomicrographs of each slide at × 40 magnification. The number of positive-staining cells was then
counted by 3 graders blinded to diagnostic category and
then averaged to yield a mean number of positive cells
per high-powered field. The photomicrographs shown are
representative results of multiple patients in the indicated
cohort.
Ayers et al.
TABLE 1. Patient demographics.
Diagnosis
Control
CRSsNP
Age (years)
Race
Gender
Diagnosis
Age (years)
Race
Gender
61
W
F
CRSwNP
36
W
M
39
H
M
7
O
M
47
W
F
49
AA
F
56
AA
M
39
O
F
44
W
F
58
W
M
56
AA
M
40
W
M
43
AA
M
36
AA
F
57
W
M
19
AA
F
34
W
F
AFRS
18
W
M
31
W
F
16
W
M
66
W
F
17
AA
M
36
AA
F
19
W
M
44
W
M
13
AA
F
64
W
F
20
W
M
45
W
F
20
AA
M
AA = African American; AFRS = allergic fungal rhinosinusitis; CRSsNP = chronic rhinosinusitis without nasal polyps; CRSwNP = chronic rhinosinusitis with nasal polyps; F
= female; M = male; O = other; W = white.
Sinus tissue lysate preparation
25
Tissue lysates were prepared as described. Briefly, mucosal tissue samples were homogenized in a solution of
tissue protein extraction reagent, T-PER and protease inhibitor (Thermo Scientific, Rockford, IL). Homogenates
were centrifuged and the supernatant was collected and
stored at −80◦ C until use. Total protein concentration of
each sample was determined using a bicinchoninic acid assay (Thermo Scientific).
Determination of sinus chemokine levels
Levels of the DC chemoattractants CCL2 (eBioscience, San
Diego, CA) and CCL20 (R&D Systems, Minneapolis, MN)
were determined by enzyme-linked immunosorbent assay
(ELISA) per the manufacturers’ instructions. Protein concentrations were normalized by dividing the chemokine
protein present by total protein concentration for each sample and were expressed as picograms/milligrams of total
protein.
Statistical analysis
Statistical analysis was conducted using GraphPad Prism
5.02 software. A 1-way analysis of variance (ANOVA) with
post hoc unpaired Student’s t test was used to determine statistically significant differences between levels of infiltrating
immune cells and chemokine protein levels between patient
cohorts.
Results
DC markers CD209, CD80, and CD86 are upregulated in the sinus tissue of CRSwNP and AFRS
The objective of this study was to examine the presence of
mature DCs in the sinus mucosa in various forms of CRS.
Specifically examined was the DC-specific marker CD209
(DC-SIGN) as well as the DC costimulatory molecules
CD80 and CD86. In sinus tissue specimens, control patients demonstrated almost little to no staining for any of
the 3 DC markers. CD209 showed increased numbers of
positively-staining cells in AFRS and CRSwNP compared to
controls (p = 0.0001 and p = 0.0006 respectively). Levels
of CD209 staining were also significantly higher in CRSwNP and AFRS vs CRSsNP (p = 0.01 and p = 0.001,
respectively). CD209 expression in CRSsNP was increased
compared to control; however, this was not statistically
significant (p = 0.255) (Fig. 1). AFRS and CRSwNP sinus
specimens also displayed elevated CD80 staining (p = 0.01
and p = 0.01, respectively) as well as CD86 staining (p =
0.01 and p = 0.04, respectively) when compared to control, indicating the presence of mature DCs throughout the
mucosa. Staining for CD80 and CD86 in CRSsNP showed
no significant difference compared to controls (p = 0.11
and p = 0.07, respectively) (Fig. 2). In addition, there was
no significant difference between CRSwNP and AFRS for
any of the 3 DC markers. These results show that there are
increased numbers of DCs in the sinus mucosa of AFRS
and CRSwNP, but not a significantly increased number of
DCs in CRSsNP.
DC chemokines CCL2 and CCL20 are upregulated
in the sinus tissue of CRSwNP and AFRS
After observing increased numbers of DCs present in the
sinus tissue of CRSwNP and AFRS, we investigated if elevated local chemoattractant production was a possible
mechanism for DC recruitment. CCL2 and CCL20 were
International Forum of Allergy & Rhinology, Vol. 1, No. 4, July/August 2011
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Increased DCs in CRSwNP and AFRS
FIGURE 1. Immunohistochemical staining of sinus mucosa from control, CRSsNP, CRSwNP, and AFRS patients. Representative staining shown for (A-D)
isotype control, (E-H) CD209, (I-L) CD80, and (M-P) CD86. Positive staining is identified by arrows in the respective photomicrograph (magnification of all
samples, × 40). Black bars indicate 25 μm. AFRS = allergic fungal rhinosinusitis; CRSsNP = chronic rhinosinusitis without nasal polyposis; CRSwNP = chronic
rhinosinusitis with nasal polyposis.
examined, as both have the capacity to recruit immature
DCs as well as monocytes, and can be derived from epithelial cells, which are abundant in the sinus mucosa.17 As
shown in Figure 3A, CRSwNP and AFRS displayed CCL2
levels that were significantly higher than controls (p = 0.04
and p = 0.007, respectively). CCL2 levels in CRSwNP and
FIGURE 2. Quantitative analysis of positive staining (A) CD209, (B) CD80,
and (C) CD86 cells/field in sinus mucosa of patients designated as controls, CRSsNP, CRSwNP, and AFRS. Data shown are mean numbers of cells
per high-powered field, with dots representative of individual patient results. Statistics shown are the result of an unpaired t test between indicated
groups. AFRS = allergic fungal rhinosinusitis; CRSsNP = chronic rhinosinusitis without nasal polyposis; CRSwNP = chronic rhinosinusitis with nasal
polyposis.
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International Forum of Allergy & Rhinology, Vol. 1, No. 4, July/August 2011
AFRS were also significantly higher compared to CRSsNP
(p = 0.04 and p = 0.01, respectively). CRSsNP displayed no
difference in the levels of CCL2 when compared to controls.
Sinus lysate protein levels of another DC chemoattractant,
CCL20, were also examined (Fig. 3B) and followed a similar pattern as CCL2. Levels of CCL20 were significantly
higher in CRSwNP and AFRS vs control (p = 0.02 and
p = 0.0029). CCL20 levels in CRSwNP and AFRS were
also significantly higher than in CRSsNP (p = 0.007 and
p = 0.0004). There were no significant differences between
AFRS and CRSwNP for expression of CCL2 or CCL20.
Taken together, these data demonstrate that CRSwNP and
AFRS display elevated levels of DC chemoattractants in the
sinus mucosa.
FIGURE 3. Quantitative analysis of DC-specific chemokines in sinus tissue
lysates. (A) CCL2 and (B) CCL20 within sinus tissue lysate samples determined by ELISA. Statistics shown are the result of an unpaired t test between
indicated groups. DC = dendritic cell; ELISA = enzyme-linked immunosorbent assay.
Ayers et al.
FIGURE 4. Immunohistochemical staining of sinus mucosa from control, CRSsNP, CRSwNP, and AFRS patients. Representative staining for (A-D) isotype
control, (E-H) CCR2, and (I-L) CCR6. Positive staining is identified by arrows in the respective photomicrograph (magnification of all samples, × 40). Black bars
indicate 25 μm. AFRS = allergic fungal rhinosinusitis; CRSsNP = chronic rhinosinusitis without nasal polyposis; CRSwNP = chronic rhinosinusitis with nasal
polyposis.
DC chemokine receptors CCR2 and CCR6 are
upregulated in the sinus tissue of CRSwNP
and AFRS
We further tested our hypothesis on possible DC recruitment by determining the expression of the CCL2 and
CCL20 chemokine receptors, CCR2 and CCR6, respectively (Fig. 4). In sinus tissue, control patients showed
limited staining for either of the chemokine receptors. Alternatively, in AFRS and CRSwNP sinus mucosa, there were
elevated numbers of CCR2-positive and CCR6-positive
cells. As shown in Figure 5, quantification of staining by
the mean number of positive cells per field demonstrated increased expression in both AFRS and CRSwNP for CCR2
(p = 0.01 and p = 0.01) and CCR6 (p = 0.01 and p =
0.01) compared to controls. CRSsNP expression of CCR2
and CCR6 was not significantly elevated compared to controls. This data demonstrates that there are elevated levels
of the DC chemokine receptors CCR2 and CCR6 in CRSwNP and AFRS, which appear to follow a similar pattern
of elevation as CCL2 and CCL20.
Discussion
DCs play a critical role in directing the Th1/Th2 immune
response, thereby implicating them in the pathophysiology
of CRS. In this study, we examined the DC infiltrate in
the sinus mucosa to determine if it was altered in CRSsNP,
FIGURE 5. Quantitative analysis of positive staining (A) CCR2 and (B) CCR6
cells/field in sinus mucosa of patients designated as controls, CRSsNP,
CRSwNP, and AFRS. Data shown are mean numbers of cells per highpowered field with dots representative of individual patient results. Statistics
shown are the result of an unpaired t test between indicated groups. AFRS =
allergic fungal rhinosinusitis; CRSsNP = chronic rhinosinusitis without nasal
polyposis; CRSwNP = chronic rhinosinusitis with nasal polyposis.
International Forum of Allergy & Rhinology, Vol. 1, No. 4, July/August 2011
300
Increased DCs in CRSwNP and AFRS
CRSwNP, and AFRS, and we investigated potential mechanism for observed differences. The results of this study
revealed that DCs are markedly increased in the sinonasal
mucosa of AFRS and CRSwNP, when compared to control
and CRSsNP. Increased in the sinus mucosa of CRSwNP
and AFRS were levels of the DC chemoattractants, CCL2
and CCL20, which corresponded with elevated numbers of
CCR2-positive and CCR6-positive cells. Interestingly, no
difference was observed in the number of DCs or levels
of DC chemoattractants between control and CRSsNP or
AFRS and CRSwNP.
Patients suffering from AFRS and CRSwNP display Th2skewed immune responses in infundibular mucosal specimens as evidenced by elevated number of mast cells,
eosinophils, and IgE + cells.2 On the other hand, patients
with CRSsNP typically display elevated levels of Th1 cytokines and moderate increases in Th2 mediators, resulting in a mixed neutrophilic, eosinophilic inflammatory
infiltrate.3,26 Furthermore, expression of CD80 and CD86
by DCs has been shown to be essential in the generation
of a Th2 immune response in mouse and human models
of allergic rhinitis.12,27 In our study, we observed increased
expression of CD80, CD86, and CD209 in AFRS and CRSwNP but not CRSsNP, which offers a possible explanation
for their similarities in Th2-skewed cytokine profile. A recent report by Kirsche et al.28 suggests that Th2-skewing
in CRSwNP is in fact DC-mediated; however, they propose
this occurs through decreased numbers of myeloid DCs. In
these studies, nasal DCs were identified by positive staining
using only 1 DC marker, CD1c.28 In the study described
herein, 3 DC markers and 2 DC chemokine receptors were
examined, thus giving the total numbers of DCs, including
both myeloid and plasmacytoid, which may account for the
differences in DC numbers.
Recruitment of DCs has been shown in multiple models to involve CCL2/CCR2 and CCL20/CCR6.29,30 In our
studies it was observed that similar to alterations in DC
numbers, CCL2 and CCL20 were elevated in AFRS and
CRSwNP compared to control and CRSsNP. These elevations in chemokines corresponded with increased numbers
of CCR2-positive and CCR6-positive cells in CRSwNP and
AFRS. This abnormal chemokine expression by airway epithelial cells offers a plausible explanation for the increase
in the number of DCs present, and the excessive Th2 response seen in patients with AFRS and CRSwNP.
As with the number of DCs and DC-specific chemokines,
numbers of CCR2 receptor–positive and CCR6 receptor–
positive cells was elevated in CRSwNP and AFRS compared
to control or CRSsNP. This suggests that alterations in locally produced chemokine levels may be involved in recruiting excessive numbers of DCs in patients with AFRS and
CRSwNP. It should be noted, however, that further studies
are needed to determine if there is a cause and effect relationship between the precise cellular source and expression
of these chemokines and elevated DC migration in CRSwNP and AFRS. Previous studies in the lower airway have
demonstrated that respiratory epithelial cells are sources of
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International Forum of Allergy & Rhinology, Vol. 1, No. 4, July/August 2011
both CCL2 and CCL20.31,32 Furthermore, we have observed that in the upper respiratory tract human sinonasal
epithelial cells are capable of producing both of these factors. Additional studies remain to determine the mechanism
by which select DC chemokines are elevated in CRSwNP
and AFRS. One possible means by which chemokine production is elevated may be through induction by Toll-like
receptors (TLRs), which can stimulate CCL2 and CCL20
production.33–35 Previous studies by our laboratory as well
as several others have demonstrated TLR expression in the
nasal mucosa,16,36–38 though its exact role in regulating
chemokine production in CRSwNP and AFRS remains to
be determined.
While both AFRS and CRSwNP are Th2-skewed and
can be grouped into the broader classification of CRS, they
may have differing immunopathogeneses. In both atopic
and nonatopic CRSwNP and AFRS we observed similar elevations in infiltrating DCs and DC chemoattractants. This
would suggest that other mechanisms besides allergic status
are driving the Th2 skewing associated with CRSwNP and
AFRS. These observations suggest that DCs may be contributing to the Th2 immune skewing observed in the AFRS
and CRSwNP patient population, though additional investigation is still warranted. For atopic patients such as AFRS,
alterations in DC numbers and DC chemokines may be related to the patients to hypersensitive responses to fungal
antigens. This would be similar to what is seen in patients
with allergic rhinitis and allergic asthma.13,15 However,
atopic status alone does not account for increased numbers
of DCs and DC chemoattractants in CRSwNP. For example, of the CRSwNP patients whose CD209 + cells were
examined in the sinus mucosa, all were found to be elevated compared to control. Of these patients, 3 of 6 were
determined to be nonatopic with the other 3 testing positive for allergies. Similarly, no differences were observed
in the number of DCs or DC chemoattractants between
nonatopic and atopic CRSwNP. While this study did not
have enough nonatopic CRSwNP patients to fully investigate the role of atopy, this is an area for further study with
a larger numbers of patients. These studies would suggest
while allergic status may play an important role in promoting elevating numbers of Th2-biased DC in numerous
disease states, other equally contributing mechanisms result
in a similar Th2-skewed phenotype in CRSwNP. In addition, studies to examine the therapeutic potential of DC
modulation in Th2 skewing associated with CRSwNP and
AFRS merits further investigation.
Conclusion
The findings presented here demonstrate that CRSwNP,
including AFRS, have increased numbers of DCs and DC
chemoattractants in the sinus mucosa compared to control
and CRSsNP. These changes in DCs numbers represent a
potential mechanism for the differing immunopathogenesis
between CRSwNP and CRSsNP.
Ayers et al.
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presence, allergic, nasal, rhinosinusitis, mucosal, fungal, cells, sinus, dendriticum, chemokine, increase, polyps, chronic
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