The Journal of International Medical Research

2010; 38: 593 – 601

T-lymphocyte Subpopulations and B7-H1/

PD-1 Expression in Nasal Polyposis
LP ZHANG1,*, L LIN1,*, CQ ZHENG1 AND GY SHI2
1
Department of Otolaryngology, Head and Neck Surgery, The Eye and Ear, Nose and Throat
Hospital of Fudan University, Shanghai, China; 2Flow Cytometry Laboratory, Shanghai Jiao
Tong University, Shanghai, China

T-lymphocyte subpopulations and B7- compared with lymphocytes from the

H1/programmed death-1 (PD-1) positive
lymphocytes infiltrating nasal polyps were
evaluated in 17 patients with chronic
sinusitis with nasal polyposis. Peripheral
blood samples were also obtained from the
patients and from 11 healthy controls. The
CD4+, CD8+, CD3+, CD19+, B7-H1+ and PD-1+
lymphocyte populations were measured
using flow cytometry. Lymphocytes from
nasal polyps had significantly fewer CD4+
but significantly more CD8+ T-cells
peripheral blood of patients and controls.
The percentages of CD19+/B7-H1+ B-cells
and of CD3+/PD-1+ T-cells were significantly
higher in the nasal polyp samples than in
those from peripheral blood of patients and
controls. Changes in the T-lymphocyte
subpopulations and in the up-regulation of
B7-H1 and PD-1 in lymphocytes infiltrating
nasal polyps may be involved in the
development of the chronic inflammation
associated with nasal polyposis.

KEY WORDS: CHRONIC SINUSITIS; NASAL POLYPS; T-LYMPHOCYTES; B-LYMPHOCYTES; CO-STIMULATORY

MOLECULES; B7-H1; PROGRAMMED DEATH-1 (PD-1)

Introduction nasal polyposis (CRSwNP) is thought to

Bilateral nasal polyposis is a form of chronic
sinusitis characterized by chronic
inflammatory disease of the mucosa of the
nasal cavity and paranasal sinuses.1 The
overall prevalence of nasal polyposis in the
general population ranges from 1% to 4%.1
Quality of life for nasal polyposis patients is
worse than for patients with hypertension,
migraine, angina pectoris, or head and neck
cancer.2 Although some hypotheses exist for
how nasal polyposis develops, the
aetiopathologenetic mechanisms of the
disease remain controversial.1,3
The pathogenesis of chronic sinusitis with
*LP Zhang and L Lin contributed equally to this work.
involve persistent inflammation of the nasal
mucosa due to infiltration by eosinophils
and other cell types (lymphocytes, mast cells,
basophils and neutrophils).1 Nasal polyposis
is histologically characterized by respiratory
epithelium covering oedematous stroma,
which is infiltrated by inflammatory cells.1
It has been shown that eosinophils and
lymphocytes are the most common
inflammatory cells in nasal polyposis.4 T-
lymphocytes are central to the development
of sinonasal inflammation. The initiation
and regulation of nasal inflammatory
responses are absolutely dependent on T-
lymphocyte recruitment, activation and
cytokine secretion, which may contribute to

593
 LP Zhang, L Lin, CQ Zheng et al.
T-lymphocyte subpopulations and B7-H1/PD-1 expression
eosinophil recruitment and activation.5 The
factors that regulate these aspects of T-cell
function are not completely understood, but
may include engagement of T-cell-specific
accessory molecules.
For efficient T-cell activation, T-cells
require both a T-cell receptor-mediated
antigen (Ag)-specific signal and co-
stimulatory signals provided by antigen-
presenting cells (APCs). Several different
types of leucocytes can act as APCs,
including dendritic cells, macrophages and
B-cells. The B7 family of molecules provides
signals that are critical both for stimulating
and for inhibiting T-cell activation, and
interaction between B7 and CD28 may
determine whether a T-cell response
develops.6 T-cell activation occurs as the
result of a balance between positive and
negative signals. The inducible co-stimulator
molecule and CD28 are positive co-
stimulatory receptors that interact with the
ligands of the B7 family present on APCs and
are essential for the activation and
proliferation of antigen-specific T-cells.6 In
contrast, negative signals through cell
surface molecules, such as cytotoxic T-
lymphocyte antigen 4 and programmed
death-1 (PD-1), inhibit T-cell activation or
induce apoptosis.6
Several members of the B7 family have
now been identified. One of these, B7-H1,
binds to the PD-1 receptor and their
interaction down-regulates T-cell
activation.6,7 PD-1 is a type I transmembrane
receptor that is expressed on activated T- and
B-cells; like cytotoxic T-lymphocyte antigen-
4, PD-1 contains an immunoreceptor
tyrosine-based inhibitory motif in its
cytoplasmic region and it acts as a negative
regulator of lymphocyte function.6
Several studies support the concept that
the B7-H1/PD-1 pathway plays an important
immunoregulatory role in the chronicity of
594
inflammatory disorders.6,7 In addition,
CRSwNP is considered to be an ultimate
manifestation of chronic inflammation;
therefore, the B7-H1/PD-1 pathway may
contribute to CRSwNP. Although Kim et al.8
have studied B7-H1 expression in nasal
epithelial cells, very few studies have
examined the expression of the B7-H1/PD-1
pathway in nasal polyposis lymphocytes.9
The aim of the present study was to
determine whether there were changes in the
T-lymphocyte subpopulations and levels of
B7-H1 and PD-1 positive lymphocytes
infiltrating nasal polyps, which may
contribute to the development of the chronic
inflammation associated with nasal
polyposis.
Patients and methods
PATIENTS
This prospective study was conducted in
CRSwNP patients attending the Department
of Otolaryngology, Head and Neck Surgery,
The Eye and Ear, Nose and Throat Hospital
of Fudan University (Shanghai, China). The
patients were enrolled sequentially between
January and December 2008 and had been
referred to this centre for endoscopic sinus
surgery because of insufficient response to
conservative treatment regimens. During the
same time period, healthy sex- and age-
matched subjects were used as a control
group. All participants gave written
informed consent using a protocol approved
by the Review Board of Fudan University and
all studies were conducted in compliance
with the Declaration of Helsinki of 1975,
revised 1983.
The diagnosis of CRSwNP was made
according to the criteria of the European
guidelines of 2007 (EP3OS 2007) and was
based on patient history, clinical
examination, nasal endoscopy and sinus
computed tomography (CT) scanning.1 A
 LP Zhang, L Lin, CQ Zheng et al.
T-lymphocyte subpopulations and B7-H1/PD-1 expression
modified Lund and Mackay CT score of ≥ 18
was required for inclusion in this study.10
None of the patients had received oral or
intranasal steroids for at least 4 weeks before
surgery. Patients with allergy, asthma,
aspirin intolerance, cystic fibrosis, an
immunocompromised status, or ciliary
dyskinesia were excluded from the study. The
atopic status was assessed by skin prick tests
to common inhalant allergens and
radioallergosorbent tests.
Normal mucosal biopsy controls were not
taken because a previous study11 had
demonstrated that the number of
lymphocytes obtained is so small that
reliable studies cannot be accurately
performed with these samples. Peripheral
blood lymphocytes from the same CRSwNP
patients were studied and compared with
nasal polyposis lymphocytes. In addition,
the peripheral blood lymphocytes of the
healthy controls were studied and compared
with those of the patients with CRSwNP.
HISTOLOGICAL TECHNIQUES
All tissues were fixed overnight in 10%
formalin and then subjected to routine
paraffin embedding. Sections 4 µm thick
were cut and placed on slides before being
stained for histological examination using
haematoxylin and eosin.
FLOW CYTOMETRY
Blood was drawn from a peripheral vein of
each subject into heparinized syringes and
processed on the day of collection. The
following antibody combinations were
added to 100 µl of peripheral blood and
incubated for 30 min at room temperature in
the dark: fluorescein isothiocyanate (FITC)-
conjugated CD4 and phycoerythrin (PE)-
conjugated CD8 (BD Biosciences, San Jose,
CA, USA); FITC-conjugated CD19 (BD
Biosciences) and PE-conjugated B7-H1
595
(eBioscience, San Diego, CA, USA); FITC-
conjugated CD3 (BD Biosciences) and
allophycocyanin (APC)-conjugated PD-
1(eBioscience); or isotype immunoglobulin
(Ig)G-PE (eBioscience). Red blood cell lysis
buffer (eBioscience; 4 ml) was added to the
samples and incubated at room temperature
for 10 min. Cells were harvested by
centrifugation for 5 min at 300 g and the
supernatant was discharged. Cells were
washed with 10 ml of 0.01 M phosphate-
buffered saline (PBS) at pH 7.4, harvested by
centrifugation for 5 min at 300 g, and the
cell pellet was then resuspended in 1%
formaldehyde/0.01 M PBS for storage prior to
fluorescence-activated cell sorting (FACS)
analysis.
To obtain tissue lymphocytes, fresh
surgical specimens of nasal polyps were
immediately incubated in RPMI 1640
medium (Gibco®, Carlsbad, CA, USA) with
10% fetal calf serum (Gibco®) and digested
with 0.25% trypsin for 10 min. The nasal
polyp tissues were then cut into small pieces
with dissecting scissors. Single-cell
suspensions were prepared by squashing
with 350 micron opening nylon mesh, and
cells were harvested by centrifugation for 5
min at 300 g. Cells were labelled with
antibodies using the same methods as
already described for peripheral blood cells
and then resuspended in 0.01 M PBS before
FACS analysis.
Analyses were performed on a
FACScalibur™ flow cytometer (BD
Biosciences) using CellQuest™ software (BD
Biosciences). For each sample, at least 10 000
events were collected and histograms were
generated.
STATISTICAL ANALYSES
The means ± SE for the data were calculated
and statistical analyses were performed
using the SPSS® statistical package, version
 LP Zhang, L Lin, CQ Zheng et al.
T-lymphocyte subpopulations and B7-H1/PD-1 expression

12.0 (SPSS Inc., Chicago, IL, USA) for
Windows®. The χ2 test and Student’s t-test
were used for comparison between groups. If
variances in groups were not homogeneous,
the non-parametric Mann–Whitney U-test
was used. A P-value < 0.05 was considered to
be statistically significant.
Results
A total of 17 patients with CRSwNP and 11
sex- and age-matched healthy control
subjects were included in this study. Based on
the histological characteristics, nine CRSwNP
cases were of the eosinophilic type (Fig. 1A)
and eight cases were of the chronic
inflammatory type characterized by a large
number of inflammatory cells, mainly
lymphocytes with fewer eosinophils (Fig. 1B).
Standard flow cytometric plots of T-cell
and B-cell subpopulations and B7-H1 and
PD-1 positive lymphocytes from nasal polyp
and peripheral blood samples from CRSwNP
patients and from healthy controls are
shown in Fig. 2A. The mean ± SE percentage
of CD4+ cells in nasal polyps and peripheral
blood from CRSwNP patients and in
peripheral blood from healthy control
samples was 24.01 ± 9.20%, 39.61 ± 7.41%
and 36.25 ± 5.87%, respectively (Fig. 2B), for
CD8+ cells the values were 37.86 ± 6.79%,
28.71 ± 4.30% and 30.50 ± 3.11%,
respectively (Fig. 2C), and the CD4/CD8
ratios were 0.70 ± 0.43, 1.42 ± 0.40 and 1.20
± 0.20, respectively. The nasal polyp
lymphocyte samples from CRSwNP patients
had significantly fewer CD4+ T-cells but
significantly more CD8+ T-cells in
comparison with the peripheral blood
samples from patients and healthy controls
(P < 0.01). There were no significant
differences in the numbers of CD4+ or CD8+
cells in peripheral blood from patients versus
healthy controls.
The mean ± SE percentage of CD19+ B-
cells expressing B7-H1 in nasal polyps and
peripheral blood from CRSwNP patients and
in peripheral blood from healthy control
samples was 13.32 ± 6.26%, 4.68 ± 1.8% and
0.98 ± 0.28%, respectively (Fig. 2D). The
mean ± SE percentage of CD19+ B-cells
expressing B7-H1 was significantly higher in
nasal polyp samples than in the peripheral
blood of the patient and healthy control
samples (P < 0.01) and was also significantly

50 µm 50 µm

FIGURE 1: Typical histological features of nasal polyposis samples from patients with
chronic sinusitis with nasal polyposis: (A) eosinophilic type (nine patients in this
study); and (B) chronic inflammatory type characterized by a large number of
inflammatory cells, mainly lymphocytes with fewer eosinophils (eight patients in this
study) (haematoxylin and eosin, scale bars 50 µm)

596
 LP Zhang, L Lin, CQ Zheng et al.
T-lymphocyte subpopulations and B7-H1/PD-1 expression

A Peripheral blood Peripheral blood Nasal polyp B

Healthy controls CRSwNP patient CRSwNP patient 50
104 104 104

CD4+ T-cells (%)

28.96% a 30.83% b 43.69% c 40

103 103 30 **
103
20
CD8 PE

CD8 PE

CD8 PE
+ +
CD4 CD8 10 2
10 2 10 2
10

10 1 1 10 1 0
10 16.44%
42.51% 40.56% C 50
100 100 100 **

CD8+ T-cells (%)

100 101 102 103 104 100 101 102 103 104 100 101 102 103 104 40
CD4 FITC CD4 FITC CD4 FITC
30

20
104 104 104
d e f 10
0.82% 2.97% 8.59%
103 103 103 0
B7-H1 PE

B7-H1 PE

B7-H1 PE
D 20
CD19+B7-H1 102 102 102

B7-H1 B-cells (%)

B-cells **
15
101 101 101
10
100 100 100 ††
100 101 102 103 104 100 101 102 103 104 100 101 102 103 104 5
CD19 FITC CD19 FITC CD19 FITC
0
104 104 104 E 50
g h i **
103 5.02% 103 11.35% 103 60.47% 40

PD-1+ T-cells
PD-1 APC

PD-1 APC

PD-1 APC

30
CD3+PD-1+ 102 102 102
20
T-cells ††

101 101 101 10

0
100 100 100 Nasal polyp Peripheral Peripheral
100 101 102 103 104 100 101 102 103 104 100 101 102 103 104 CRSwNP blood blood
CD3 FITC CD3 FITC CD3 FITC patient CRSwNP Healthy
patient controls

FIGURE 2: (A) Sample flow cytometric plots of T-cell subpopulations and B7-H1 and
programmed death-1 (PD-1) positive lymphocytes from standard patient samples.
The mean percentage ± SE of (B) CD4+ T-cells was significantly lower and of (C) CD8+
T-cells was significantly higher in nasal polyp samples from patients with chronic
sinusitis with nasal polyposis (CRSwNP) compared with peripheral blood from
CRSwNP patients and healthy controls (**P < 0.01). The mean percentage ± SE of (D)
CD19+ B7-H1+ B-cells expressing B7-H1 and of (E) CD3+ PD-1+ T-cells expressing PD-
1 was significantly higher in nasal polyp samples from CRSwNP patients compared
with peripheral blood from CRSwNP patients and healthy controls (**P < 0.01), and
also significantly higher in peripheral blood samples from CRSwNP patients compared
with healthy controls (††P < 0.01) (APC, allophycocyanin-conjugated; PE,
phycoerythrin-conjugated; FITC, fluorescein isothiocyanate-conjugated)

higher in peripheral blood samples from the nasal polyp samples than in the
CRSwNP patients than in peripheral blood peripheral blood of the patient and healthy
from healthy control samples (P < 0.01). control samples (P < 0.01), and was also
The mean percentage ± SE of CD3+ T-cells significantly higher in peripheral blood
expressing PD-1 in nasal polyps and samples from CRSwNP patients than in
peripheral blood from CRSwNP patients and peripheral blood from healthy control
in peripheral blood from healthy control samples (P < 0.01).
samples was 38.17 ± 12.18%, 10.72 ± 2.98%
and 4.21 ± 1.27%, respectively (Fig. 2E). The Discussion
mean ± SE percentage of CD3+ T-cells Although multiple host and environmental
expressing PD-1 was significantly higher in factors have been implicated in the aetiology

597
 LP Zhang, L Lin, CQ Zheng et al.
T-lymphocyte subpopulations and B7-H1/PD-1 expression
of idiopathic CRSwNP and the aetiology
remains a matter of vigorous debate,12 it is
clear that nasal polyposis is primarily a
disorder of persistent inflammation. Since
inflammation is normally a self-limiting
process, ‘chronicity’ of inflammation results
from either the persistence of a stimulus, for
example a micro-organism or allergen, or
from dysregulation of the endogenous anti-
inflammatory mechanisms that normally
co-ordinate resolution. The sinonasal cavity
is constantly exposed to foreign particulates,
antigens and potential pathogens such as
viruses, fungi and bacteria, because it is the
first site of contact for many airborne
particulates and micro-organisms entering
the body. Although many innate immune
mechanisms exist to eliminate potential
pathogens before they reach the epithelial
cell surface, antigens encountered in the
nasal lumen are routinely sampled by the
mucosa for evaluation by the adaptive
immune system. In the sinonasal tract, the
acquired immune response involves the
activation of antigen-specific B- and T-
lymphocytes which initiate and maintain
the local immune response.11 Once the
immune responses targeting the invading
pathogen are established, the host cells
usually up-regulate a set of regulatory
molecules that protect themselves from
further or unwanted injury by those immune
responses that were originally aimed at the
immunogenic antigens. As discussed
previously, current studies have focused on
identification of the predominant,
presumably microbial, agents which initiate
CRSwNP rather than searching for putative
defects in the host response that might
contribute to the development of
CRSwNP. 3,13,14
Emerging evidence has
suggested that, in many instances, aberrant
host immune responses, rather than
pathogen-specific toxins, are the real
598
pathogenic factors that cause the disease or
function as its risk factors.6,7 In this context,
it is critical to identify the defects in the
immune response of patients, in addition to
identifying unique environmental agents
that contribute to the development of
CRSwNP.
One of the B7 family members of co-
stimulatory molecules that regulate T-cell
responses is B7-H1 (also called CD274 or PD-
L1). Although the expression of B7-H1 is
limited to a small fraction of haematopoietic
cells, it is largely inducible in various non-
lymphoid tissues and cells.6,8,9 The CD28
family member, PD-1, is inducibly expressed
on activated T-cells, B-cells and monocytes,
and it is likely that it regulates these cell
types.6 Although the precise role of the B7-
H1/PD-1 pathway in the regulation of T-cell
function in inflammation and
autoimmunity remains a topic for further
investigation, the B7-H1/PD-1 pathway has
consistently been reported to play an
important role in regulating T-cell activation
and peripheral tolerance.6,15 – 17
In the present study, B7-H1 and PD-1 were
significantly up-regulated in lymphocytes
from nasal polyps of CRSwNP patients in
comparison with lymphocytes from the
peripheral blood of both CRSwNP patients
and healthy controls. The up-regulation of
B7-H1 on CD19+ B-cells, and PD-1 on CD3+ T-
cells suggests that the B7-H1/PD-1 pathway
may act to modulate immune responses in
CRSwNP patients. Currently, CD19 is the
main marker used to identify human B-cells
that can act as APCs. B-cells do not normally
express co-stimulatory molecules such as B7-
H1, but their expression is induced by
pathogenic exposure.6 Although the role of
infectious agents in the development of
CRSwNP remains unclear, studies have
implicated toxigenic Staphylococcus aureus
bacteria and Alternaria fungi in CRSwNP
 LP Zhang, L Lin, CQ Zheng et al.
T-lymphocyte subpopulations and B7-H1/PD-1 expression
pathogenesis.3,18 The peripheral blood
lymphocytes from patients with CRS release
more interferon-γ (IFN-γ) when cultured with
fungal extracts than normal controls.13
Douglas et al.19 have further demonstrated
that staphylococcal superantigen type B
(SEB) increased the expression of IFN-γ in
peripheral blood lymphocytes, and this effect
was magnified by the addition of both SEB
and fungal extracts to the culture medium.
Lymphocytes producing IFN-γ have been
identified in nasal polyposis.5,11 IFN-γ is a
multifunctional cytokine and a strong
inducer of B7-H1 expression.16 It has been
found that B7-H1 expression of primary
nasal epithelial cells can be selectively
induced by IFN-γ and that human rhinovirus
16 infection induced the expression of B7-H1
on human airway epithelial cells.8,9
Together, these observations raise the
possibility that secretion of high levels of
IFN-γ by activated T-cells upon stimulation
increases B7-H1 levels on the surface of B-
cells and causes a down-regulation of T-cell
responses, resulting in a negative feedback
loop in nasal polyposis. Molecular defects in
the B7-H1/PD-1 pathway could, therefore, be
responsible for impairment of the
immunoregulatory balance of the
inflammatory response in nasal polyposis
patients. The reason for this phenomenon is
not clear, but data from the present study
suggest that nasal polyposis could represent
a state in which B7-H1 and PD-1 are induced
as a response to chronic inflammation
within the nasal mucosa. We surmise that
significant B7-H1/PD-1 co-stimulatory
molecule up-regulation in CRSwNP patients
may eventually delay the T-cell response,
result in a failure to clear pathogens from
the sinuses and lead to a chronic
inflammatory state due to bacterial, viral or
fungal re-exposure.
Another interesting result of the present
599
study was the difference in the percentages of
B-cells expressing B7-H1, T-cells expressing
PD-1 and CD4/CD8 ratios between
lymphocytes samples taken from nasal
polyps and from peripheral blood in
CRSwNP patients. These were similar to
previously published findings that showed
that there were significant differences
between levels of cytokines produced by the
T-cells from nasal polyps and peripheral
blood.5,11 The organization of the secondary
lymphoid tissue within the nasal polyp tissue
may contribute to the dissociation between
the total IgE, IgG and IgA antibodies in the
serum and nasal polyp tissue.20,21 Nasal
polyposis is a unique mucosal chronic
inflammation of nasal polyp tissue in which
a specialized local immune subsystem may
exist. The peripheral blood lymphocytes
probably reach the nasal polyp tissue. The
lymphocytes of the local mucosal immune
system also reach the lamina propria of the
polyps as a result of migration of lymphoid
cells from mucosa-associated lymphoid
tissue (MALT), which comprises the
adenoids, paired palatine tonsil, and other
smaller lymphoid structures of Waldeyer’s
pharyngeal ring.22 The mucosal immune
system is more complex than its systemic
counterpart. MALT is populated by
phenotypically and functionally distinct B-
cells, T-cells and accessory cell
subpopulations from those in systemic
lymphoid tissues.22 MALT also has limited
recirculation of lymphoid cells between
mucosal sites.23 Data from the present study
were in agreement with the concept of
Bernstein et al. 11 that nasal polyp
lymphocyte subpopulations may originate
from both the local mucosal immune
system and from random migration of
peripheral blood lymphocytes. These
findings also suggest that a specialized local
mucosal immune subsystem may be
 LP Zhang, L Lin, CQ Zheng et al.
T-lymphocyte subpopulations and B7-H1/PD-1 expression
present in nasal polyps.
In conclusion, the present study, which
was based on a small number of subjects
with severe bilateral diffuse nasal polyps,
demonstrated changes in the T-lymphocyte
subpopulations and up-regulation of B7-H1
and PD-1 in lymphocytes infiltrating the
nasal polyps. These changes may be
involved in development of the chronic
inflammation associated with nasal
polyposis. These results require confirmation
• Received for publication 15 October 2009 • Accepted subject to revision 22 October 2009
• Revised accepted 27 January 2010
Copyright © 2010 Field House Publishing LLP
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Author’s address for correspondence

Dr Chun Quan Zheng
Department of Otolaryngology, Head and Neck Surgery, The Eye, Ear, Nose and Throat
Hospital of Fudan University, 83 Fenyang Road, 200031 Shanghai, China.
E-mail: cqzheng@online.sh.cn

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