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Evidence of Dysregulated Cytokine Production by Sinus Lavage and Peripheral Blood Mononuclear Cells in Patients With Treatment-Resistant Chronic Rhinosinusitis
Harumi Jyonouchi, MD;
Sining Sun, DDS;
Hoa Le, BS;
Frank L. Rimell, MD
Arch Otolaryngol Head Neck Surg. 2001;127:1488-1494.
ABSTRACT
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Background Treatment-resistant chronic rhinosinusitis (CRS) imposes a clinical
challenge. Its pathogenesis may be associated with dysregulated immune/inflammatory
responses in the sinus.
Objective To evaluate production of types 1 and 2 T cytokines (interferon gamma
[IFN- ] and interleukin [IL] 5/IL-4, respectively) and regulatory/inflammatory
cytokines (IL-10, IL-12, and IL-18) by sinus lavage (SL) cells and peripheral
blood mononuclear cells (PBMCs) in patients with treatment-resistant CRS.
Methods Sample SL cells and PBMCs obtained from 19 patients with treatment-resistant
CRS were cultured with or without stimuli, and cytokine levels in the supernatant
were measured using enzyme-linked immunosorbent assay. Control PBMC samples
were obtained from 26 children.
Results Chronic otitis media was found in 15 patients. Neutrophils and/or epithelial
cells were dominant in SL cells. IFN-, IL-12p40, and IL-10 (>100 pg/mL)
were detected in SL cell cultures from 12, 9, and 8 patients, respectively.
Production of IL-12p40 and IL-18 by SL cells correlated positively with phytohemagglutinin
and IL-12p70 stimuli. In 12 patients, we detected IL-18 (>100 pg/mL) in SL
cell cultures without stimuli, whereas PBMCs produced little IL-18, irrespective
of stimuli. There was no correlation between cytokine levels produced by SL
cells and PBMCs, except for IL-12p40 produced using IL-18. Decreased IFN-
production by PBMCs was observed in 6 patients with CRS compared with controls,
but 4 of them had elevated IFN- production by SL cells. Production
of IL-12p40 by PBMCs was higher in 10 patients with CRS than in controls,
and 7 of these patients had lower IL-10 production, resulting in an increased
IL-12p40/IL-10 ratio.
Conclusions There is a role for locally produced regulatory cytokines in IFN-
production in the sinus in patients with treatment-resistant CRS. However,
aberrant cytokine production patterns by PBMCs can be detected at high frequency
in these patients, indicating that this can be used as a prognostic marker
for patients with CRS.
INTRODUCTION
CHRONIC rhinosinusitis (CRS) resistant to standard treatments imposes
a considerable clinical challenge. A few patients with treatment-resistant
CRS exhibit antibody (Ab) deficiency syndrome, but most reveal normal immune
functions by conventional immune workup (serum immunoglobulin [Ig] and IgG
subclass levels, immunophenotyping of lymphocytes, lymphocyte proliferative
responses, and Ab titers against common pathogens).1-2
Nevertheless, these patients continue to experience sinus inflammation requiring
prolonged courses of oral and intravenous antibiosis, anti-inflammatory medications
(nasal inhalers, leukotriene receptor antagonists, etc), and multiple surgical
procedures. They also frequently experience chronic otitis media and bronchitis
and/or asthma.1, 3-4
In these patients, there may be aberrant immune and inflammatory responses
occurring in the sinus, airway, and middle ear, but such abnormalities may
not be detected by conventional immune workup.
Recent progress in basic immunologic studies revealed an intricate immune
defense network mounted by innate and adaptive immunity. Innate immunity mounts
initial immune responses by recognizing pathogen-associated molecular patterns
shared by groups of microbial pathogens.5 These
patterns are recognized by pattern recognition receptors expressed by phagocytes
and natural killer cells, leading to production of soluble factors and augmentation
of phagocytosis and destruction of pathogens.5-6
Innate immunity plays a key role in subsequent adaptive immune responses by
inducing co-stimulatory molecules on antigen (Ag)-presenting cells, stimulating
proinflammatory cytokine production, and facilitating Ag processing. Cytokines
produced by innate immunity also partly determine subsequent T-cell differentiation.7 However, excessive inflammatory responses induced
by innate immunity could be harmful.
On Ag presentation, resting T cells are activated into the effector-stage
T-cell subsets characterized by their distinguished cytokine production patterns:
type 1 and type 2 (T1/T2) T cells.7-8
Type 1 responses induce phagocytic cell-mediated immune responses by producing
T1 cytokines (IFN-, interleukin [IL] 2, and tumor necrosis factor  )
and IgG1/IgG3 Abs that enhance opsonization.7-8
Type 2 responses induce eosinophil-mediated inflammatory responses by producing
T2 cytokines (IL-4, IL-5, and IL-13) and IgG4/IgE Abs.7-9
Type 1 and T2 responses counter-regulate each other, and imbalance of T1/T2
responses is implicated in the various disorders.8-9
Previously, we reported T1-dominant inflammatory responses in the sinus in
patients with nonatopic CRS as evidenced by increased production of IFN-
by sinus lavage (SL) cells.10 However, inappropriate
IFN- production could lead to persistent sinus inflammation. In patients
with lacuna immunodeficiency involving regulatory mechanisms of IFN-
production, clinical features may include treatment-resistant CRS.11
In this study, we address production of IFN- and its regulatory
cytokines by SL cells and peripheral blood mononuclear cells (PBMCs) in patients
with treatment-resistant CRS. The hypotheses to be tested were that we could
detect changes in the production of T1/T2 cells and their regulatory cytokines
by SL cells or PBMCs in patients with treatment-resistant CRS and that this
could serve as a prognostic biomarker. We assessed the production of IFN-
(a T1 cytokine), IL-4/IL-5 (T2 cytokines), IL-10 (a counter-regulatory cytokine),
and IL-12p40/IL-18 (cytokines that induce IFN- production) by SL cells
and PBMCs using findings from SL cell cytologic examination, the results of
microbial cultures, and clinical features.
PARTICIPANTS, MATERIALS, AND METHODS
STUDY POPULATION
We recruited 19 patients with treatment-resistant CRS (aged 3-18 years;
7 girls and 12 boys) who underwent sinus surgery, pressure equalization tube
placement plus sinus tap, or both at the Fairview University Medical Center,
Minneapolis, Minn. All patients had clinical signs of rhinosinusitis (facial
pain, sinus headache, nasal congestion [engorgement or swelling of the inferior
turbinates], discolored rhinorrhea, cough, etc) for more than 3 months; failed
more than 2 courses of intravenous antibiosis (>14 days) and at least 1 sinus
surgery; and had positive findings on multiple computed tomographic scans
of the sinus. All the participants underwent adenoidectomy before sinus surgery
or at the time of the first sinus surgery. However, sinusitis did not resolve
or recurred within 3 months of surgery in all patients. The clinical features
are summarized in Table 1. Antibiotic
therapy was discontinued 1 week before surgery. The study protocol was approved
by the institutional review committee of the University of Minnesota, Minneapolis,
and a signed written consent form was obtained before surgery. The presence
of asthma and allergic rhinitis was evaluated by history, physical examination,
prick skin test reactivity, or IgE Ab levels against common aeroallergens
(dust mites, grass/tree/ragweed pollens, cats, and molds, including Alternaria, Cladosporium, Aspergillus fumigatus, Epicoccum,
and Penicillium), and pulmonary function tests, including
responses to ß2 agonist or metacholine challenge (>12 years).12 Patients with CRS who have cystic fibrosis, known
primary or secondary immunodeficiency (including Ab deficiency syndrome),
or illness involving major organs were excluded from the study. Control peripheral
blood samples were obtained from 26 healthy children without asthma, allergic
rhinitis, or CRS.
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Table 1. Summary of Clinical Features and the Results of Sinus Cultures
in Study Participants*
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SAMPLE COLLECTION
Samples of SL cells were obtained by flushing the maxillary sinus through
an 18-gauge spinal needle attached to a collection trap via a 2-way stop.
This design allows flushing with instantaneous sample collection. Needle flushing
was performed under the inferior turbinate for each side in all patients and
before endoscopic sinus surgery, if performed. Sample collection was performed
after the induction of general anesthesia.
BACTERIAL AND FUNGAL CULTURE
Samples of SL cells were sent to the clinical microbiology laboratory
at the University of Minnesota for bacterial and fungal culture; bacteria
culture results were expressed as light, moderate, and heavy growth when the
bacterial growth was detected on the first, second, or third agar plate, respectively,
on which samples were streaked consequently without reapplying the sample
to an applicator.
NONSPECIFIC INFLAMMATORY PARAMETERS
The number of cells in SL samples was measured by trypan blue dye exclusion
in a hemocytometer. Then, 1 to 2 x 105 cells in 200 µL
of phosphate-buffered saline solution were cytospinned, dried, and stained
(Diff-Quick Giemsa stain; Baxter, McGraw Park, Ill). A single person (H.J.)
throughout the study evaluated the cytologic features of cytospinned samples.
IMMUNOPARAMETERS
Sinus lavage cells were filtered through coarse gauze to remove mucins
and tissue debris, spun down briefly, and washed once with phosphate-buffered
saline solution. Peripheral blood mononuclear cells were obtained by centrifuging
cells with Ficoll-Hypaque density gradient at 1500 rpm for 30 minutes at room
temperature. Sinus lavage cells (2 x 105 cells/mL) as well
as PBMCs (106 cells/mL) were cultured with or without stimuli in
RPMI 1640 supplemented for 4 days in a 5% carbon dioxide incubator, as reported
previously.10 We used mitogens (phytohemagglutinin
[PHA], 2 mg/L, and concanavalin A, 1 mg/L) (Sigma-Aldrich Corp, St Louis,
Mo) and dust mite extract (a mixture of Dermatophagoides
farinae and Dermatophagoides pteronyssinus
[5 mg/L of each]) (Greer Laboratories Inc, Lenoir, NC) as polyclonal and recall
Ag stimuli, respectively. Dust mite Ag was selected as a recall Ag because
most patients demonstrate responses to dust mite Ag in the assays of cytokine
production by PBMCs without seasonal variation (Prescott et al13
and H.J., unpublished observations, 2000). Levels of IFN- and IL-5
were measured as representative T1 and T2 cytokines, respectively. Levels
of IL-10, IL-12p40, and IL-18 were also measured as representative regulatory
cytokines for IFN- production; IL-12/IL-18 augments IFN- production,
and IL-10 suppresses it.14-16
Levels of IL-4 were also measured as a representative T2 cytokine, but we
detected little in the cultures of PBMCs and SL cells, partly owing to autocrine
consumption of IL-4 by T cells. Interleukin 12p70, a biologically functional
IL-12, was not measured because it is rapidly degraded into IL-12p40 and IL-12p35
and is difficult to detect when PBMCs are cultured with these stimuli.14-15 Cytokines (IFN-, IL-4, IL-5,
IL-10, IL-12p40, and IL-18) added to the culture medium without cells are
stable, and we recovered more than 90% of cytokines after 4 days' incubation.
All the cytokine levels except IL-18 were measured using enzyme-linked immunosorbent
assay sets (OptEIA; BD PharMingen, San Diego, Calif). Levels of IL-18 were
measured by using standards and Abs from R & D Systems, Minneapolis.
Briefly, appropriately diluted duplicate samples with the culture medium
or standards were added to the enzyme-linked immunosorbent assay plate (Nunc,
Naperville, Ill), precoated with the first Ab, and blocked with assay diluents.
Then the plate was incubated at room temperature for 2 hours, washed well,
and incubated with biotinylated second Ab and streptavidin–horseradish
peroxidase conjugate (100 µL/well) at room temperature for 1 hour. After
washing, the color was developed by adding substrate solution (tetramethylbenzidine,
100 µL/well) (DAKO, Carpinteria, Calif), and optical density at 450
nm was read, using optic density at 650 nm as a reference value. Intravariation
and intervariation in cytokine levels were less than 5%.
STATISTICS
The equality of 2 sets of data values was evaluated using the Mann-Whitney
test (2 sets of independent samples) or the Wilcoxon weighed ranks test (2
sets of related samples). Comparison of multiple values was performed using
the Kruskal-Wallis test. Correlation of 2 variables was assessed using the
Kendall  test. Differences with P<.05 were
considered statistically significant.
RESULTS
CLINICAL FEATURES
Clinical features revealed little atopic components in the study patients.
Although 4 of 19 patients had elevated IgE levels (>24 mg/dL) (Table 1), 2 of them were skin test nonreactive. Fifteen of 19 patients
experienced chronic otitis media (effusion >8 weeks), with no response to
pressure equalization tube before the development of CRS. Four patients with
chronic otitis media underwent mastoidectomy owing to mastoiditis.
CULTURE RESULTS
Bacterial cultures were positive in 18 of 19 patients tested. Bacterial
culture revealed heavy growth of Staphylococcus aureus
or coagulate-negative Staphylococcus species. Light
and moderate growth of a mixed bacterial flora (S aureus, coagulate-negative Staphylococcus species, Moraxella catarrhalis, -hemolytic streptococci, Haemophilus parainfluenzae, Corynebacterium, Neisseria species, Streptococcus
pneumoniae, Haemophilus haemolyticus, and Haemophilus influenzae) were found in 12 of 18 patients
with bacterial culture–positive CRS (Table 1). Fungal cultures were negative in all the study patients.
CYTOLOGIC FINDINGS
The number of SL cells recovered was variable (median, 0.30 cells; range,
0.10-5.76 x 106 cells). Cytologic examination showed that
neutrophils were most common (median, 69.6%; range, 11.3%-95.4%). Epithelial
cells were also found (median, 14.8%; range, 1.5%-74.5%). Eosinophils were
found in SL cell samples from 4 of 19 patients (maximum, 3.4%), but none of
them had elevated serum IgE levels.
CYTOKINE PRODUCTION BY SL CELLS
We10 reported previously that IFN-,
IL-4, IL-10, and IL-12p40 production levels by SL cells obtained from healthy
adults were below the detectable levels of the assay. We also found that SL
cells from healthy adults produce little IL-5 or IL-18 (<3.9 pg/mL). In
contrast, despite the low number of SL cells cultured (2 x 105 cells/mL), IFN- (>100 pg/mL) was detected with PHA or IL-12p70
in 14 (74%) of 19 patients (Table 2).
Interleukin 12p40 and IL-10 (>100 pg/mL) were detected in 12 (63%) and 8 (42%)
patients, respectively, with any of these stimuli. Of these patients, 7 and
5 revealed spontaneous IL-12p40 and IL-10 production (>100 pg/mL), respectively.
Eighteen of 19 patients produced IL-18, greater than 50 pg/mL, and 12 patients
(63%) produced IL-18, greater than 100 pg/mL, spontaneously (Table 2 and Figure 1).
The IL-5 and IL-4 levels were under the detectable levels. We found low IFN-
production (<3.9 pg/mL) in 4 patients despite elevated IL-12/IL-18 production
(>100 pg/mL).
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Table 2. Summary of Cytokine Production Patterns by SL Cells in Children
With Treatment-Resistant CRS*
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Figure 1. Spontaneous interferon gamma (IFN-),
interleukin (IL) 10, IL-12p40, and IL-18 production by cultured sinus lavage
cells from patients with treatment-resistant chronic rhinosinusitis. As given
in Table 2, several patients spontaneously
produced IL-12p40 and IL-18 at high levels. There was no correlation between
percentage of neutrophils or endothelial cells and the cytokine levels produced
spontaneously by sinus lavage cells.
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Levels of IL-18 produced by SL cells correlated positively with IL-12p40
levels in SL cell cultures stimulated with PHA and IL-12p70 (P<.02) (Figure 2). There
was no correlation between levels of other cytokines, irrespective of the
stimuli used. There was also no correlation between the cytokine levels produced
by SL cells and PBMCs, except for IL-12p40 levels stimulated by IL-18 (r = 0.67; P<.02).
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Figure 2. Significant positive correlation
between interleukin (IL) 12p40 and IL-18 levels produced by sinus lavage cells
when cells were stimulated with phytohemagglutinin (A) or biologically functional
IL-12 (IL-12p70) (B).
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CYTOKINE PRODUCTION BY PBMCs
Peripheral blood mononuclear cells from children with CRS produced less
IFN- than those from controls in the presence of concanavalin A, partly
because the cells of 5 patients with CRS produced lower IFN- levels
than the range observed in controls. One patient with CRS who had low IFN-
production had a signal transduction defect through the IL-12 receptor.11 However, we found elevated IFN- production
by SL cells in 4 of these 5 patients. In contrast, 6 (32%) of 19 patients
with CRS revealed elevated IFN- production with PHA or IL-12p70 (Table 3), but their IFN- production
by SL cells was not elevated, except in 1 patient. These results indicate
a discrepancy in IFN- production by SL cells and PBMCs.
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Table 3. Summary of Cytokine Production Patterns by PBMCs in 19 Children
With Treatment-Resistant CRS and 26 Controls*
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Production of IL-12p40 was higher in children with CRS than in controls
with medium, PHA, and IL-12, partly because PBMCs produced IL-12p40 higher
than its range in controls with PHA and IL-12 in 7 and 8 patients with CRS,
respectively (Table 3). Peripheral
blood mononuclear cells from patients with CRS produced less IL-10 with PHA
than those from controls, and 7 children with CRS produced IL-10 less than
the range in controls with PHA and IL-12 (Table 3). As a result, the IL-12p40/IL-10 ratios produced with PHA
and IL-12p70 stimuli were higher in patients with treatment-resistant CRS
than in controls (Figure 3). Production
of IL-18, IL-5, and IL-4 by PBMCs was low in patients with treatment-resistant
CRS, and these values did not differ from those of controls (Table 3 and data not shown).
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Figure 3. The ratio of interleukin (IL)
12p40/IL-10 levels produced by peripheral blood mononuclear cells with stimuli
of phytohemagglutinin (A) and IL-12p70 (B) in children with treatment-resistant
chronic rhinosinusitis (CRS) (n = 19) and controls (n = 15). The results are
expressed as median and range. Asterisk indicates statistically significantly
higher than controls.
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COMMENT
We10 previously showed that elevated
IFN- production was more likely to be found in the sinus of patients
with CRS without atopy along with increased frequency of positive microbial
cultures, indicating microbial-triggered T1 responses. This study determined
production of IFN- and its regulatory cytokines, including IL-10, IL-12p40,
and IL-18, by SL cells and PBMCs in patients with treatment-resistant CRS.
The results revealed substantial production of IFN-, IL-18, IL-12p40,
and IL-10 in the sinus in patients with treatment-resistant CRS. Sinus lavage
cells produced IL-18 (>100 pg/mL) without stimuli in these patients at high
frequency, whereas PBMCs produced little IL-18. In addition, an aberrant cytokine
production pattern by PBMCs was found in a subset of patients with treatment-resistant
CRS.
Pathogenesis of CRS seems to be heterogeneous, and a subset of patients
with CRS undergoes multiple courses of antibiosis and surgical procedures
despite appropriate medical and surgical treatments.4
It is important to identify patients with CRS resistant to conventional treatments
in the early stage of the disease to improve disease outcome and complications;
this is particularly true for children with CRS. Postulated risk factors for
CRS include atopic disorders, asthma, peripheral eosinophilia, aspirin sensitivity,
specific Ab deficiency, and age (>50 years), but risk factors may vary depending
on the study population.1-4,17-20
For example, peripheral eosinophilia has been frequently reported in adults
with CRS, but we did not find considerable peripheral eosinophilia in children
with CRS in the previous study.10
Our previous results10 suggest that elevated
IFN- production by SL cells likely indicates absence of atopy and positive
microbial cultures. However, IL-10/IL-12p40 production by SL cells did not
reveal any close association with IFN- production by SL cells in the
previous study.10 The present study was an
extension of our previous study addressing regulatory mechanisms of IFN-
production in the sinus of children with treatment-resistant CRS. We hypothesized
that growth of microbes triggers IFN- production by activating constitutive
cells to produce IL-12/IL-18 in the sinus.14-16,21
In this study, 18 of 19 patients had positive bacterial cultures of
SL cell samples. We also revealed elevated IFN- production (>100 pg/mL)
by SL cells with PHA or IL-12p70 in 14 (74%) of 19 patients with CRS. This
is striking given the low numbers of SL cells cultured (2 x 105 cells/mL). We also observed substantial IL-12p40 and IL-18 production
(>100 pg/mL) in many patients (Table 2).
Moreover, 7 (37%) and 12 (63%) of 19 patients showed spontaneous IL-12p40
and IL-18 production (>100 pg/mL) by SL cells, respectively. This is in contrast
to the minimal amount of IL-18 produced by PBMCs, although the concentration
of PBMCs cultured (106 cells/mL) was 5-fold higher than that of
SL cells. These findings indicate that in children with treatment-resistant
CRS, SL cells are likely activated to produce IL-12 and IL-18 spontaneously.
Cytologic examination revealed that the main cells found in SL were
neutrophils and epithelial cells. These cells could be the main source of
IL-12 and IL-18, 2 IFN-–inducing cytokines in the sinus; both
lineage cells are known to produce these cytokines.14-16,21
Moreover, IL-12p40 and IL-18 levels produced by SL cells correlated when cells
were stimulated with PHA and IL-12p70. These results point to the synergistic
actions of these 2 cytokines for IFN- production in the sinus.
In this study, we also found 4 patients with CRS who had little IFN-
production by SL cells despite elevated IL-12p40 and IL-18 levels. This might
be explained by increased production of counter-regulatory cytokines such
as IL-10 and transforming growth factor ß.22-23
However, we did not find any negative correlation between the IFN-
and IL-10 levels produced by SL cells. Production of IL-10 by SL cells was
generally low compared with IL-12p40/IL-18 production. In 2 patients with
low IFN- production by SL cells, we did not find considerable transforming
growth factor ß production (H.J., S.S., H.L., F.L.R., unpublished observation,
2001). In our patients with high IL-12p40/IL-18 but low IFN- production
by SL cells, it is unlikely that excessive production of IL-10/transforming
growth factor ß caused low IFN- production by SL cells. Interferon
gamma is crucial for eradicating certain microbial pathogens. Our results
thus indicate that in children with treatment-resistant CRS, dysregulation
of IFN- production in the sinus could be associated with persistent
sinus inflammation.
Abnormalities involving regulatory cytokines for IFN- production
do not result in abnormal Ab production or changes in PBMC phenotypes or lymphocyte
proliferative responses. Nevertheless, such a defect could cause inefficient
microbial clearance in the sinus and middle ear. Thus, we reasoned that although
all the study patients revealed normal immune functions with conventional
immune workup, we could still detect aberrant cytokine production by PBMCs
in some children with treatment-resistant CRS. Many study patients (15/19;
79%) had chronic otitis media requiring surgical procedures for the middle
ear before the development of CRS, further indicating lacuna immunodeficiency
in these patients.
This study revealed IFN-, IL-12p40, and IL-10 production by PBMCs
higher or lower than the ranges observed in control children in subsets of
patients with CRS (Table 3). In
5 (26%) of 19 patients, we found IFN- production lower than the reference
range for children despite normal to elevated IL-12p40 production. Production
of IL-10 was not elevated in these patients. One of these patients was later
found to have a signal transduction defect through IL-12R, resulting in a
partial defect in IFN- production.11
In our assay system, T cells are likely the major source of IFN-. Other
patients with treatment-resistant CRS may also reveal other types of lacuna
immunodeficiency involving IFN- production by T cells. However, we
still found substantial IFN- production by SL cells in 4 of 5 patients
with low IFN- production by PBMCs. These results indicate other cellular
sources for IFN- in the sinus in these patients, may be compensating
for defective IFN- production by T cells.
In 6 (32%) of 19 patients with CRS, we also found IFN- production
by PBMCs higher than the reference range along with higher IL-12p40 production
and lower IL-10 production than the ranges in controls. Interleukin 12 promotes
IFN- production, whereas IL-10 suppresses it.14-16,22
Elevated IFN- production by PBMCs in these children with CRS could
be partly due to unbalanced production of regulatory cytokines for IFN-
production. Only 1 of these 6 patients revealed elevated IFN- production
by SL cells. These results again indicate the importance of microenvironmental
factors for IFN- production in the sinus. It may be worthwhile to include
the assays of T1/T2 cytokine production and its regulatory cytokines by PBMC
as a second-line workup in children with treatment-resistant CRS if conventional
immune workup does not reveal any abnormalities. If such abnormality is detected,
intervention treatments such as exogenous IFN- can be considered an
option.
This study presents evidence of dysregulated regulatory mechanisms for
IFN- production in the sinus in a subset of children with treatment-resistant
CRS. Moreover, we also revealed the possibility that in a subset of children
with treatment-resistant CRS, we may detect abnormal production of IFN-
and its regulatory cytokines by PBMCs. Further analysis of the dysregulated
mechanisms of IFN- production may reveal prognostic biomarkers for
treatment-resistant CRS.
AUTHOR INFORMATION
Accepted for publication August 1, 2001.
This study was supported in part by grants from the Lion's Multiple
5M Hearing Foundation and the Minnesota Medical Foundation, Minneapolis (Drs
Jyonouchi and Rimell).
Corresponding author and reprints: Harumi Jyonouchi, MD, Department
of Pediatrics, University of Minnesota, MMC 610 FUMC, 420 Delaware St SE,
Minneapolis, MN 55455 (e-mail: jyono001{at}tc.umn.edu).
From the Departments of Pediatrics (Drs Jyonouchi and Sun and Mr Le)
and Otolaryngology (Dr Rimell), School of Medicine, University of Minnesota,
Minneapolis.
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