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Abstract
Introduction
Materials and Methods
Results
Discussion
References
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Total serum immunoglobulin (Ig)E levels are genetically regulated, but the mechanism of inheritance is
not well understood. Cytokines produced by T-helper (Th)1 and Th2 lymphocytes control IgE synthesis.
Bacterial antigens may favor the development of Th1 cells from naive CD4-positive T cells through a
CD14-dependent pathway. CD14 is constitutively expressed on the surface of monocytes and macrophages, and is also present in serum in a soluble form (sCD14). The CD14 gene maps to chromosome
5q31.1, a candidate region for loci regulating total serum IgE. We hypothesized that genetic variants in the
CD14 gene could influence Th-cell differentiation and thus total serum IgE. We identified a C-to-T transition at base pair 
159 from the major transcription start site (CD14/159). Among 481 children recruited
from a general population sample, frequency of allele C was 51.4%. TT homozygotes had significantly higher sCD14 levels than did carriers of both the CC and CT genotypes (P = 0.01). TT homozygotes also
had significantly lower levels of IgE than did carriers of the other two genotypes, but differences were significant only among children who were skin test-positive to local aeroallergens (P = 0.004). There was no
association between CD14/159 and either interleukin (IL)-4 or interferon (IFN)-
responses by peripheral blood mononuclear cells. However, IFN- and IL-4 responses were positively and negatively correlated, respectively, with serum sCD14 levels. We conclude that CD14/159 plays a significant role in regulating serum sCD14 levels and total serum IgE levels.
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Introduction |
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Abstract
Introduction
Materials and Methods
Results
Discussion
References
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Illnesses associated with dysfunction of immunoglobulin (Ig)E responses such as asthma, allergic rhinitis, and atopic dermatitis appear to be on the rise (1), and are presently an important cause of morbidity at all ages (2). These conditions have consistently been found to be associated with increased total serum IgE level in population studies (3). Studies of family aggregation and segregation have suggested that total serum IgE levels are under genetic control (4), although the mechanism of inheritance has not been determined. Results of genetic linkage studies have shown that one or more loci present in chromosome 5q may control total serum IgE (11, 13, 14) and may also be involved in the expression of asthma (15, 16) and of bronchial hyperresponsiveness to nonspecific stimuli (17).
Among the genes that have been mapped to chromosome 5q, several have biologic functions that are important in the pathways leading to IgE synthesis: interleukin (IL)-4, IL-5, granulocyte macrophage colony-stimulating factor, IL-9, IL-13, and IL-3. For this reason they have been considered potential candidate genes that may explain the linkage signal observed between total serum IgE and genetic markers in this region. Several of these genes have already been explored for genetic variants associated with total serum IgE and with other IgE-related phenotypes, but the results have not been conclusive (18).
It has recently been suggested that bacterial signals may play a role in promoting T-helper (Th) differentiation and polarization at the time of development of primary immune response (19). In this framework, a potentially important but as yet unexplored gene located in chromosome 5q31.1 is CD14 (20). CD14 is a multifunctional receptor constitutively expressed primarily on the surface of monocytes, macrophages, and neutrophils (mCD14) (21). A soluble form of CD14, sCD14, is abundant in serum and is apparently derived both from secretion of CD14 and from enzymatically cleaved glycosyl-phosphatidylinositol- anchored mCD14 (21, 22). CD14 is a receptor that has specificity for lipopolysaccharides (LPS) and other bacterial wall-derived components (21, 23). Engagement of CD14 by these bacterial components is associated with strong IL-12 responses by antigen-presenting cells (23, 24), and IL-12 is regarded as an obligatory signal for the maturation of naive T cells into Th1 cells (26). It is now well established that IgE responses are regulated by inhibitory signals derived from Th1-type cells and by stimulatory signals provided by Th2-type cells (27). Together, these findings led to the hypothesis that variants in the promoter region of the CD14 gene might alter expression of CD14, and this in turn could regulate the proportion of Th2- to Th1-type cells responding to environmental stimuli, thus influencing total serum IgE levels.
Presented here are studies that test this hypothesis. We
screened the promoter region of the CD14 gene for potential polymorphisms. We identified one such polymorphism
and found that it was associated with total serum IgE levels. The polymorphism was also associated with circulating
sCD14 levels, which in turn were correlated with IL-4 and
interferon (IFN)- responses of peripheral blood mononuclear cells (PBMC).
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Materials and Methods |
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Abstract
Introduction
Materials and Methods
Results
Discussion
References
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Subjects
The subjects of this report were recruited as part of the Tucson Children's Respiratory Study (CRS), a large longitudinal assessment of asthma and allergies in a general population sample enrolled at birth (28). A total of 1,246 healthy newborns and their nuclear families were enrolled between 1980 and 1984. More than three-fourths of these subjects (n = 943) have been followed for the first 14 to 16 yr of life. During an in-depth evaluation performed at a mean age ± SD of 10.8 ± 0.6 yr, the parents of 513 unrelated enrollees who were still living in Tucson gave consent for genetic studies of asthma and allergies. Blood was obtained by venipuncture, and genomic DNA was separated from the cell pellet using conventional methods. Of these 513 subjects, 314 were non-Hispanic whites, 89 were Hispanics, 99 were mixed non-Hispanic whites/other (90% non-Hispanic white/Hispanic), and 11 were of other ethnicities.
The Human Subjects Committee of the University of Arizona (Tucson, AZ) approved this study. Informed consent for genetic studies and for all other procedures was obtained from parents of all subjects involved.
Total Serum IgE
Total serum IgE levels were measured with the paper radioimmunosorbent test using commercially available kits obtained from Pharmacia Diagnostic (Piscataway, NJ). The assay threshold was set at 0.1 IU/ml, as described elsewhere (29).
Allergy Skin Tests
Skin tests of eight local aeroallergens (Bermuda grass, olive tree, mesquite tree, mulberry tree, careless weed, Alternaria alternata, cat dander, and Dermatophagoides farinae) were performed by the prick technique as described elsewhere (30). Children were considered to be skin test- positive if they showed at least one positive skin test with diameter sums of more than 3 mm.
Serum sCD14 Levels
Serum sCD14 levels were measured using a commercially available enzyme-linked immunosorbent assay (ELISA) kit supplied by Biosource (Camarillo, CA).
IFN- and IL-4 Responses by PBMC
Blood was collected in heparin and processed within 24 h
of collection. Blood was layered on Lymphocyte Separation Medium obtained from Organon-Teknika-Cappel
(Malvern, PA). The cells at the blood-medium interface
were collected, washed with Ca2+- and Mg2+-free Hanks'
balanced saline solution, and resuspended in RPMI-1640 medium. Immediately after cell separation was performed,
2 × 106 PBMC were incubated in 1-ml aliquots of RPMI-1640 medium supplemented with 5% heat-inactivated fetal calf serum, 200 µg/ml L-glutamine, 0.01 M N-2-hydroxyethylpiperazine-N'-ethane sulfonic acid, 50 U/ml penicillin, and 50 µg/ml streptomycin at 37°C in a 5% CO2 air
atmosphere. Cells were stimulated with 10 µg/ml concanavalin-A (Pharmacia) and 10 ng/ml phorbol myristate acetate
(Sigma Chemical Co., St. Louis, MO). Supernatant fluids
from these cells and from nonstimulated cells were harvested at 18 to 24 h and stored at 70°C. IFN- and IL-4
were assayed in the supernatants using ELISA kits obtained from R&D Systems (Minneapolis, MN).
Molecular Genetic Methods
Genomic DNA from 15 unselected subjects was used to
screen for genetic variants in the promoter region of the
CD14 gene. Two overlapping polymerase chain reaction
(PCR) products based on the reported sequence (31, 32)
were amplified. The first product (P1) encompassed the
interval between base pair (bp) 513 and bp 61 from the
transcription start site, and was amplified using primers 5'-GTGCCAACAGATGAGGTTCAC-3' and 5'-CCTCTGTGAACCCTGATCAC-3'. The second product (P2), including the interval between bp 151 and bp +291 from
the transcription start site, was amplified using primers 5'-CCTGAAACATCCTTCATTGC-3' and 5'-CGCAGCGGAAATCTTCATC-3'.
Both PCR were carried out in a volume of 25 µl containing 40 ng of genomic DNA, 10 mM Tris-HCl (pH 8.3), 50 mM KCl, 1.5 mM MgCl2, 200 µM of each deoxynucleotide triphosphate, 0.8 unit of Taq DNA polymerase supplied by Promega Corp. (Madison, WI), and 5 pmol of each primer. The DNA was denatured at 96°C for 3 min, and temperature cycling was set at 96°C for 40 s, 56°C (P1) or 58°C (P2) for 40 s, and 72°C for 50 s for 38 cycles, followed by a final extension at 72°C for 10 min. The sizes of the generated PCR products were 479 (P1) and 442 bp (P2).
PCR products were electrophoresed on 2% agarose gels and visualized with ethidium bromide staining and ultraviolet illumination. A gel extraction kit obtained from Qiagen Inc. (Valencia, CA) was used to isolate and purify the PCR products, and optical densities of 260 nm (Beckman Instruments, Inc., Fullerton, CA) were used to estimate PCR product concentration. Sequencing reactions were performed using the ABI PRISM Dye Terminator Cycle Sequencing Ready Reaction Kit (Perkin-Elmer Corp., Foster City, CA): reactions were carried out in a volume of 20 µl containing 4 µl of Terminator Ready Reaction Mix, 50 (P1) or 45 ng (P2) of PCR product, 4 pmol of either forward or reverse primer, and as much ddH2O as needed. Sequencing temperature cycling was 96°C for 30 s, 50°C for 15 s, and 60°C for 4 min for 25 cycles, and 4°C for at least 2 h. After ethanol precipitation, samples were mixed with a loading buffer containing 25 mM ethylenediaminetetraacetic acid (EDTA) (pH 8.0), 50 mg/ml Blue dextran, and deionized formamide in a ratio of 5:1 formamide to EDTA/Blue dextran, heated at 92°C for 3 min, loaded in a 4.75% acrylimide gel, and electrophoresed using an ABI 373 Sequencer (Perkin-Elmer). Data collection and analysis were performed using 373 Data Collection and 373 Sequencing Analysis Software (Perkin-Elmer). Forward- and reverse-complement P1 and P2 sequences were matched with the corresponding reference sequences (31, 32) for each subject using SeqEd software (Perkin- Elmer).
Statistical Analysis
Both parametric and nonparametric analyses of variance
were used to assess phenotypic differences between carriers of different genotypes and to assess the association between sCD14 levels and both IFN- and IL-4 responses
(33). Allele frequencies were estimated as the following
sum: (frequency of homozygotes) + 1/2 (frequency of heterozygotes) (34).
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Results |
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Abstract
Introduction
Materials and Methods
Results
Discussion
References
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The screening of the promoter region of the CD14 gene
revealed the presence of only one polymorphism, a C-to-T
transition at bp 159 (CD14/159) from the major transcription start site (Figure 1). To genotype a large number
of subjects for CD14/159, a restriction fragment assay
was developed. A 497-bp PCR product encompassing the
interval bp 513/bp 17 was generated using primers 5'-GTGCCAACAGATGAGGTTCAC-3' and 5'-GCCTCTGACAGTTTATGTAATC-3'.
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Commercially available AVAII endonuclease (New
England Biolabs, Beverly, MA) is specific for the sequence GGTCC, which is present in this PCR product
only among carriers of the CD14/159 T allele. The assay
thus yields one 497-bp band for the CC genotype (Figure
2, lane 4); three bands of 144, 353, and 497 bp for CT heterozygotes (lanes 1, 2, 5-8, 10, and 11); and two bands of 144 and 353 bp for TT homozygotes (lanes 3 and 9). Genotypes were obtained for 481 CRS enrollees. Frequencies of
CC, CT, and TT genotypes were 29.4, 49.4, and 21.3%, respectively. Allele frequency for C was estimated at 51.4%,
and distribution was very similar to the expected Hardy-
Weinberg equilibrium. There were no significant ethnic
differences in allele frequency among the 470 subjects who
were Hispanic, non-Hispanic white, or mixed (see MATERIALS AND METHODS).
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Association between CD14/159 and sCD14
We assessed serum levels of sCD14 in 67 unselected CC subjects and 42 unselected TT subjects (with the performer of the assays blinded as to genotype). Median (interquartile distance) values were 4.1 µg/ml (3.6 to 4.5) for CC subjects and 4.5 µg/ml (4.1 to 5.0) for TT subjects (P = 0.01) (Figure 3).
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Association of CD14/159 with Total Serum IgE Levels
and with Sensitization to Aeroallergens
Among non-Hispanic whites, those with the TT genotype had lower total serum IgE levels than both CC homozygotes and heterozygotes. When stratified by positive and negative allergen skin-test reactivity, differences were statistically significant only among those positive for allergen skin tests (Table 1). Heterozygotes had very similar total serum IgE levels when compared with CC homozygotes, suggesting a dominance of the C allele. Among skin test- positive subjects, the combined CC plus CT group (n = 124) had geometric mean total serum IgE of 178.4 IU/ml (confidence interval [CI], 137.4 to 231.9), which was significantly higher than that of TT homozygotes (geometric mean, 81.4; CI, 51.6 to 128.3; P = 0.004).
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There was no association between CD14/159 genotypes and prevalence of skin-test reactivity to aeroallergens in either Hispanic or non-Hispanic white children
(data not shown). However, among skin test-positive non-Hispanic white children, the number of positive skin tests
was strongly associated with the CD14/159 genotypes
(Table 2). Again, CC homozygotes had mean numbers of positive skin tests that were very similar to those of CT
heterozygotes, and the difference in number of positive
skin tests between the combined group (CC + CT) and
that of TT subjects was highly significant (P = 0.001).
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Among Hispanic children there was no significant association between total serum IgE levels and CD14/159
genotypes for either skin test-positive or skin test-negative children (Table 3). There was also no association between number of positive skin tests and CD14/159 genotypes among skin test-positive Hispanic children (data not
shown).
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Association of IFN- and IL-4 Responses by
Stimulated PBMC with CD14/159 Genotypes
and with sCD14 Levels
We assessed IFN- and IL-4 responses to concanavalin-A
and phorbol myristate acetate stimulation of PBMC in
children assessed for sCD14 levels. The proportion of children with detectable IL-4 responses did not differ by genotype (19.0% in 63 CC subjects versus 20.0% in 40 TT subjects, P = 0.9). Geometric mean IFN- responses (95%
CI) were 63.6 pg/ml (49.2 to 82.2) for 67 CC subjects and
67.8 pg/ml (50.9 to 90.5) for 41 TT subjects (P = 0.7).
Figure 4 shows the results of a multiple regression in
which sCD14 was the dependent variable and both IFN-
(in four categories) and IL-4 (as detectable versus undetectable) were introduced into the model as independent
variables. Subjects with low IL-4 responses had significantly higher circulating levels of sCD14 when compared with subjects with high IL-4 responses. Subjects with high
IFN- responses had higher levels of sCD14 than did subjects with low responses.
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Discussion |
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Abstract
Introduction
Materials and Methods
Results
Discussion
References
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We have identified a polymorphism in the 5' flanking region of the CD14 gene at position 159 from the transcription start site. This polymorphism is very frequent
among both Hispanic and non-Hispanic white subjects,
with approximately half of all chromosomes carrying the T
allele and half the C allele. Although the specific role of
this polymorphism in the CD14 gene transcription has not yet been elucidated, it appears that the T allele increases
CD14 expression, as assessed by the increased sCD14 levels in homozygous carriers of this allele. It is also possible,
however, that CD14/159 may be in linkage disequilibrium with a different polymorphism located in this region
that controls the CD14 gene transcription rates. Functional evaluation of the role of CD14/159 in determining transcription rates of the CD14 gene will thus be necessary
to clarify this issue.
CD14/159 TT homozygotes showed significantly
lower levels of total serum IgE than did both CC and CT
subjects. The mechanisms that may explain the association
between CD14/159 and total serum IgE are not yet well
understood. IgE responses are regulated by the cytokines
produced by Th1-like and Th2-like cells (27). IL-4, produced by Th2-like cells, is one of two major signals determining the 
class switch in B-cell IgE synthesis (35). Both
production of IgE by B cells and differentiation of Th2-like cells (35) are inhibited by IFN-, which is produced by
Th1-like cells. There is increasing evidence suggesting that
the predominant type of response (Th1- or Th2-like) to a
given antigen is determined at the time of the primary encounter with the antigen (36, 37). Our data demonstrate
an association between sCD14 levels and low IL-4 and
high IFN-, suggesting a role for CD14 in influencing T-cell differentiation. Thus, CD14/159 may influence
sCD14 levels (and presumably mCD14 expression), which
in turn may regulate IgE responses and consequently serum IgE levels.
It has been suggested that dendritic cells (DCs) are professional antigen-presenting cells that play a major role in
primary responses to antigens and in determining differentiation of naive Th cells into either Th1- or Th2-like cells
(19). In the absence of IL-12-inducing factors, DCs have
been shown to induce both IL-4 and IFN- production in
maturing naive Th cells (38), supporting the hypothesis
that IL-12 production by DCs may be an obligatory signal
for the differentiation of naive T cells into Th1-like cells
(26). Certain adjuvants have been found to enhance or induce IL-12 secretion, including the engagement of CD14
by LPS and other bacterial cell wall-derived molecules
(21, 23, 39). CD14 may thus serve as a crucial link between nonadaptive and adaptive responses to environmental antigens (40). Interestingly, DCs do not express
mCD14 on their surfaces (41, 42), but can mount IL-12 responses to LPS stimulation by recognizing complexes formed as a result of interactions among sCD14 and LPS
(40). Recent evidence suggesting that cytokine responses
by DCs to LPS show dose-response relations with sCD14
concentration support the potential involvement of these
complexes in DC activation (40). LPS is ubiquitous in nature, being present in normal indoor environments as a
constituent of house dust (43), and hence is ideally localized to play a "bystander" role in immune responses to
inhalant allergens that are controlled by the DC network
in the airway epithelium (44, 45). LPS derived from respiratory bacterial infections may play a similar role. In
addition, microbial stimulation via LPS may exert more
generalized effects on immune function, which influence
Th1/Th2 switch regulation in allergen-specific immune responses. In particular, recent studies suggest that key events determining the cytokine phenotype of long term
Th-cell memory responses to allergens occur during infancy and early childhood, a life period during which the
Th2-polarization characteristic of the fetal immune system
is progressively replaced by Th1 dominance (38, 46). The
primary trigger for postnatal maturation of Th1 function is
believed to be microbial stimulation, in particular via bacterial LPS derived from the commensal flora of the gastrointestinal tract (47, 48). Consequently, any alteration in
CD14 function may interrupt this form of signaling
through to the adaptive immune system, and this may contribute to the transient developmental defect in Th1 function now recognized as a characteristic of the atopic phenotype.
Experimental support has recently been provided for
this hypothesis. Yoshimoto and coworkers (49) reported
that SJL mice, a strain known to be poor producers of IgE,
showed no intrinsic deficits in B-cell IgE responses when
directly stimulated with LPS and IL-4. However, macrophages from SJL mice, when stimulated with LPS, produced increased amounts of both IL-12 and IL-18, and
these two cytokines induced T cells to produce increased
amounts of IFN-. As a consequence, proliferation and
IgE production by LPS and IL-4 stimulated B cells were
significantly reduced. Furthermore, the ability of SJL B
cells to produce normal amounts of IgE was restored either by addition of anti-IL-12 plus anti-IL-18 antibodies or by removal of macrophages (49). These results strongly
suggest that a mechanism that increases macrophage susceptibility to LPS stimulation may increase macrophage
production of cytokines that inhibit a Th2-predominant immunity.
Further support for this hypothesis is our finding that
sCD14 levels were directly correlated with IFN- responses and inversely correlated with IL-4 responses by
mitogen-stimulated PBMC. The preponderance of Th2-like cytokines such as IL-4 may thus tilt the immune response in favor of IgE production, and may explain the
higher levels of IgE observed in CC subjects, who had
lower levels of circulating sCD14.
Among TT homozygotes, lower levels of IgE were observed in both skin test-positive and -negative subjects,
but results only reached statistical significance among the
latter group (see Table 1). Skin test-negative subjects had
markedly lower geometric mean serum IgE levels than did
skin test-positive subjects, suggesting that the main factor
determining IgE production in this population involves
the susceptibility to becoming sensitized to environmental aeroallergens. Because susceptibility to becoming sensitized to at least one aeroallergen was independent of
CD14/159 genotypes, other genes may modulate such
susceptibility, thus interacting with CD14/159 in determining total serum IgE levels. It is possible that in the absence of such epistatic influences, the effect of CD14/159
on total serum IgE levels would be more difficult to detect,
as suggested by our results among skin test-negative subjects. Interestingly, we found that among skin test-positive
subjects, the number of positive skin-test reactions was
strongly associated with CD14/159 genotypes, with the
TT genotype having a significantly lower mean number of
positive skin tests when compared with CC and CT genotypes. These results suggest that, although the likelihood of becoming sensitized to any aeroallergen is independent
of CD14/159 genotypes, the propensity to mount IgE
responses to different aeroallergens that are sufficiently
strong to be detected by skin-prick test does depend upon
CD14/159 genotypes. In population studies, prevalence
of asthma is a function both of total serum IgE levels (50)
and of the number of positive skin tests to local aeroallergens (3). It is tempting to speculate that linkage signals between asthma and markers in chromosome 5q may be due,
at least in part, to the association between CD14/159 and
both total serum IgE levels and the number of positive
skin tests to aeroallergens. Unfortunately, our general
population study included too few asthmatic subjects to allow us to test this hypothesis.
We found that the association between total serum IgE
levels and CD14/159 genotypes reached statistical significance only among non-Hispanic white children. This is in
apparent agreement with recent reports from the Collaborative Study of the Genetics of Asthma, which indicate
that linkage between markers in chromosome 5q and
asthma is present among non-Hispanic whites but not
among Hispanic subjects (51). In addition, Laitinen and
colleagues (52) were unable to show linkage between total
serum IgE levels and markers in chromosome 5q in a relatively isolated population in Finland. Thus, there may be a
significant ethnic heterogeneity in the genetic determination of total serum IgE levels. Our results should be interpreted cautiously, however, because the number of Hispanic subjects included may have been too small to
provide sufficient power in our sample.
The identification of a genetic variant associated with sCD14 levels may have implications that go beyond those discussed herein related to allergic conditions. Apart from its role in primary immune responses, CD14 plays a crucial role as a mediator of inflammatory responses during gram-negative sepsis (53). Clinical studies have suggested that levels of sCD14 measured shortly after a diagnosis of gram-negative sepsis are strongly associated with subsequent mortality (54). Overexpression of the CD14 gene in transgenic mice is associated with increased mortality after intravenous administration of LPS (55). CD14-deficient mice produced by gene targeting in embryonic stem cells, on the other hand, show markedly lower mortality rates after LPS administration when compared with their wild-type counterparts (56). It is thus tempting to speculate that, although TT subjects may be at decreased risk of developing high IgE responses to environmental stimuli, they may be at increased risk of mortality associated with gram-negative sepsis.
In summary, we found that a genetic polymorphism in
the 5' regulatory region of the CD14 gene may explain, at
least in part, the linkage signal observed between total
serum IgE levels and markers in chromosome 5q. We
demonstrated that CD14/159 influences serum sCD14
levels. Further elucidation of the molecular pathways that
explain this association may provide important new insights into the mechanisms that regulate IgE responses in humans.
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Footnotes |
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Address correspondence to: Fernando D. Martinez, M.D., University of Arizona, P.O. Box 245030, 1501 N. Campbell Ave., Tucson, AZ 85724. E-mail: fernando{at}resp-sci.arizona.edu
(Received in original form July 20, 1998 and in revised form October 15, 1998).
* Genbank Accession No. AFO97335.Abbreviations: base pair(s), bp; polymorphic locus at bp
159 from the
AGT transcription start site of the CD14 gene, CD14/159; dendritic cell,
DC; interferon, IFN; immunoglobulin, Ig; interleukin, IL; lipopolysaccharide(s), LPS; a multifunctional receptor constitutively expressed primarily
on the surface of monocytes, macrophages, and neutrophils, mCD14; peripheral blood mononuclear cells, PBMC; polymerase chain reaction,
PCR; a soluble form of CD14, sCD14; T-helper, Th.
Acknowledgments: The authors thank Debra A. Stern, Susan Solomon, and Penelope E. Graves for their invaluable technical support; and Maureen Driscoll for preparing the manuscript. This study was supported by grants HL14136 and HL56177 from the National Heart, Lung and Blood Institute (NHLBI). One author (F.D.M.) was also funded by a Research Development Award for Minority Faculty (HL03154) from NHLBI.
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References |
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Introduction
Materials and Methods
Results
Discussion
References
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M. E. H. Bashir, S. Louie, H. N. Shi, and C. Nagler-Anderson Toll-Like Receptor 4 Signaling by Intestinal Microbes Influences Susceptibility to Food Allergy J. Immunol., June 1, 2004; 172(11): 6978 - 6987. [Abstract] [Full Text] [PDF]
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N. Hizawa, E. Yamaguchi, D. Takahashi, J. Nishihira, and M. Nishimura Functional Polymorphisms in the Promoter Region of Macrophage Migration Inhibitory Factor and Atopy Am. J. Respir. Crit. Care Med., May 1, 2004; 169(9): 1014 - 1018. [Abstract] [Full Text] [PDF]
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M. N. Blumenthal New Thoughts Regarding the Genetics of Atopy Am. J. Respir. Crit. Care Med., March 1, 2004; 169(5): 555 - 556. [Full Text] [PDF]
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 M. Kabesch and R. P. Lauener Why Old McDonald had a farm but no allergies: genes, environments, and the hygiene hypothesis J. Leukoc. Biol., March 1, 2004; 75(3): 383 - 387. [Full Text] [PDF]
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A. R. O'Donnell, B. G. Toelle, G. B. Marks, C. M. Hayden, I. A. Laing, J. K. Peat, J. Goldblatt, and P. N. Le Souef Age-specific Relationship between CD14 and Atopy in a Cohort Assessed from Age 8 to 25 Years Am. J. Respir. Crit. Care Med., March 1, 2004; 169(5): 615 - 622. [Abstract] [Full Text] [PDF]
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S. Guerra, I. C. Lohman, M. Halonen, F. D. Martinez, and A. L. Wright Reduced Interferon {gamma} Production and Soluble CD14 Levels in Early Life Predict Recurrent Wheezing by 1 Year of Age Am. J. Respir. Crit. Care Med., January 1, 2004; 169(1): 70 - 76. [Abstract] [Full Text] [PDF]
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O. Michel Role of lipopolysaccharide (LPS) in asthma and other pulmonary conditions Innate Immunity, October 1, 2003; 9(5): 293 - 300. [Abstract] [PDF]
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C. L. Holmes, J. A. Russell, and K. R. Walley Genetic Polymorphisms in Sepsis and Septic Shock: Role in Prognosis and Potential for Therapy Chest, September 1, 2003; 124(3): 1103 - 1115. [Abstract] [Full Text] [PDF]
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 M Boniotto, L Braida, A Ventura, S Percopo, A Amoroso, and S Crovella Promoter polymorphisms of the CD14 gene in Italian patients with coeliac disease J. Med. Genet., September 1, 2003; 40(9): e108 - 108. [Full Text] [PDF]
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 K. Yamazaki, K. Ueki-Maruyama, T. Oda, K. Tabeta, Y. Shimada, H. Tai, T. Nakajima, H. Yoshie, D. Herawati, and G.J. Seymour Single-nucleotide Polymorphism in the CD14 Promoter and Periodontal Disease Expression in a Japanese Population Journal of Dental Research, August 1, 2003; 82(8): 612 - 616. [Abstract] [Full Text] [PDF]
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F Nja, W Nystad, O Hetlevik, K C Lodrup Carlsen, and K-H Carlsen Airway infections in infancy and the presence of allergy and asthma in school age children Arch. Dis. Child., July 1, 2003; 88(7): 566 - 569. [Abstract] [Full Text] [PDF]
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 J. M. Fernandez-Real, M. Broch, C. Richart, J. Vendrell, A. Lopez-Bermejo, and W. Ricart CD14 Monocyte Receptor, Involved in the Inflammatory Cascade, and Insulin Sensitivity J. Clin. Endocrinol. Metab., April 1, 2003; 88(4): 1780 - 1784. [Abstract] [Full Text] [PDF]
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K. A. Pacheco, C. McCammon, A. H. Liu, P. S. Thorne, M. E. O'Neill, J. Martyny, L. S. Newman, R. F. Hamman, and C. S. Rose Airborne Endotoxin Predicts Symptoms in Non-Mouse-sensitized Technicians and Research Scientists Exposed to Laboratory Mice Am. J. Respir. Crit. Care Med., April 1, 2003; 167(7): 983 - 990. [Abstract] [Full Text] [PDF]
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P. Risley, P. Jerrard-Dunne, M. Sitzer, A. Buehler, S. von Kegler, and H. S. Markus Promoter Polymorphism in the Endotoxin Receptor (CD14) Is Associated With Increased Carotid Atherosclerosis Only in Smokers: The Carotid Atherosclerosis Progression Study (CAPS) Stroke, March 1, 2003; 34(3): 600 - 604. [Abstract] [Full Text] [PDF]
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H-J Yoon, J H Shin, S H Yang, D-W Chae, H Kim, D-S Lee, H L Kim, S Kim, J S Lee, and Y S Kim Association of the CD14 gene -159C polymorphism with progression of IgA nephropathy J. Med. Genet., February 1, 2003; 40(2): 104 - 108. [Abstract] [Full Text] [PDF]
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 M. B. Bracken, K. Belanger, W. O. Cookson, E. Triche, D. C. Christiani, and B. P. Leaderer Genetic and Perinatal Risk Factors for Asthma Onset and Severity: A Review and Theoretical Analysis Epidemiol. Rev., December 1, 2002; 24(2): 176 - 189. [Full Text] [PDF]
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B. A. Raby, W. T. Klimecki, C. Laprise, Y. Renaud, J. Faith, M. Lemire, C. Greenwood, K. M. Weiland, C. Lange, L. J. Palmer, et al. Polymorphisms in Toll-Like Receptor 4 Are Not Associated with Asthma or Atopy-related Phenotypes Am. J. Respir. Crit. Care Med., December 1, 2002; 166(11): 1449 - 1456. [Abstract] [Full Text] [PDF]
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 P.G. Holt and P. D. Sly Interactions between RSV Infection, Asthma, and Atopy: Unraveling the Complexities J. Exp. Med., November 18, 2002; 196(10): 1271 - 1275. [Full Text] [PDF]
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L I Holla, D Buckova, A Fassmann, T Halabala, A Vasku, and J Vacha Promoter polymorphisms in the CD14 receptor gene and their potential association with the severity of chronic periodontitis J. Med. Genet., November 1, 2002; 39(11): 844 - 848. [Full Text] [PDF]
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 S. T. Weiss Eat Dirt -- The Hygiene Hypothesis and Allergic Diseases N. Engl. J. Med., September 19, 2002; 347(12): 930 - 931. [Full Text] [PDF]
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K. Dabbagh, M. E. Dahl, P. Stepick-Biek, and D. B. Lewis Toll-Like Receptor 4 Is Required for Optimal Development of Th2 Immune Responses: Role of Dendritic Cells J. Immunol., May 1, 2002; 168(9): 4524 - 4530. [Abstract] [Full Text] [PDF]
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P.G. Holt and P.D. Sly Interactions between respiratory tract infections and atopy in the aetiology of asthma Eur. Respir. J., March 1, 2002; 19(3): 538 - 545. [Abstract] [Full Text] [PDF]
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W. O. C. Cookson Asthma Genetics Chest, March 1, 2002; 121 (2009): 7S - 13S. [Abstract] [Full Text] [PDF]
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T. Kusunoki, T. Nakahata, T. Miyanomae, and Y. Inoue POSSIBLE DUAL EFFECT OF CD14 MOLECULE ON ATOPY Am. J. Respir. Crit. Care Med., February 15, 2002; 165(4): 551a - 552. [Full Text]
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I. Sabroe, C.M. Lloyd, M.K.B. Whyte, S.K. Dower, T.J. Williams, and J.E. Pease Chemokines, innate and adaptive immunity, and respiratory disease Eur. Respir. J., February 1, 2002; 19(2): 350 - 355. [Abstract] [Full Text] [PDF]
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H. Renz and U. Herz The bidirectional capacity of bacterial antigens to modulate allergy and asthma Eur. Respir. J., January 1, 2002; 19(1): 158 - 171. [Abstract] [Full Text] [PDF]
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 B. Granum and M. Lovik The Effect of Particles on Allergic Immune Responses Toxicol. Sci., January 1, 2002; 65(1): 7 - 17. [Full Text] [PDF]
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J Douwes, N Pearce, and D Heederik Does environmental endotoxin exposure prevent asthma? Thorax, January 1, 2002; 57(1): 86 - 90. [Abstract] [Full Text] [PDF]
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H. HAKONARSON, U. S. BJORNSDOTTIR, E. OSTERMANN, T. ARNASON, A. E. ADALSTEINSDOTTIR, E. HALAPI, D. SHKOLNY, K. KRISTJANSSON, S. A. GUDNADOTTIR, M. L. FRIGGE, et al. Allelic Frequencies and Patterns of Single-nucleotide Polymorphisms in Candidate Genes for Asthma and Atopy in Iceland Am. J. Respir. Crit. Care Med., December 1, 2001; 164(11): 2036 - 2044. [Abstract] [Full Text] [PDF]
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T. D. LeVan, J. W. Bloom, T. J. Bailey, C. L. Karp, M. Halonen, F. D. Martinez, and D. Vercelli A Common Single Nucleotide Polymorphism in the CD14 Promoter Decreases the Affinity of Sp Protein Binding and Enhances Transcriptional Activity J. Immunol., November 15, 2001; 167(10): 5838 - 5844. [Abstract] [Full Text] [PDF]
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 J-C Renauld New insights into the role of cytokines in asthma J. Clin. Pathol., August 1, 2001; 54(8): 577 - 589. [Abstract] [Full Text] [PDF]
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B. Klintberg, N. Berglund, G. Lilja, M. Wickman, and M. van Hage-Hamsten Fewer allergic respiratory disorders among farmers' children in a closed birth cohort from Sweden Eur. Respir. J., June 1, 2001; 17(6): 1151 - 1157. [Abstract] [Full Text] [PDF]
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 K. Pekkari, J. Avila-Carino, A. Bengtsson, R. Gurunath, A. Scheynius, and A. Holmgren Truncated thioredoxin (Trx80) induces production of interleukin-12 and enhances CD14 expression in human monocytes Blood, May 15, 2001; 97(10): 3184 - 3190. [Abstract] [Full Text] [PDF]
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G. H. KOPPELMAN, N. E. REIJMERINK, O. COLIN STINE, T. D. HOWARD, P. A. WHITTAKER, D. A. MEYERS, D. S. POSTMA, and E. R. BLEECKER Association of a Promoter Polymorphism of the CD14 Gene and Atopy Am. J. Respir. Crit. Care Med., March 15, 2001; 163(4): 965 - 969. [Abstract] [Full Text]
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A L Wright, C J Holberg, L M Taussig, and F D Martinez Factors influencing the relation of infant feeding to asthma and recurrent wheeze in childhood Thorax, March 1, 2001; 56(3): 192 - 197. [Abstract] [Full Text]
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D. Vercelli, M. Baldini, D. Stern, I. C. Lohman, M. Halonen, and F. Martinez CD14: a bridge between innate immunity and adaptive IgE responses Innate Immunity, February 1, 2001; 7(1): 45 - 48. [Abstract] [PDF]
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D. A. Schwartz Does Inhalation of Endotoxin Cause Asthma? Am. J. Respir. Crit. Care Med., February 1, 2001; 163(2): 305 - 306. [Full Text]
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J.-H. PARK, D. R. GOLD, D. L. SPIEGELMAN, H. A. BURGE, and D. K. MILTON House Dust Endotoxin and Wheeze in the First Year of Life Am. J. Respir. Crit. Care Med., February 1, 2001; 163(2): 322 - 328. [Abstract] [Full Text]
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A.B. Kay Allergy and Allergic Diseases- First of Two Parts N. Engl. J. Med., January 4, 2001; 344(1): 30 - 37. [Full Text] [PDF]
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W. O.C. Cookson and M. F. Moffatt Genetics of asthma and allergic disease Hum. Mol. Genet., October 1, 2000; 9(16): 2359 - 2364. [Abstract] [Full Text] [PDF]
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 L. J. Palmer and W. O.C.M. Cookson Genomic Approaches to Understanding Asthma Genome Res., September 1, 2000; 10(9): 1280 - 1287. [Abstract] [Full Text]
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P. G. HOLT, C. MACAUBAS, S. L. PRESCOTT, and P. D. SLY Primary Sensitization to Inhalant Allergens Am. J. Respir. Crit. Care Med., September 1, 2000; 162(3): S91 - 94. [Full Text] [PDF]
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F. D. MARTINEZ Viruses and Atopic Sensitization in the First Years of Life Am. J. Respir. Crit. Care Med., September 1, 2000; 162(3): S95 - 99. [Full Text] [PDF]
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G. L. LARSEN and P. G. HOLT The Concept of Airway Inflammation Am. J. Respir. Crit. Care Med., August 1, 2000; 162(2): S2 - 6. [Full Text] [PDF]
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 M. Tulic, P. G. Holt, and P. D. Sly Modification of the Inflammatory Response to Allergen Challenge after Exposure to Bacterial Lipopolysaccharide Am. J. Respir. Cell Mol. Biol., May 1, 2000; 22(5): 604 - 612. [Abstract] [Full Text]
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M. A. Arias, J. E. Rey Nores, N. Vita, F. Stelter, L. K. Borysiewicz, P. Ferrara, and M. O. Labeta Cutting Edge: Human B Cell Function Is Regulated by Interaction with Soluble CD14: Opposite Effects on IgG1 and IgE Production J. Immunol., April 1, 2000; 164(7): 3480 - 3486. [Abstract] [Full Text] [PDF]
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N. HIZAWA, E. YAMAGUCHI, E. JINUSHI, and Y. KAWAKAMI A Common FCER1B Gene Promoter Polymorphism* Influences Total Serum IgE Levels in a Japanese Population Am. J. Respir. Crit. Care Med., March 1, 2000; 161(3): 906 - 909. [Abstract] [Full Text] [PDF]
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P. G. HOLT Key Factors in the Development of Asthma: Atopy Am. J. Respir. Crit. Care Med., March 1, 2000; 161(3): S172 - 175. [Full Text] [PDF]
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A. J. SANDFORD and P. D. PARE The Genetics of Asthma . The Important Questions Am. J. Respir. Crit. Care Med., March 1, 2000; 161(3): S202 - 206. [Full Text] [PDF]
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J. A. DOUGLASS and R. E. O'HEHIR What Determines Asthma Phenotype? . Respiratory Infections and Asthma Am. J. Respir. Crit. Care Med., March 1, 2000; 161(3): S211 - 214. [Full Text] [PDF]
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