ARTICLE
Auteur(s) : Jesus F
Bermejo-Martin1, Maria C Garcia-Arevalo1,
Raul Ortiz De Lejarazu2, Julio Ardura3, Jose
M Eiros2, Ana Alonso3, Vanesa
Matías3, Maria Pino3, David
Bernardo1, Eduardo Arranz1, Alfredo
Blanco-Quiros1
1Lab. de Inmunología de Mucosas, Dept. of Pediatrics
and Immunology. Universidad de Valladolid, Facultad de Medicina,
Ramón y Cajal 7, Valladolid 47005, Spain. Jesus F. Bermejo-Martin
and Maria C. Garcia-Arevalo contributed equally to the development
of this work.
2Hospital Clínico, Microbiología, Valladolid, Spain
3Hospital Clínico, Pediatría, Valladolid, Spain
accepté le 18 Août 2007
Respiratory syncytial virus (RSV) is a major viral pathogen
affecting both infants and adults. RSV infections usually last less
than a week and tend to be more severe in children aged eight to 30
weeks. About 1 to 2% of all infants require hospitalization for
bronchiolitis [1]. During the course of an RSV infection,
inflammatory host cell recruitment to the lung is thought to play a
central role in determining disease outcome. Chemokines mediate
cell recruitment to sites of inflammation and are influenced by,
and influence, the production of cytokines [2]. Cytokines and
chemokines have been detected in nasopharyngeal aspirates (NPAs),
serum and plasma during acute RSV disease in children [3-11]. The
mucosal-associated immune tissues (MALT) represents a highly
compartmentalized immunological system which functions essentially
independently from the peripheral immune system apparatus [12].
Consistent with this high degree of compartmentalization, the MALT
is populated by phenotypically and functionally distinct B cells, T
cells and accessory cell subpopulations as compared with systemic
lymphoid tissues. At the same time, chemokines, growth factors and
cytokines are differentially expressed among mucosal tissues [12].
As a consequence, when immune mediators are profiled in respiratory
or plasma samples in the context of a viral infection affecting the
respiratory tract, the compartmentalization of the immune system at
these levels could influence the conclusions about the pathogenic
events. The objective of our study was to study the particularities
of the mucosal profiles of immune mediators in comparison to the
plasma profiles, during a severe, respiratory syncytial virus
infection in young children. For this, we profiled 27 immune
mediators in parallel, in nasopharyngeal aspirates and plasma from
22 < 2 year-old children with a severe respiratory syncytial
virus infection involving the lower respiratory tract.
Materials and methods
Patients and samples
Children up to 24 months old showing clinical signs of lower
respiratory tract infection of viral origin (tachypnea, prolonged
expiratory time, wheezing, rales, chest retractions, dyspnoea of
sudden appearance, fever) [13] needing hospitalisation in the
Paediatric Department of the “Hospital Clínico Universitario” (HCU)
in Valladolid (Spain) from December 1st, 2005 to
March 31st, 2006. Evaluation of clinical severity was
done at admission following the Wood`s Clinical Asthma Score
modified by Martinon-Torres et al. (M-WCAS) [13]. Twenty two
children under 2 years of age, diagnosed with asymptomatic heart
murmurs were recruited as controls. In all cases, an informed
consent was requested from the parents or legal guardians prior to
the inclusion of the child in the study. Approval of the Committee
for Ethics in Clinical Research of our hospital was obtained prior
to the beginning of recruitment. NPAs were harvested at admission
from patients and controls by instillation of 2.5 mL of an
isotonic saline solution into each nostril (NaCl 0.9%) as described
elsewhere [3] The samples were sent on ice to the virology
laboratory for viral diagnosis, and the remainder of the sample was
centrifuged and the supernatant stored at -70oC until
cytokine, chemokine and growth factor evaluation. In parallel, an
aliquot of 1 mL of blood was obtained only from those patients
for whom the paediatricians had requested, at admission, analytical
support for clinical reasons. Blood samples were taken in EDTA
vacutainer tubes and plasma samples were obtained after proper
centrifugation. Since blood extraction is an invasive technique,
blood was not obtained from controls because of the ethical
considerations.
Viral diagnosis
Patients were classified as having a suspected RSV infection using
a rapid immuno-chromatographic test (NOW RSV test; Binax, Inc.
Portland, ME, USA). Viral presence was subsequently confirmed in
infected infants by direct immunofluorescent staining of viral
cultures from NPAs (IMAGEN; DakoCytomation, Glostrup, Denmark), for
RSV, adenovirus, parainfluenza 1, 2 and 3, influenza A and B
viruses on MDCK, LLCMK2, A549 and Hep2 cells. All subjects included
in the study were culture-positive for RSV, and culture-negative
for all other viruses tested.
Immune mediator detection
Twenty-seven cytokines, chemokines and growth factors were profiled
in both NPA supernatants and plasma samples using a multiplex assay
(Biorad, Hercules, CA, USA) on a Luminex TM platform (Austin, TX,
USA). Limits of detection (pg/mL) were as follows for NPAs and
plasma respectively: eotaxin (2.95; 0.89), granulocyte macrophage
colony-stimulating factor (GM-CSF) (6.76; 6.6), interleukin 1
receptor antagonist (IL-1RA), (2.17; 10.16), IL-5 (2.33; 2.3);
IL-9: (2.21; 2.12); IL-13 (0.56; 0.43), IL-1β (2.19; 2.2); monocyte
chemo-attractant protein-1 (MCP-1) (1.28; 1.47); platelet-derived
growth factor (PDGF-BB) (2.45; 2.39), vascular endothelial growth
factor (VEGF) (2.79; 2.87), human fibroblast growth factor-basic
(FGF-b) (2.81; 13.22), IL-2 (1.43; 1.08); IL-6 (2.46; 2.4), IL-10
(1.61; 1.62), IL-15 (1.92; 1.95), IL-8 (1.96; 1.86), macrophage
inflammatory protein-1α (MIP-1α) (0.93; 0.95), regulated upon
activation, normal T-cell expressed, and secreted (RANTES) (1.38;
1.35), granulocyte colony-stimulating factor (G-CSF) (2.01; 9.62),
interferon γ (IFN-γ): (2.35; 10.42), IL-4 (0.26; 0.31), IL-7: (3.2;
3.17), IL-12p70 (2.76; 2.73), IL-17 (1.17; 1.21);
interferon-inducible protein-10 (IP-10) (3.88; 3.18), macrophage
inflammatory protein-1β (MIP-1β) (1.36; 1.24); and tumour necrosis
α (TNF-α) (7.69; 30.96). Those values below the level of detection
were reported as being equal to the level of detection. Levels of
IL-9, IL-15 and GM-CSF in NPAs and IL-5 in both NPAs and plasma
were consistently less than the limits of detection. Therefore,
comparisons involving these mediators were not performed during the
analysis of data.
White cell counts were performed on whole blood samples
collected in EDTA-vacutainer tubes (BD Biosciences, San Jose, CA,
USA) using a Sysmex XE-2100 analyzer (Roche, Basel,
Switzerland).
Statistical analysis of data was performed using the Microsoft
Excel and the SPSS 15.0 software for Windows. Differences in the
levels of mediators between NPAs from patients and controls were
assessed using the Mann-Whitney U test. Ratios between
innate-immunity mediators (IL-6, TNFα, IL-1β, IL-8) and adaptive
immunity mediators (IL-4, IL-13, IL-2, IFNγ), between Th2 cytokines
(IL-4, IL-10, IL-6, IL-13) and Th1 cytokines (IL-2, IL-12, TNF-α,
IFN-γ) and between CXC chemokines [CXCL8 (IL8), CXCL10 (IP10)] and
CC chemokines [CCL2 (MCP-1), CCL3 (MIP1α), CCL4 (MIP-1β), CCL5
(RANTES), CCL11 (Eotaxin)] were calculated for each patient in both
NPAs and plasma samples. Differences in these ratios between NPAs
(n = 22) and plasma samples (n = 22) were assessed using the
Wilcoxon signed ranks test with the Bonferroni`s correction.
Associations between mediators, severity parameters and blood
counts were studied calculating the Spearman-Karber correlation
coefficients.
Results
1. Clinical characteristics (data expressed as mean
+ SD). Recruited children were 8.3 + (5.6)
months old. O2 saturation at admission was 92.0
+ (5.2), indicating a severe respiratory condition
(normal O2 saturation: > 96%). All children received
treatment with oxygen and beta(2)-adrenoceptor agonists (salbutamol
0.15 mg/kg, every 4-8 hours). The mean time spent at hospital
was 4.6 + (2.9) days, requiring oxygen for 2.3
+ (2.7) days. A significant inverse association between
O2 saturation at admission and “days of hospitalization”
was observed in our study (Spearman correlation coefficient: -0.42;
p = 0.05).
2. Concentrations of mediators in NPAs and plasma samples. The
concentration of cytokines, chemokines and growth factors in NPAs
from patients and controls, along with the concentrations of these
mediators in plasma from patients is shown in table 1. The concentration of all mediators
studied, with the exception of MCP-1, RANTES, IL-7, eotaxin and
VEGF, were significantly higher in the NPAs from patients compared
to those measured in NPAs from controls. Interestingly, while IL-9,
IL-15 and GM-CSF were detected in plasma, they were not detected in
NPAs.
3. Comparison of ratios between innate and adaptive immunity
mediators in NPAs and plasma (figure 1). Ratios of
IL-6/IL-4, IL-6/IL-13, IL-6/IL-2, IL-6/IFNγ, TNFα/IL-4, TNFα/IL-13,
TNFα/IL-2, TNFα/IFNγ, IL-1β/IL-4, IL-1β/IL-13, IL-1β/IL-2,
IL-1β/IFNγ, IL-8/IL-4, IL-8/IL-13, IL-8/IL-2, IL-8/IFNγ were
significantly higher in patient NPAs (p < 0.05) than in patient
plasma, indicating a relative predominance of innate-immunity
mediators in the respiratory mucosa.
4. Comparison of ratios between Th2 and Th1 cytokines in NPAs
and plasma (figure
1). Ratios of IL-13/IL-12, IL-4/IL-12, IL-10/IFNγ,
IL-4/IL-2, IL-10/IL-2, IL-10/IL-12, IL-6/IL-2, IL-6/IL-12,
IL-6/IFNγ and IL-13/IL-2 were significantly higher in patient NPAs
(p < 0,05) than in patient plasma, indicating a relative
predominance of Th2 cytokines in the respiratory mucosa.
5. Comparison of ratios between CXC and CC chemokines in NPAs
and plasma (figure
1). Ratios of IL-8/MIP-1β, IP-10/MIP-1β, IL-8/MCP-1,
IL-8/MIP-1α, IL-8/RANTES, IL-8/eotaxin, IP-10/MCP-1; IP-10/MIP-1α,
IP-10/RANTES, IP-10/eotaxin were significantly higher in patient
NPAs (p < 0,05) than in patient plasma, indicating a relative
predominance of CXC-chemokines in the respiratory mucosa.
6. Study of the associations between the concentration of
mediators in NPAs and plasma: interestingly, no significant
association was found (p > 0.05) between the concentration of
each mediator in NPA and plasma.
8. Association between mediators and severity: the following
mediators showed a significant association between the
concentration in plasma and severity; results expressed as
[mediator, severity parameter (Spearman correlation coefficient;
p)]: [PDGFbb, “days in hospital” (0.49; p = 0.02)], [VEGF, “days in
hospital” (0.44; p = 0.04)], [MIP-1α, M-WCAS (-0.48; p = 0.025)],
[PDGFbb, “O2 saturation” (-0.55; p = 0.008)], [IL-8,
“O2 saturation” (-0.54 ; p = 0.001)], [VEGF,
“O2 saturation” (-0.49; p = 0.02)]. In NPAs, the only
significant association found was [IL-8, “days in hospital” (-0.43;
p = 0.044)].
9. Association between mediators and white cell counts: we found
the following significant associations between mediators in plasma
and white cells counts in peripheral blood [mediator, cell type
(Spearman correlation coefficient; p)]: [IL6, total leucocytes
(0.48; p = 0.02)], [IL-6, neutrophils (0.48; p = 0.02)], [IL-6,
monocytes (0.42; p = 0.05)], [RANTES, neutrophils (-0.5; p =
0.01)], [RANTES, monocytes (0.42; p = 0.05)]. Conversely, in NPAs,
the only significant association found was [PDGFbb, monocytes
(0.53; p = 0.01)].
Table 1 Concentration of mediators in NPAs and plasma.
Results are expressed as median (pg/mL) + inter-quartile range
|
[NPAs from patients] (n = 22)
|
[NPAs from controls] (n = 22)
|
[Plasma] (n = 22)
|
|
IL-1RA
|
8831.0 [16046.2]
|
3136.4 [4924,9]
|
2119.3 [807,8]
|
|
IL-13
|
3.7 [4.4]
|
1.4 [2.3]
|
19.8 [10.5]
|
|
IL-1β
|
468.0 [1008.9]
|
55.4 [221.7]
|
17.5 [11.5]
|
|
FGF-β
|
7.7 [17.3]
|
2.8 [3.81]
|
141.0 [65.1]
|
|
IFN-γ
|
96.9 [55.4]
|
29.4 [65.4]
|
448.9 [134,3]
|
|
MCP-1
|
6.5 [19.4]
|
1.2 [6.0]
|
78.3 [49.9]
|
|
PDGF
|
17.4 [14.4]
|
4.8 [7.4]
|
4899.5 [8628,9]
|
|
IL-2
|
3.8 [4.4]
|
1.4 [0.3]
|
68.2 [60.7]
|
|
IL-6
|
237.7 [351.1]
|
8.6 [43.4]
|
61.5 [65.9]
|
|
IL-10
|
15.9 [23.3]
|
1.8 [3.7]
|
16.2 [13.7]
|
|
IP-10
|
13033.9 [19867.0]
|
3304.6 [4455.5]
|
1285.2 [888.0]
|
|
IL-8
|
7112.5 [6935.6]
|
799.8 [5156.9]
|
166.3 [452.6]
|
|
G-CSF
|
1370.3 [1707.3]
|
160.3 [455.2]
|
141.2 [65.9]
|
|
MIP-1α
|
40.6 [76.2]
|
3.325 [29.8]
|
20.2 [9.4]
|
|
RANTES
|
72.9 [155.3]
|
63.1 [128.5]
|
5335.5 [3210.4]
|
|
IL-4
|
2.2 [1.9]
|
0.26 [0.8]
|
8.6 [3.8]
|
|
IL-7
|
9.4 [9.8]
|
8.6 [13.5]
|
10.0 [10.6]
|
|
IL-12P70
|
3.6 [2.3]
|
2.7 [0.0]
|
28.9 [22.6]
|
|
TNF-α
|
103.0 [999.9]
|
7.6 [0.0]
|
68.4 [132.9]
|
|
EOTAX.
|
35.7 [37.9]
|
29.0 [31.5]
|
161.1 [135.8]
|
|
IL-17
|
6.7 [11.5]
|
1.1 [4.3]
|
29.0 [23.4]
|
|
MIP-1β
|
483.8 [1470.7]
|
38.5 [204.6]
|
92.6 [69.8]
|
|
VEGF
|
1230.7 [1683.3]
|
513.2 [1552.0]
|
75.4 [94.1]
|
Discussion
In this work, we have simultaneously profiled 27 soluble immune
mediators in both NPAs and plasma samples from children with a
severe RSV infection. RSV induced an increase in 18 of the 27
mediators studied in the nasal mucosae, as assessed by the
comparisons between NPAs from patients and controls. The increased
mediators corresponded to Th1 cytokines (IL-1β, IL-2, IL-12p70,
IFNγ, TNFα), Th2 cytokines (IL-13, IL-4, IL-6, IL-10), chemokines
(IP-10, IL-8, MIP1α, MIP-1β), growth factors (FGFb, PDEGFbb, GCSF)
and also IL-1RA and IL-17. Theoretically, IL-1β, TNFα, IFNγ, IL-2,
IL-12p70, IP10 (proinflammatory mediators) could promote
inflammation in the respiratory tract and consequently contribute
to the respiratory compromise showed by these children. Conversely,
our findings showed that none of these mediators measured in NPAs
was associated with severity. IL-17 has been proposed to play a
role in the increased mucus production in the bronchi of children
with RSV infection [14]. IP10 is a lymphocyte-targeting CXC
chemokine produced at high concentrations by activated bronchial
epithelial cells in response to infection [15]. A persistent
increase of IP10 has been found in patients infected with the
SARS-associated Coronavirus and a poor prognosis [16]. With regard
to TNFα, the production of this cytokine during the inductive
immune response to RSV seems to serve an important protective role,
while exaggerated production of TNFα during the adaptive phase of
the immune response seems to induce significant lung
immunopathology [17]. Although not directly proinflammatory, bFGF
synergistically potentiates inflammatory mediator-induced leukocyte
recruitment, at least in part, by enhancing endothelial adhesion
molecule up-regulation [18]. IL-13 is produced in large quantities
by stimulated Th2 cells. IL-4 and IL-13 contribute as major
effectors of Th2 inflammation and tissue remodelling [19, 20].
IL-10 is an anti-inflammatory cytokine produced by macrophages, T
cells and B cells. It has been suggested that RSV may inhibit an
effective immune response by inducing the production of this
cytokine [21]. Alternatively to this point of view, the ability of
IL10 to inhibit RSV replication has also been demonstrated in mice
models [22]. IL-6 and IL-8 have been observed to occur in bronchial
biopsy specimens of asthmatics [23]. The beta chemokine macrophage
inflammatory protein-1alpha (MIP1a) and monocyte chemotactic
protein 1 (MCP-1) are also considered as possibly important in
inciting the inflammatory response in asthma [24]. Since children
suffering from severe RSV bronchiolitis seem to be predisposed to
asthma, the elevation of these mediators could be related to the
incidence of this disease afterwards. It is interesting that
elevated levels of IL-6, IL-8, IFN-gamma, and MIP-1β, as well as of
IL-10, may be protective against hypoxia in bronchiolitis [25].
Finally, GM-CSF may influence the function of polymorphonuclear
cells attracted to the site of infection [26]. When comparisons of
ratios between innate and adaptive immunity mediators in NPAs and
plasma were performed, a predominance of innate-immune mediators
was found in the mucosal compartment (NPAs). It could be a
consequence of the early immune response to the virus, developed
locally at the place where the virus replicates and initially comes
into contact with the immune system, the respiratory mucosa
[27]. The cells normally present in the nasal
compartment could also contribute to the predominance of
innate-immunity mediators at the mucosal level: these cells are
basically epithelial cells of the nasal mucosa, and neutrophils
[28]. The matched comparisons between several Th2/Th1 ratios in
both types of sample (NPAs and plasma) indicated a relative
predominance of Th2 cytokines in the mucosal compartment. Several
factors could explain this situation. Under normal conditions, Th2
responses are typical of mucosal surfaces [29]. Additionally,
during pregnancy, a range of soluble factors is produced by the
placenta that switch maternal immune regulation towards a
protective Th2 phenotype. These factors also influence the
developing fetal immune system and all newborns initially have an
immunological milieu skewed towards Th2 immunity [30]. Both the
respiratory tract and the immune system undergo rapid maturation
during the first year of life. Postnatal development seems to be
affected by and affects responses against viral infections [31].
Viral factors could cause the Th2-predominant profile at the
mucosal level. It has been reported that RSV evades the human
adaptive immune response by skewing the Th1/Th2 cytokine balance
toward increased levels of Th2 cytokines [32]. Interference with
the development of Th1 responses at the place of viral replication
(the respiratory mucosa) could thus represent a mechanism of viral
evasion. When the ratios between CXC and CC chemokines (or α and
β-chemokines) were compared between both compartments, the mucosal
compartment showed a relative predominance of CXCL8 (IL-8) and
CXCL10 (IP-10). This finding agrees with previous reports [33], and
indicates an active role of these chemokines in the respiratory
system following infection with RSV. IP-10 recruits Th1 lymphocytes
and monocytes to the lower respiratory tract [33]. IL-8 primarily
mediates activation and migration of neutrophils from peripheral
blood into tissue and is involved in the initiation and
amplification of inflammatory processes [34]. These chemokines
could promote virus clearance, but also participate in inflammatory
pathogenic events following infection. Furthermore, we examined the
relationships between the immune mediators of the plasma and
mucosal compartments. The absence of a significant association
between the concentration of each mediator in NPA and plasma
indicates that both compartments maintain a certain degree of
independence, since positive or negative increments in one
compartment are not paralleled in the other. Finally, it is worth
noting that that plasma mediators showed a higher number of
significant associations with the parameters of clinical severity
and with the leukocyte counts in peripheral blood than mediators in
the mucosal compartment. This could occur as consequence of certain
events taking place at the systemic level, such as leukocyte
mobilization in response to the infection. Moreover, PDGFbb and
VEGF, two growth factors involved in angiogenesis [35], were
inversely correlated with O2 saturation and directly
correlated with the duration of the hospitalization period. Since
an inverse association between O2 saturation and the
parameter “days in hospital” was observed in the children of our
study, PDGF and VEGF could be promoting angiogenesis in response to
hypoxemia, as an attempt to ameliorate the uptake of O2.
VEGF has also been demonstrated to reduce in vitro RSV replication
and inflammation [36].
Conclusion
Our study demonstrates that respiratory syncytial virus induces
increases in Th1 and Th2 cytokines, chemokines and growth factors
in the mucosal compartment. When ratios between mediators in the
nasal mucosae and plasma were compared in parallel, a relative
predominance of innate-immunity mediators, Th2 cytokines and CXC
chemokines was observed in the mucosal compartment. This mucosal
profile may contribute not only to viral clearance but also to the
immuno-pathogenic events taking place in the respiratory tract.
Acknowledgements
The authors thank the Nursing Team of the Infants Section of our
Hospital, who kindly performed the nasal washes in the most
comfortable way for the children. The authors also thank Ana I.
Sanz, Flora Zatarain and Carmen García for diligence in the sample
processing.
Conflict of interest.
This work has been possible thanks to the financial support
obtained from the “2005 Nutriben Award” of the “AEP”, from the
“2007 MSD Award from SCCALP”, and from “Fondo de Investigaciones
Sanitarias, FIS”, PI050358. J F. Bermejo-Martin is supported by
“FIS” (CD05/00153); D. Bernardo received a grant from the “MEC:
prog. FPU”.
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