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Immunology Letters
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22 a r t i c l e i n f o a b s t r a c t
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11 Article history: Previous studies have revealed the clinical relevance of pro-inflammatory cytokine production during
12 Received 29 December 2013 dengue virus (DENV) infections. In this study, we evaluated the production of interleukin-21 (IL-21), a
13 Received in revised form 22 April 2014 key soluble mediator mainly produced by CD4+ T cells.
14 Accepted 7 May 2014
The aim of this study was to investigate the role of IL-21 production during the clinical course of
15 Available online xxx
primary and secondary DENV infections and the potential association of IL-21 serum levels with the
16
disease pathogenesis. Blood samples from DENV-infected patients were collected on different days after
17 Keywords:
the onset of symptoms. Patients were classified according to their phase of disease (acute vs. convalescent
18 Dengue
19 Interleukin 21
phases), the type of infection (primary vs. secondary), and the clinical severity of their disease (dengue
20 Antibody response fever (DF) vs. dengue hemorrhagic fever (DHF)). IL-21 levels were measured using a quantitative capture
21 Cellular immunity ELISA assay. The levels of IL-21 were significantly elevated in the disease group compared with the
control group. IL-21 was detected in primary and secondary DENV infections, with a significantly higher
concentration in the convalescent phase of primary infections. IL-21 levels were significantly higher
in patients with secondary acute DHF infections when compared with those with secondary acute DF
infection. There was a relationship between the elevated serum levels of IL-21 and the production of
DENV-specific IgM and IgG antibodies. Taking together, our results show for the first time the involvement
of IL-21 during the clinical course of DENV infections.
We speculate that IL-21 may play a protective role in the context of the convalescent phase of primary
infections and the acute phase of secondary infections.
© 2014 Published by Elsevier B.V.
23 1. Introduction of both protection and the pathogenesis of the severe forms of this 32
24Q4 Dengue fever is the most common transmitted arboviral disease during acute dengue infections, including cytokines from innate 34
25 worldwide. The infection is caused by one of the four serotypes immunity cell sources, such as TNF-␣, IL-1, IL-6, and IFN-␣, and 35
26 of dengue virus, the etiologic agents, all of which are members of chemokines, such as MIP1-␣, IP-10 and IL-8. Pro-inflammatory 36
27 the Flavivirus group into the family Flaviviridae [1]. The pathophy- cytokines are implicated in host protection roles such as activat- 37
28 siology of DF/DHF/DSS in humans is complex and multi-factorial, ing innate and adaptive immune cells, chemotaxis and inhibition of 38
29 involving the interplay of host and viral factors that influence dis- viral replication. Some detrimental roles for the high inflammatory 39
30 ease severity and the clinical outcome [2]. With respect to host cytokine levels that are often observed in severe disease include the 40
31 factors, the immune response to DENV plays a dual role in terms induction of cell death (apoptosis and necrosis), endothelial activa- 41
immune cells, such as CD4+ and CD8+ T cells, also play a major role 43
http://dx.doi.org/10.1016/j.imlet.2014.05.006
0165-2478/© 2014 Published by Elsevier B.V.
Please cite this article in press as: Vivanco-Cid H, et al. Dynamics of interleukin-21 production during the clinical course of primary and
secondary dengue virus infections. Immunol Lett (2014), http://dx.doi.org/10.1016/j.imlet.2014.05.006
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IMLET 5522 1–7 ARTICLE IN PRESS
2 H. Vivanco-Cid et al. / Immunology Letters xxx (2014) xxx–xxx
50 clinical pathogenesis of DHF on the basis of in vitro studies and the of the Instituto de Investigaciones Medico-Biológicas, Universidad 110
51 ex vivo analysis of the cytokine patterns in the serum samples of Veracruzana (Veracruz, México). The study protocol was approved 111
52 patients with severe disease [5,8–10]. by the institutional ethics review board. 112
57 of DENV infections. IL-21 is a cytokine member of the common ␥- transcription-polymerase chain reaction (RT-PCR) and three refer- 115
58 chain family, which includes IL-2, IL-4, IL-7, IL-9 and IL-15 [11]. ence anti-dengue enzyme-linked immunosorbent assays (ELISA): 116
59 IL-21 is produced by various subsets of activated CD4+ T cells, Platelia Dengue NS1 Ag Test (BIORAD Laboratories, France), Dengue 117
60 which include Th17 cells, T-follicular helper (Tfh) and CD4+ natu- IgM (Panbio, Australia) and, to discriminate among primary and 118
61 ral killer (NK) T cells, and exerts multiple and pleiotropic effects on secondary infections, a commercial kit (capture IgG ELISA, Pan- 119
62 various innate and adaptive immune cells, such as NK cells, mono- bio) that is used for the quantitative detection of elevated titers of 120
63 cytes, macrophages, B cells, and CD4+ and CD8+ T lymphocytes, IgG antibodies to dengue virus in patients with secondary infection 121
64 as well as on non-immune cells such as keratinocytes [12], fibro- according to previously established criteria [16]. 122
65 blasts [13,14] and vascular endothelial cells [15]. The aim of this
66 work was to investigate whether the serum levels of IL-21 are ele- 2.4. Classification of samples 123
69 viduals and the potential association of IL-21 serum levels with the patients into acute (1–7 days after disease onset) and convales- 125
70 disease pathogenesis. cent (samples collected on days 8–10 after disease onset) phases. 126
Primary dengue infection was defined for patients with positive 127
results for RT-PCR, NS1 and/or IgM tests and negative IgG ELISA 128
71 2. Materials and methods
results. Secondary dengue infection was defined for IgG ELISA pos- 129
The Chi square test was used to compare categorical variables. 160
106 2.2. Ethics statement The non-parametric Kruskal–Wallis test was used to comparison 161
more than two groups. Comparisons among each patient group 162
107 Written consent to participate in the study was obtained from were performed using Dunn’s multiple comparison tests. Statis- 163
108 each participant after a full explanation of the study was provided tical significance between two individual groups was determined 164
109 and in accordance with the guidelines of the Ethics Committee with the Mann–Whitney U test using GraphPad Prism software V 165
Please cite this article in press as: Vivanco-Cid H, et al. Dynamics of interleukin-21 production during the clinical course of primary and
secondary dengue virus infections. Immunol Lett (2014), http://dx.doi.org/10.1016/j.imlet.2014.05.006
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IMLET 5522 1–7 ARTICLE IN PRESS
H. Vivanco-Cid et al. / Immunology Letters xxx (2014) xxx–xxx 3
Table 1
Classification of dengue patients according to phase and severity disease.
166 5.0. P values <0.05 were considered statistically significant. Correla- 3.3. The highest serum levels of IL-21 are produced during the 196
167 tion between IL-21 and Dengue IgM and IgG levels among different convalescent phase of primary infections 197
second cutoff (≥133.4 pg/ml) were classified as high IL-21 produc- 222
189 To investigate whether IL-21 is produced during DENV infection, ers. We related these categories with the type of infection (primary 223
190 the serum levels of IL-21 were measured by enzyme immunoassay. or secondary) and the course of the disease (acute or convalescent 224
191 In a first analysis, we observed very low serum levels of IL-21 in the phases). A high percent (61.3%) of patients with primary infections 225
192 healthy control group (mean 14.5 ± 59.4 pg/ml, median 1.6 pg/ml) in the convalescent phase produced the highest levels of IL-21. High 226
193 and a higher and heterogeneous production of IL-21 in dengue- concentrations of IL-21 were also detected in 40.3% of patients with 227
194 infected patients (mean 147.2 ± 200.4 pg/ml, median 83.37 pg/ml), secondary infections in the acute phase. In contrast, 1.3% of the 228
195 P < 0.0001, Fig. 1A. healthy controls were classified as high IL-21 producers, whereas 229
Fig. 1. The serum levels of IL-21 are elevated in dengue-infected patients. (A) IL-21 concentrations in the sera of healthy controls (HC) (n = 78) and dengue-infected patients
(DEN) (n = 360). (B) Comparison of the serum levels of IL-21 in acute (n = 91) and convalescent phases (n = 31) of primary dengue infections vs. acute (n = 149) and convalescent
phases (n = 89) of secondary dengue infections. Statistical confidence was analyzed in figure A by Mann–Whitney U test. The Kruskall–Wallis test was used for statistical
analysis in figure B. The IL-21 levels are represent in pg/ml. **P < 0.01, ***P < 0.001, ****P < 0.0001. Abbreviations: AP (acute primary), CP (convalescent primary), AS (acute
secondary), CS (convalescent secondary).
Please cite this article in press as: Vivanco-Cid H, et al. Dynamics of interleukin-21 production during the clinical course of primary and
secondary dengue virus infections. Immunol Lett (2014), http://dx.doi.org/10.1016/j.imlet.2014.05.006
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IMLET 5522 1–7 ARTICLE IN PRESS
4 H. Vivanco-Cid et al. / Immunology Letters xxx (2014) xxx–xxx
Table 2
Stratified analysis of IL-21 levels in dengue-infected patients, according to the clinical stage and the type of infection.
IL-21 production APn (%) CPn (%) ASn (%) CSn (%) HCn (%) P value
230 97.4% of the control group was classified as low IL-21 producers
231 (Table 2).
232 3.5. The serum levels of IL-21 are associated with the severity of
233 dengue infection during the acute phase of secondary infections
Please cite this article in press as: Vivanco-Cid H, et al. Dynamics of interleukin-21 production during the clinical course of primary and
secondary dengue virus infections. Immunol Lett (2014), http://dx.doi.org/10.1016/j.imlet.2014.05.006
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IMLET 5522 1–7 ARTICLE IN PRESS
H. Vivanco-Cid et al. / Immunology Letters xxx (2014) xxx–xxx 5
Table 3
Q6 Stratified analysis of IL-21 levels in dengue fever and dengue hemorrhagic fever patients, according to the clinical stage and the type of infection.
Total (n) 20 8 49 48 78
Fig. 3. Correlation between the Dengue-specific IgM antibodies levels and the IL-21 serum levels in the acute (A) or convalescent phases (B) of primary dengue infections.
The serum levels of IL-21 were significantly and positively correlated with the increase of anti-dengue IgM levels (r = 0.4260, P < 0.0189), just in the convalescent phase of
primary infections. Correlation between the Dengue-specific IgG antibodies levels and the IL-21 serum levels in the acute (C) or convalescent phases (D) of secondary dengue
infections. A significant and positive correlation between the serum levels of IL-21 and the increase of anti-dengue IgG levels was found during the acute phase (r = 0.2928,
P < 0.0097). Each dot represents one subject.
278 undetectable or low levels of DEN-specific IgM antibodies (IgM 4. Discussion 293
279 ratio, 2.052 ± 2.641) with no significant correlation values with the
280 serum IL-21 levels (Fig. 3A). The levels of dengue-specific IgM anti- Cytokine levels differ dramatically from steady state conditions 294
281 bodies increase in the convalescent phase of primary infections, in healthy controls compared with patients exhibiting active dis- 295
282 on days 8–10 to a mean ratio of 4.598 ± 2.599. The serum lev- ease. In dengue infections, there is a highly heterogeneous host 296
283 els of IL-21 were significantly and positively correlated with the immune response to the viral infection depending of the severity of 297
284 increase of anti-dengue IgM levels (r = 0.4260, P < 0.0189) in the the disease. Here, we present for the first time evidence of IL-21 pro- 298
285 convalescent phase of primary infections (Fig. 3B). For secondary duction during dengue infections. It is apparent from our findings 299
286 infections we found a significant and positive correlation between that the levels of IL-21 increase significantly during DENV infection 300
287 the serum levels of IL-21 and the increase of anti-dengue IgG lev- compared with the levels in healthy individuals. In our study, the 301
288 els (IgG ratio, 5.818 ± 1.881) during the acute phase (r = 0.2928, highest IL-21 concentrations were measured in patients during the 302
289 P < 0.0097). However, no significant correlation value was found convalescence phase of primary infections. This particular produc- 303
290 between dengue-IgG levels and the serum levels of IL-21 during the tion pattern of IL-21 was demonstrated for both clinical forms: DF 304
291 convalescent phase of secondary infections (r = 0.2110, P < 0.1026) and DHF. A high percent of DF (60.9%) and DHF patients (62.5%) 305
292 (Fig. 3D). in the convalescent phase of primary infections were classified as 306
Please cite this article in press as: Vivanco-Cid H, et al. Dynamics of interleukin-21 production during the clinical course of primary and
secondary dengue virus infections. Immunol Lett (2014), http://dx.doi.org/10.1016/j.imlet.2014.05.006
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IMLET 5522 1–7 ARTICLE IN PRESS
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307 the highest IL-21 producers. Interestingly, we found in the same MIP-1␣, Eotaxin, and IP-10, by human NK cells [33,34], monocytes 373
308 clinical stage that the serum IL-21 levels correlated well with the [35], macrophages [36], dendritic cells [37] and T cells [38–40]. 374
309 DENV-specific IgM production. These observations are consistent Although the IL-21 receptor is expressed on vascular endothelial 375
310 with the role IL-21 plays in plasma cell differentiation [17]. cells, a direct effect of this cytokine on vascular activation and vas- 376
311 High IL-21 levels during the convalescent phase correlate well cular leakage has not been reported. 377
312 with the time when the dengue-infected patients began to recover.
313 The recovery phase is characterized by improving general well 5. Conclusions 378
314 being and hemodynamic stability, which suggest a protective role
315 of this cytokine in this clinical stage of primary infections. Fur- Here, we report for the first time the role of IL-21 during the 379
316 thermore, during the acute phase of secondary dengue infections, clinical course of DENV infections. Our present study is the first 380
317 a positive correlation between the serum IL-21 levels and DENV- to report that there is a relationship between the elevated serum 381
318 specific IgG levels was found. This association also is consistent with levels of IL-21 and the production of DENV-specific IgM and IgG 382
319 the critical role IL-21 plays as a potent inducer of IgG production antibodies. 383
320 [18–20] and promoting the activation of memory B cells by T cells We speculate that IL-21 may play a protective role in the context 384
321 [17]. of the convalescent phase of primary infections and the acute phase 385
322 Because of the cellular-restricted origins of IL-21, this cytokine of secondary infections. Given the different biological effects and 386
323 could be considered a good potential biomarker of the protection the pleiotropic activities of IL-21, our results open a very attractive 387
324 mediated by CD4+ T or NKT cells against dengue virus in pri- field of study for this cytokine in a very complex infectious disease 388
325 mary infections. Interestingly, a recent study has identified that an such as dengue fever. 389
326 important proportion of DENV-specific CD4+ T cells isolated from
327 PBMCs from convalescent dengue virus patients displayed a pheno-
Funding 390
328 type characteristic of circulating follicular helper T cells (TFH cells),
329 suggesting that they are interacting with B cells in vivo [21]. A frac-
This study was supported by Fondo Sectorial en Ciencia Básica Q5 391
330 tion of DENV-specific CXCR5+ cells was capable of producing IL-21
SEP-CONACyT, project ID 157274 and Fondo Mixto CONACyT- 392
331 or IFN-␥ following stimulation with DENV peptides. The evidence
Gobierno del Estado de Veracruz, project ID 109270 and 128001. 393
332 provided by Rivino et al., and our own results, support the idea
Maldonado-Rentería MJ, Sánchez-Vargas LA, Izaguirre-Hernández 394
333 that a fraction of DENV-specific CD4+ T cells could be involved in
IY and Hernández-Flores KG gratefully acknowledge the scholar- 395
334 supporting B cell antibody production through an IL-21 dependent
ship from CONACyT to pursue their postgraduate studies. 396
335 mechanism.
336 The biological effects and clinical relevance of the production
337 of IL-21 in primary dengue infections could be related to the Ethical approval 397
340 cence phase, IL-21 could be very important to support the humoral lines of the Ethics Committee of the Instituto de Investigaciones 399
341 response through the proliferation and differentiation of B cells Medico-Biológicas, Universidad Veracruzana. 400
346 role of IL-21 in other viral diseases, including HIV [22–25], HBV the experiments, enrolled patients, recorded clinical and data 403
347 [26], herpes simplex virus [27], and respiratory syncytial virus [28]. analysis: MRMJ, SVLA, IHIY, HFKG, VCH, and RRR. Contributed 404
348 Recently, a protective role for IL-21 has been demonstrated during reagents/materials/analysis tools: VCH and RRR. Wrote the paper: 405
349 the course of the chronic Hepatitis C infections in humans [29]. Hep- VCH, MRMJ, and SVLA. All authors read and approved the final 406
350 atitis C virus is a member of the Flaviviridae family and is closely manuscript. 407
351 related to the dengue fever virus. Although IL-21 has been mainly
352 associated with protective roles and sustaining T cell responses Competing interests 408
353 during chronic viral infections, little is known about the role of this
354 cytokine in the course of acute viral infections such as dengue. The We declare that the authors have not any financial or personal 409
355 role of IL-21 during secondary infection by DENV is more intrigu- relationship with other people or organizations that could create 410
356 ing than in primary infections. In our study, IL-21 levels indeed a potential conflict of interest or the appearance of a conflict of 411
357 were significantly higher in DHF patients than in patients with DF interest with regard to the work. 412
358 in the acute phase of secondary infections. However, the higher lev-
359 els of IL-21 in secondary infections of DHF patients compared to DF
Acknowledgments 413
360 patients probably are a reflection of the more intense immune acti-
361 vation in DHF rather than a cause of the severity of disease. It is well
We are grateful for the support from Health Centers “El Coyol”, 414
362 known that secondary infections with a distinct DENV serotype led
“Anastasio Iturralde”, and “21 de Abril” and the Hospital Regional 415
363 to the activation of serotype-cross-reactive T cells, resulting in ele-
de Alta Especialidad de Veracruz, Servicios de Salud de Veracruz 416
364 vated levels of adaptive immune response-derived cytokines such
for providing access to dengue-infected patients. We also thank the 417
365 as IFN-␥, IL-2, IL-4, IL-10 and TNF-␣, which have been reported to be
Centro Estatal de la Transfusión Sanguínea del Estado de Veracruz 418
366 more pronounced in DHF compared to DF in some studies [30–32].
for providing access to healthy controls. 419
367 A potential detrimental role for IL-21 during the acute phase of
368 DHF secondary infections could be through the activation of dif-
369 ferent immune cell populations, such as monocytes, macrophages, References 420
370 dendritic cells and T cells. IL-21 has been reported to induce the
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secondary dengue virus infections. Immunol Lett (2014), http://dx.doi.org/10.1016/j.imlet.2014.05.006
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Please cite this article in press as: Vivanco-Cid H, et al. Dynamics of interleukin-21 production during the clinical course of primary and
secondary dengue virus infections. Immunol Lett (2014), http://dx.doi.org/10.1016/j.imlet.2014.05.006