Analysis of lymphocytes in patients with Plasmodium vivax malaria and its relation to the annexin-A1 and IL-10
© Borges et al.; licensee BioMed Central Ltd. 2013
Received: 18 April 2013
Accepted: 22 November 2013
Published: 20 December 2013
Malaria is the most prevalent parasitic disease in the world. In Brazil, the largest number of malaria cases (98%) is within the Legal Amazon region, where Plasmodium vivax is responsible for over 80% of diagnosed cases. The aim of this study was to investigate the annexin-A1 expression in CD4+, CD8+ T cells, regulatory T cells (Treg) and cytokine IL-10 quantification in plasma from patients with malaria caused by P. vivax.
The quantification of the cytokine IL-10 of patients infected with P. vivax and healthy controls were evaluated by enzyme-linked immunosorbent assay (ELISA). The determination of the expression of annexin-A1 in lymphocytes from patients and healthy controls was determined by immunofluorescence staining. All results were correlated with the parasitaemia and the number of previous episodes of malaria.
The cytokine IL-10 plasma levels showed a significant increase in both patients with low (650.4 ± 59.3 pg/mL) and high (2870 ± 185.3 pg/mL) parasitaemia compared to the control (326.1 ± 40.1 pg/mL). In addition, there was an increase of this cytokine in an episode dependent manner (individuals with no previous episodes of malaria - primoinfected: 363.9 ± 31.1 pg/mL; individuals with prior exposure: 659.9 ± 49.4 pg/mL). The quantification of annexin-A1 expression indicated a decrease in CD4+ and CD8+ T cells and an increase in Treg in comparison with the control group. When annexin-A1 expression was compared according to the number of previous episodes of malaria, patients who have been exposed more than once to the parasite was found to have higher levels of CD4+ T cells (96.0 ± 2.5 A.U) compared to primoinfected (50.3 ± 1.7). However, this endogenous protein had higher levels in CD8+ (108.5 ± 3.1) and Treg (87.5 ± 2.5) from patients primoinfected.
This study demonstrates that in the patients infected with P. vivax the release of immunoregulatory molecules can be influenced by the parasitaemia level and the number of previous episodes of malaria. annexin-A1 is expressed differently in lymphocyte sub-populations and may have a role in cell proliferation. Furthermore, annexin-A1 may be contributing to IL-10 release in plasma of patients with vivax malaria.
In Brazil, the largest number of malaria cases (98%) occurs within the Legal Amazon region. Between 2005 and 2009, the number of cases decreases from 607,801 to 306,908. A similar reduction was found for mortality (52.5%) and malaria incidence (25.6 to 12.1 cases per thousand inhabitants). In 2011, only 263,323 cases were reported . In other Brazilian regions, the transmission risk is low or nonexistent . In Mato Grosso, the disease is predominantly focal. It is endemic only in the northern region of the State  with 2,161 cases reported in 2010 .
The infection caused by Plasmodium vivax has long been considered a benign disease, especially when compared to infections caused by Plasmodium falciparum. Recently, literature report has shown that vivax malaria caused more severe forms of the disease than previously described, and the most common symptoms of these complications are severe anaemia, respiratory distress and acute lung injury, coma, among other manifestations [6, 7]. The increasing drug resistance and the complications of this parasitic disease require joint efforts for a better understanding and resolution.
Evidence suggests that during infection, malaria causes activation and dysfunction of T cells and lymphopaenia . The CD8+ T cells and the cytokines IFN-γ and TNF confer protection against parasites pre-erythrocytic Plasmodium within hepatocytes , whereas CD4+ T cells restricted growth of parasites erythrocytes of Plasmodium through secretion of cytokines, activation of macrophages and direction of humoral immunity . Recently, the involvement of regulatory T cells in infection caused by P. vivax was demonstrated , suggesting that the balance between pro-and anti-inflammatory cytokines is needed to track changes related to malaria .
Besides cytokines, other factors can modulate the differentiation of T helper lymphocytes, for example, the affinity of the antigen by a T cell receptor (TCR). With low affinity antigen generally induce a Th2 response, whereas high affinity induces differentiation into a Th1 response [13, 14]. Annexin-A1 (ANXA1) is an endogenous protein with anti-inflammatory functions, endowed with potent anti-migratory activity of neutrophils, ensuring the transitory nature of the inflammatory response [15, 16]. This protein is identified in several types of leukocytes [17, 18] and positively modulates TCR signaling, making it an important molecular target in the differentiation and proliferation of lymphocytes. In the lymphocytes, ANXA1 has been characterized as an antiproliferative protein , but new studies have indicated other mechanisms, like regulates the T cell production of IFN-γ, IL-17, TNF and IL-6  and the suppressive activity of apoptotic cells on the immune response .
Therefore, the aim of this study was to investigate the expression of ANXA1 in CD4+, CD8+ T cells, regulatory T cells (Treg) and quantification of the cytokine IL-10 in plasma from patients with malaria caused by P. vivax. The relationship between the presence of lymphocyte sub-populations and release of immunoregulatory molecules may contribute to the understanding of the dynamics of the immune response in vivax malaria.
Malaria patients and healthy controls
Sixty-nine malaria patients from the Julio Müller University Hospital of the Federal University of Mato Grosso State, Cuiabá – MT, were included in this study. The age, number of previous episodes of malaria, and other infectious diseases history of each participant were recorded using a standard questionnaire. Patients who have already been treated with some type of anti-malarial drug were excluded from the study. Thirty-seven healthy volunteers living in Cuiabá, a non-endemic malaria area, were recruited as the control group. These volunteers had no history of malaria infection. Written informed consent was obtained from all patients or their legal representatives before enrollment in the study. The study protocol was approved by the Ethics Committee from Julio Müller University Hospital (633/CEP-HUJM/09). The study subjects were matched by sex and age. The average age of patients with malaria was 33.7 ± 1.9 years. And it was 37.6 ± 2.2 years in the control group.
Blood samples were taken from each patient. A finger-tip smear was taken for the parasitological diagnosis, and then approximately 5 mL of venous blood was collected for the analysis of cytokines and ANXA1 expression. The blood was drawn aseptically into Vacutainer® tubes (Becton Dickson and company, Franklin Lakes, NJ, USA) with EDTA. The haemoglobin, platelets and whole blood cells (WBC) were quantified with the Blood Cell Count (Pentra, Horiba Diagnostics, Kyoto, Japan). After, the blood was centrifuged at 1,200 g for 10 min at room temperature. The serum was separated out and the samples were aliquoted and stored at −20°C until assayed.
Thick blood smears were stained with 5% Giemsa solution and examined for Plasmodium species by two microscopists. Parasitaemia was assessed by counting the number of parasites per 200 leukocytes. If nine or fewer parasites were found, 300 additional leukocytes were counted. Parasitaemia were expressed as parasites/μL of blood from each individual. Patients were grouped by level of parasitaemia (low parasitaemia up to 750 parasites/μL and high parasitaemia above 752.5 parasites/μL) as recommended by clinical procedures  and number of previous episodes of malaria (Ø episode - no previous episodes of malaria or primoinfected and > 1 episode - more than one previous episode of malaria).
The plasma levels of the cytokine IL-10 was assessed by enzyme-linked immunonosorbent assay (ELISA), using pairs of cytokine-specific monoclonal antibodies provided by commercially available assay (BD Biosciences - Pharmingen, San Diego, CA, USA). All tests were performed according to the manufacturer’s instructions. Each plate included a standard curve of recombinant human cytokine in parallel with the samples, the final enzyme activity was measured by a microplate reader automatic, V-max (Molecular Devices, Sunnyvale, USA) at 405 nm. All samples were measured in duplicate, and the average of the two values of optical density was used for all analyses.
Blood smears of patients infected with P. vivax and healthy controls were incubated with 5% albumin bovine in PBS (PBSA) to block nonspecific binding and permeabilized with Teen 20 at 0.4% in PBS, as described before . A cocktail of primary antibodies were used to identify ANXA1 expression and lymphocyte subpopulation. Thus a polyclonal rabbit anti-ANXA1 antibody (1/200 in 1% PBSA) (Invitrogen, USA) and a specific lymphocyte marker: mouse anti-CD8, anti-CD4, anti-CD25 and anti-FOXP3 (Invitrogen, USA) (1/200 in 1% PBSA) were added into the slides and incubated overnight at 4°C. After repeated washings in 1% PBSA, a goat anti-rabbit (Fc fragment-specific) antibody conjugated to fluorochrome ALEXAFLUOR 488® and goat anti-mouse, conjugated to fluorochrome ALEXAFLUOR 546® (1/50 in 1% PBSA) and the marker DAPI nuclei (4′,6-diamidino-2-phenylindole) were added. Analysis was conducted with a microscope AxioScopeA1 (Carl Zeiss, GR) equipped with a DXM1200 digital camera, using the Software AXIOVISION, version 4.8. For cell number quantification: CD4+, CD8+ and Treg cells (CD4+/CD25+/FOXP3+) and ANXA1 expression 100 separate fields of each individual smears were evaluated. The protein ANXA1 expression was quantified by mean optical density (MOD) measured by the Software Axiovision. Data was obtained from the light spectrum, with values that range from 0 to 255 (arbitrary units – A.U.).
Data were expressed as mean ± standard error of the mean (SEM). To compare the haematological and parasitological data of individuals, the Mann-Whitney’s U and student’s t test was used. To compare cytokine IL-10 levels and ANXA1expression, data were tested using a one-way analysis of variance (one-way ANOVA) with a Bonferroni pos-test. For all statistical analysis, the Software GraphPad PRISM (La Jolla, CA, USA) was used. The p value < 0.05 was considered significantly different.
Description of the population by haematological parameters
Individuals (mean ± SEM)
Malaria P. vivax(n = 69)
Controls (n = 37)
Haemoglobin (g/ dL)
12.6 ± 0.3**
13.8 ± 0.2
37.4 ± 0.9*
40.1 ± 0.7
Total WBC (10 3 /mm 3 )
5561 ± 232.1***
7520 ± 350.2
Lymphocytes (10 3 /mm 3 )
1415 ± 163.9***
2309 ± 137.4
Platelets (cells/mm 3 )
128.9 ± 11.6***
285.4 ± 10.9
3255 ± 454.9
858.4 ± 99.9**
1355.0 ± 51.3
422.8 ± 49.2***
742.4 ± 50.3
CD4 + CD25 + FOXP3 + cells
52.1 ± 7.4
40.7 ± 5.9
CD4/ CD8 cells
2.2 ± 0.1
1.9 ± 0.1
With respect to Treg cell number, the data showed no statistical difference when compared between the malaria patients and the control. However, evaluating these patients according to the number of parasites and the number of previous episodes, it was observed that patients with low parasitaemia and who have had more than one previous episode of malaria showed a significant increase in these cells (96.0 ± 8.6 × 103 cells/mm3, and 81.9 ± 8.2 respectively) when compared to control individuals. Primoinfected patients with high parasitaemia showed no statistical difference when compared to the control (52.6 ± 7.2 and 37.8 ± 6.8, respectively).
IL-10 plasma levels
Circulating cytokine levels measured in the plasma of infected individuals P. vivax and healthy controls
Plasma concentration of cytokine (pg/mL) Mean ± SEM
650.4 ± 59.3*###
2870.0 ± 185.3***
326.1 ± 40.1
Concentration of IL-10 in infected by P. vivax, distributed according to the number of previous episodes of malaria
Number of previous episodes of malaria
Plasma concentration of cytokine (pg/mL) Mean ± SEM
363.9 ± 31.1###
> 1 episode
659.9 ± 49.4
Quantification of ANXA1 expression in lymphocytes CD4+, CD8+ and Treg
Expression of ANXA1 and the level of parasitaemia in infected patients with P. vivax
Intracellular expression of ANXA1 (A.U.) in T CD4+, T CD8+ and Treg Mean ± SEM
86.7 ± 3.0***
88.5 ± 1.9***
108.4 ± 3.4
76.7 ± 2.0***
86.3 ± 2.6***
110.9 ± 5.5
118.1 ± 3.9***###
90.5 ± 2.6
95.3 ± 2.9
Expression of ANXA1 in infected by P . vivax , according to the number of previous episodes of malaria
Number of previous episodes of malaria
Intracellular expression of ANXA1 (U.A.) Mean ± SEM
50.3 ± 1.7###
108.5 ± 3.1###
87.5 ± 2.5###
> 1 episode
96.0 ± 2.5
83.5 ± 2.1
65.5 ± 1.7
Studies evaluating the mechanisms involved in Plasmodium infection showed that the immune system develops a potent response against the parasite causing changes in several haematological components and mediators of immune system [23, 24]. Moreover, more than 80% of diagnosed cases in Brazil are caused by P. vivax.
Several studies have reported haematological changes in patients with malaria. In this study, a reduction in haematocrit, haemoglobin, leukocytes and platelets was observed during the acute phase of the disease induced by P. vivax[26–28]. In the literature, there are two mechanisms that can explain the lymphocytes depletion in patients with P. falciparum and P. vivax in the acute phase of the disease: sequestration of cells to lymph nodes or other body parts and abnormal cell death through apoptosis .
Furthermore, Braga et al.  demonstrated that malaria-specific proliferative T cell responses to various malaria antigens are commonly observed to be higher in non-immune or semi-immune rather than in the immune subjects, i.e., continuous exposure to malaria in areas of low endemicity may lead to a specific decrease of the T cell function. As described in the literature [28, 31–33], the number of CD4+ and CD8+ T cells were significantly lower during acute malaria.
There is a well-recognized but unmet need for improved diagnostics based on biological markers to characterize disease status, parasitaemia and clinical outcome. Therefore, the evaluation of IL-10 and ANXA1 in the individuals with malaria was performed. Plasma levels of IL-10 were elevated in patients with high parasitaemia and who have had more than one episode of malaria. This result shows that re-exposure to P. vivax may induce IL-10 production. High levels of IL-10 were also detected in African and Indian children with anaemia and high levels of parasitaemia [33, 34]. Other studies also showed a positive relationship between the levels of IL-10 and parasite density in individuals infected with P. vivax. IL-10 plays an important role in immunoregulation, inhibiting Th1 function and promoting the activity of NK cells [35–40]. Other studies indicate that IL-10 were associated with Th2 response during malaria . The results obtained in this work together with previous literature findings, emphasize that IL-10 may regulate the proinflammatory response, participates in parasite elimination and contributes to the pathogenesis of the disease.
The expression of ANXA1 in subpopulations of T lymphocytes CD4+, CD8+ and Treg were assessed. ANXA1 is known to be constitutively expressed on leukocytes and epithelial cells [17, 18, 42, 43]. Depending on the cell stimulus, ANXA1 expression may be increased endogenously in order to regulate the inflammatory processes [18, 44]. In this work, lymphocytes sub-populations were observed to expressed ANXA1. This data is in agreement with findings in the literature, which indicates a pleiotropic mechanism of action of this protein in the innate and adaptive immune system [18, 19, 45, 46].
Some studies suggest that ANXA1 demonstrated an antiproliferative activity in lymphocytes [17, 19, 44, 47]. It was demonstrated a reduction in ANXA1 expression in CD4+ and CD8+ T cells. It was also observed a positive relation between ANXA1 expression and the number of previous episodes of malaria in CD4+ T cells. These data might indicate that ANXA1 could regulate the number of this cell population. This is the first time a paper analyses the expression of ANXA1 in infection by this parasite.
With respect to Treg lymphocytes, the number of these cells and the ANXA1 expression were increased in patients with low parasitaemia. There are no data on the literature about the ANXA1 functionality in Treg cells. These results are interesting and may indicate that this protein can function differently in each lymphocytes subpopulation.
Also, it is important to highlight that high ANXA1 expression in some lymphocytes and other leukocytes might had influence on the levels of IL-10 in malaria patients. Some studies described that ANXA1 can induce the IL-10 production [20, 47, 48] through activation of ERK cascade . This cytokine can be produced by several cell types, such as lymphocytes Treg , CD8+ lymphocytes and monocytes .
In conclusion, this study evidenced that in patients infected with P. vivax the release of immunoregulatory molecules can be influenced by the level of parasitaemia and the number of previous episodes of malaria. ANXA1 is expressed differently in lymphocyte sub-populations and may have a role in regulating lymphocyte proliferation. Furthermore, ANXA1 may be contributing to IL-10 production in plasma of patients with vivax malaria.
This work was supported by the Conselho Nacional de Pesquisa - Brazil (CNPq grant number 555652/2009-2) and Fundação de Amparo à Pesquisa do Estado de Mato Grosso - Brazil (FAPEMAT), PRONEX-Rede Malária, Mato Grosso, Brazil. QIB is funded by Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - Brazil (CAPES) (master studentship). A.S.D. is funded by Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq, 303997/2011-7).
- Ministério da Saúde (Brasil): Dados epidemiológicos de malária por Estado. Amazônia Legal, jan. a dez. de 2010 a 2011. 2012, Portal da saúde,http://www.portal.saude.gov.br,Google Scholar
- Arruda ME, Zimmerman RH, Souza RM, Oliveira-Ferreira J: Prevalence and level of antibodies to the circumsporozoite protein of human malaria parasites in five states of the Amazon region of Brazil. Mem Inst Oswaldo Cruz. 2007, 102: 367-371. 10.1590/S0074-02762007005000041.View ArticlePubMedGoogle Scholar
- Scopel KK, Fontes CJ, Nunes AC, Horta MF, Braga EM: High prevalence of Plamodium malariae infections in a Brazilian Amazon endemic area (Apiacás-Mato Grosso State) as detected by polymerase chain reaction. Acta Trop. 2004, 90: 61-64. 10.1016/j.actatropica.2003.11.002.View ArticlePubMedGoogle Scholar
- Ministério da Saúde (Brasil): Sistema nacional de vigilância em saúde: Mato Grosso. 2010, Brasil, [http://portal.saude.gov.br/portal/arquivos/pdf/26_mato_grosso_final.pdf]Google Scholar
- Anstey NM, Russell B, Yeo TW, Price RN: The pathophysiology of vivax malaria. Trends Parasitol. 2009, 25: 220-227. 10.1016/j.pt.2009.02.003.View ArticlePubMedGoogle Scholar
- Ladeia-Andrade S, Ferreira MU, de Carvalho ME, Curado I, Coura JR: Age-dependent acquisition of protective immunity to malaria in riverine populations of the Amazon Basin of Brazil. Am J Trop Med Hyg. 2009, 80: 452-459.PubMedGoogle Scholar
- Anstey NM, Douglas NM, Poespoprodjo JR, Price RN: Plasmodium vivax: clinical spectrum, risk factors and pathogenesis. Adv Parasitol. 2012, 80: 151-201.View ArticlePubMedGoogle Scholar
- Kemp K, Akanmori BD, Adabayeri V, Goka BQ, Kurtzhals JAL, Behr C, Hviid L: Cytokine production and apoptosis among T cells from patients under treatment for Plasmodium falciparum malaria. Clin Exp Immunol. 2002, 127: 151-157. 10.1046/j.1365-2249.2002.01714.x.PubMed CentralView ArticlePubMedGoogle Scholar
- Schmidt NW, Butler NS, Harty JT: Plasmodium-host interactions directly influence the threshold of memory CD8 T cells required for protective immunity. J Immunol. 2011, 186: 5873-5884. 10.4049/jimmunol.1100194.PubMed CentralView ArticlePubMedGoogle Scholar
- Imai T, Shen J, Chou B, Duan X, Tu L, Tetsutani K, Moriya C, Ishida H, Hamano S, Shimokawa C, Hisaeda H, Himeno K: Involvement of CD8+ T cells in protective immunity against murine blood-stage infection with Plasmodium yoelii 17XL strain. Eur J Immunol. 2010, 40: 1053-1061. 10.1002/eji.200939525.View ArticlePubMedGoogle Scholar
- Bueno LL, Morais CG, Araújo FF, Silva JA, Correa-Oliveira R, Soares IS, Lacerda MV, Fujiwara RT, Braga EM: Plasmodium vivax: induction of CD4 + CD25 + FoxP3 regulatory T cells during infection are directly associated with the level of circulating parasite. PLoS One. 2010, 5: e9623-10.1371/journal.pone.0009623.PubMed CentralView ArticlePubMedGoogle Scholar
- Andrade BB, Reis-Filho A, Souza-Neto SM, Clarêncio J, Camargo LMA, Barral A, Barral-Netto M: Severe Plasmodium vivax malaria exhibits marked inflammatory imbalance. Malar J. 2010, 9: 13-10.1186/1475-2875-9-13.PubMed CentralView ArticlePubMedGoogle Scholar
- Janeway CA, Bottomly K: Signals and signs for lymphocyte responses. Cell. 1994, 76: 275-285. 10.1016/0092-8674(94)90335-2.View ArticlePubMedGoogle Scholar
- Blander JM, Sant’Angelo DB, Bottomly K, Janeway CA: Alteration at a single amino acid residue in the T cell receptor alpha chain complementarity determining region 2 changes the differentiation of naive TCD4 cells in response to antigen from T helper cell type 1 (Th1) to Th2. J Exp Med. 2000, 191: 2065-2074. 10.1084/jem.191.12.2065.PubMed CentralView ArticlePubMedGoogle Scholar
- Perretti M: Endogenous mediators that inhibit the leukocyte-endothelium interaction. Trends Pharmacol Sci. 1997, 18: 418-425.PubMedGoogle Scholar
- Perretti M, Flower RJ: Annexin 1 and the biology of the neutrophil. J Leukoc Biol. 2004, 76: 25-29. 10.1189/jlb.1103552.View ArticlePubMedGoogle Scholar
- Kamal AM, Flower RJ, Perretti M: An overview of the effects of annexin 1 on cells involved in the inflammatory process. Mem Inst Oswaldo Cruz. 2005, 100: 39-47.View ArticlePubMedGoogle Scholar
- Spurr L, Nadkarni S, Pederzoli-Ribeil M, Goulding NJ, Perretti M, D’Acquisto F: Comparative analysis of Annexin A1-formyl peptide receptor 2/ALX expression in human leukocyte subsets. Int Immunopharmacol. 2011, 11: 55-66. 10.1016/j.intimp.2010.10.006.View ArticlePubMedGoogle Scholar
- Yang YH, Song W, Deane JA, Kao W, Ooi JD, Ngo D, Kitching AR, Morand EF, Hickey MJ: Deficiency of annexin A1 in CD4+ T cells exacerbates T cell-dependent inflammation. J Immunol. 2013, 190: 997-1007. 10.4049/jimmunol.1202236.View ArticlePubMedGoogle Scholar
- Weyd H, Abeler-Dörner L, Linke B, Mahr A, Jahndel V, Pfrang S, Schnölzer M, Falk CS, Krammer PH: Annexin A1 on the surface of early apoptotic cells suppresses CD8+ T cell immunity. PLoS One. 2013, 8: e62449-10.1371/journal.pone.0062449.PubMed CentralView ArticlePubMedGoogle Scholar
- Brasil. Ministério da Saúde. Secretaria de Vigilância em Saúde. Departamento de Vigilância Epidemiológica: Guia prático de tratamento da malária no Brasil. 2010, Brasília: Ministério da SaúdeGoogle Scholar
- Damazo AS, Paul-Clark MJ, Straus AH, Takahashi HK, Perretti M, Oliani SM: Analysis of the annexin 1 expression in rat trachea: study of the mast cell heterogeneity. Annexins. 2004, 1: 12-18.Google Scholar
- Schofield L, Grau GE: Immunological processes in malaria pathogenesis. Nat Rev Immunol. 2005, 9: 722-735.View ArticleGoogle Scholar
- Riley EM, Wahl S, Perkins DJ, Schofield L: Regulating immunity to malaria. Parasite Immunol. 2006, 28: 35-49. 10.1111/j.1365-3024.2006.00775.x.View ArticlePubMedGoogle Scholar
- WHO World Health Organization: World Malaria Report 2008. Edited by: Who Press. 2008, Geneva: WHOGoogle Scholar
- Erhart LM, Yingyuen K, Chuanak N, Buathong N, Laoboochai A, Miller RS, Meshnick SR, Gasser RA, Wongsrichanalai C: Hematologic and clinical indices of malaria in a semi-immune population of Western Thailand. Am J Trop Med Hyg. 2004, 70: 8-14.PubMedGoogle Scholar
- Kassa D, Petros B, Mesele T, Hailu E, Wolday D: Characterization of peripheral blood lymphocyte subsets in patients with acute Plasmodium falciparum and P. vivax malaria infections at Wonji Sugar Estate, Ethiopia. Clin Vaccine Immunol. 2006, 13: 376-379. 10.1128/CVI.13.3.376-379.2006.PubMed CentralView ArticlePubMedGoogle Scholar
- Hanscheid T, Langihazoinemon M, Lell B, Potschke M, Oyakhirome S, Kremsner PG, Grobusch MP: Full blood count and hemozoin-containing leukocytes in children with malaria: diagnostic value and association with disease severity. Malar J. 2008, 7: 109-10.1186/1475-2875-7-109.PubMed CentralView ArticlePubMedGoogle Scholar
- Riccio EKP, Júnior IN, Riccio LRP, Alecrim MG, Corte-Real S, Daniel-Ribeiro CT, Ferreira-da-Cruz MF: Malaria associated apoptosis is not significantly correlated with either parasitaemia or the number of previous malaria attacks. Parasitol Res. 2003, 90: 9-18.PubMedGoogle Scholar
- Braga EM, Carvalho LH, Fontes CJF, Krettli AU: Low cellular response in vitro among subjects with long-term exposure to malaria transmission in Brasilian endemic areas. Am J Trop Med Hyg. 2002, 66: 299-303.PubMedGoogle Scholar
- Walther M, Jeffries D, Finney OC, Njie M, Ebonyi A, Deininger S, Lawrence E, Ngwa-Amambua A, Jayasooriya S, Cheeseman IH, Gomez-Escobar N, Okebe J, Conway DJ, Riley EM: Distinct roles for FOXP3+ and FOXP32 CD4+ T cells in regulating cellular immunity to uncomplicated and severe Plasmodium falciparum malaria. PLoS Pathog. 2009, 5: e1000364-10.1371/journal.ppat.1000364.PubMed CentralView ArticlePubMedGoogle Scholar
- Hviid L, Kurtzhals JA, Goka BQ, Oliver-Commey JO, Nkrumah FK, Theander TG: Rapid reemergence of T cells into peripheral circulation following treatment of severe and uncomplicated Plasmodium falciparum malaria. Infect Immun. 1997, 65: 4090-4093.PubMed CentralPubMedGoogle Scholar
- Lisse IM, Aaby P, Whittle H, Knudsen K: A community study of T lymphocyte subsets and malaria parasitaemia. Trans R Soc Trop Med Hyg. 1994, 88: 709-710. 10.1016/0035-9203(94)90242-9.View ArticlePubMedGoogle Scholar
- Gopinathan VP, Subramanian AR: Vivax and falciparum malaria seen at an Indian service hospital. J Trop Med Hyg. 1986, 89: 51-55.PubMedGoogle Scholar
- Ouma C, Davenport GC, Were T, Otieno MF, Hittner JB, Vulule JM, Martinson J, Ong’echa JM, Ferrell RE, Perkins DJ: Haplotypes of IL-10 promoter variants are associated with susceptibility to severe malarial anemia and functional changes in IL-10 production. Hum Genet. 2008, 124: 515-524. 10.1007/s00439-008-0578-5.PubMed CentralView ArticlePubMedGoogle Scholar
- Zeyrek FY, Kurcer MA, Zeyrek D, Simsek Z: Parasite density and serum cytokine levels in Plasmodium vivax malaria in Turkey. Parasite Immunol. 2006, 28: 201-207. 10.1111/j.1365-3024.2006.00822.x.View ArticlePubMedGoogle Scholar
- Cai G, Kastelein RA, Hunter CA: IL-10 enhances NK cell proliferation, cytotoxicity and production of IFN-γ when combined with IL-18. Eur J Immunol. 1999, 29: 2658-2665. 10.1002/(SICI)1521-4141(199909)29:09<2658::AID-IMMU2658>3.0.CO;2-G.View ArticlePubMedGoogle Scholar
- Conti P, Kempuraj D, Kandere K, Di Gioacchino M, Barbacane RC, Castellani ML, Felaco M, Boucher W, Letourneau R, Theoharides TC: IL-10, an inflammatory/inhibitory cytokine, but not always. Immunol Lett. 2003, 86: 123-129. 10.1016/S0165-2478(03)00002-6.View ArticlePubMedGoogle Scholar
- Pestka S, Krause CD, Sarkar D, Walter MR, Shi Y, Fisher PB: Interleukin-10 and related cytokines and receptors. Annu Rev Immunol. 2004, 22: 929-979. 10.1146/annurev.immunol.22.012703.104622.View ArticlePubMedGoogle Scholar
- Jangpatarapongsa K, Chootong P, Sattabongkot J, Chotivanich K, Sirichaisinthop J, Tungpradabkul S, Hisaeda H, Troye-Blomberg M, Cui L, Udomsangpetch R: Plasmodium vivax parasites alter the balance of myeloid and plasmacytoid dendritic cells and the induction of regulatory T cells. Eur J Immunol. 2008, 38: 2697-2705. 10.1002/eji.200838186.PubMed CentralView ArticlePubMedGoogle Scholar
- Torre D, Speranza F, Giola M, Matteelli A, Tambini R, Biondi G: Role of Th1 and Th2 cytokines in immune response to uncomplicated Plasmodium falciparum malaria. Clin Diagn Lab Immunol. 2002, 9: 348-351.PubMed CentralPubMedGoogle Scholar
- Morand EF, Jefferiss CM, Dixey J, Mitra D, Goulding NJ: Impaired glucocorticoid induction of mononuclear leukocyte lipocortin 1 in rheumatoid arthritis. Arthritis Rheum. 1994, 37: 207-211. 10.1002/art.1780370209.View ArticlePubMedGoogle Scholar
- Goulding NJ, Dixey J, Morand EF, Dodds RA, Wilkinson LS, Pitsillides AA, Edwards JC: Differential distribution of annexins-I, -II, -IV and -VI in synovium. Ann Rheum Dis. 1995, 54: 841-845. 10.1136/ard.54.10.841.PubMed CentralView ArticlePubMedGoogle Scholar
- D’acquisto F, Perretti M: Annexin-A1: a pivotal regulator of the innate and adaptive immune systems. Br J Pharm. 2008, 155: 152-169.View ArticleGoogle Scholar
- Goulding NJ, Ogbourn S, Pipitone N, Biagini P, Gerli R, Pitzalis C: The inhibitory effect of dexamethasone on lymphocyte adhesion molecule expression and intercellular aggregation is not mediated by lipocortin 1. Clin Exp Immunol. 1999, 118: 376-383.PubMed CentralView ArticlePubMedGoogle Scholar
- Paschalidis N, Huggins A, Rowbotham NJ, Furmanski AL, Crompton T: Role of endogenous annexin-A1 in the regulation of thymocyte positive and negative selection. Cell Cycle. 2010, 15: 784-793.Google Scholar
- Parente L, Solito E: Annexin 1: more than an anti-phospholipase protein. Inflamm Res. 2004, 53: 125-132. 10.1007/s00011-003-1235-z.View ArticlePubMedGoogle Scholar
- Cunha EE, Oliani SM, Damazo AS: Effect of annexin-A1 peptide treatment during lung inflammation induced by lipopolysaccharide. Pulm Pharmacol Ther. 2012, 25: 303-311. 10.1016/j.pupt.2012.04.002.View ArticlePubMedGoogle Scholar
- Ferlazzo V, D’Agostino P, Milano S, Caruso R, Feo S, Cillari E, Parente L: Anti-inflammatory effects of annexin-1: stimulation of IL-10 release and inhibition of nitric oxide synthesis. Int Immunopharmacol. 2003, 3: 1363-1369. 10.1016/S1567-5769(03)00133-4.View ArticlePubMedGoogle Scholar
- Nussenblatt V, Mukasa G, Metzger A, Ndeezi G, Garrett E, Semba RD: Anemia and interleukin-10, tumor necrosis factor alpha, and erythropoietin levels among children with acute, uncomplicated Plasmodium falciparum malaria. Clin Diagn Lab Immunol. 2001, 8: 1164-1170.PubMed CentralPubMedGoogle Scholar
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