Skip Navigation

Genetic Evidence for the Aggravation of Plasmodium falciparum Malaria by Interleukin 4

  1. Sandrine Cabantous1,3,
  2. Belco Poudiougou6,
  3. Aboubacar A. Oumar7,
  4. Abdoualye Traore6,
  5. Abdoulaye Barry8,
  6. Joana Vitte2,4,5,
  7. Pierre Bongrand2,4,5,
  8. Sandrine Marquet1,3,
  9. Ogobara Doumbo6 and
  10. Alain J. Dessein1,3
  1. 1Institut National de la Santé et de la Recherche Médicale (INSERM), Unité 906
  2. 2INSERM, Unité 600,
  3. 3Faculté de Médecine, Aix-Marseille Université, IFR88
  4. 4Centre National de Recherche Scientifique, Unité 6212,
  5. 5Laboratoire d'Immunologie, Faculté de Médecine de Marseille, Assistance Publique-Hôpitaux de Marseille, Marseille, France
  6. 6Malaria Research and Training Centre, Faculty of Medicine, Pharmacy, and Odonto-Stomatology
  7. 7Centre des Œuvres Universitaires, University of Bamako
  8. 8Paediatric Wards, Gabriel Toure Hospital, Bamako, Mali
  1. Reprints or correspondence: Dr Sandrine Cabantous, Genetics and Immunology of Parasitic Diseases, INSERM UMR906, Faculty of Medicine Timone, 27 blvd Jean Moulin, Marseille 13005, France (sandrine.cabantous{at}univmed.fr)
 
Next Section

Abstract

BackgroundSevere malaria (SM) due to Plasmodium falciparum causes millions of child deaths in sub-Saharan Africa. It comprises a variety of clinical disorders, including cerebral malaria (CM) and severe anemia (SA). In previous work, we have shown that interferon γ and interleukin 12 protect against CM. Here, we investigated whether interleukin 4 (IL-4) aggravates the risk of severe disease

MethodsWe prospectively recruited children with CM (n=240), SA (n=101), and uncomplicated malaria (UM) (n=42) in Bamako, Mali, and measured IL-4 production in plasma by enzyme-linked immunosorbent assay. We then assessed the influence of 11 polymorphisms on predisposition to SM by the family-based association test (FBAT)

ResultsIL-4 concentrations were higher in children with CM than in children with UM during malaria (P=.003). FBAT analyses showed that the most significant association was between the IL4 variable-number tandem repeat (VNTR) 1/2 genotype and SM (P<.001); an association was also observed for IL4 −33 C/T, rs2243267 G/C, rs2243268 C/A, and rs2243282 C/A (P<.05). Interestingly, we found that the plasma concentration of IL-4 was higher in subjects with the IL4 VNTR 1/2 or 1/1 genotype than with the IL4 VNTR 2/2 genotype (P=.003)

ConclusionsThese results support the view that IL-4 may be a risk factor for SM. IL-4 may aggravate the disease by interfering with type 1 T helper cell differentiation or by promoting local inflammation at sites of parasite sequestration

Plasmodium falciparum infections cause severe clinical complications in some children and adults. These complications include respiratory distress syndrome, hypoglycemia, metabolic acidosis, cerebral malaria (CM), and severe anemia (SA). It is thought that many of these complications result from the sequestration of parasitized red blood cells in small vessels and the formation of aggregates between noninfected and infected red cells [1]. Note that both of these phenomena contribute to tissue hypoxia. The host immune response is highly significant: it may limit hypoxia by destroying the parasites [2 –4] or promote hypoxia by producing substances that increase the adhesiveness of infected red blood cells or down-regulate blood tissue perfusion [5, 6]. It is also possible that the inflammation that develops locally at the sites of parasite sequestration may also cause damage to endothelial cells by releasing reactive oxygen and nitrogen intermediates and act directly on some sensitive cells in tissues [7]. A current view is that progression toward severe malaria (SM) depends on a balanced cytokine response that must allow elimination of the parasite without causing much tissue damage. Type 1 T helper (Th1) lymphocytes have been reported in mice infected with murine Plasmodium and in the blood of infected humans. They may play a Janus-type role: they may be protective by releasing interferon γ (IFN-γ), which in turn activates macrophages to destroy parasitized red blood cells, promotes the production of opsonizing antibody, and contributes to destroying Plasmodium in hepatocytes [2, 4, 8]; however, IFN-γ also has proinflammatory effects that could contribute to disease severity [9]. There is evidence that IFN-γ contributes to protection against CM at least in those who recover from the disease [3, 10]. It is nevertheless possible that IFN-γ might have different effects according to which other immune components have been activated. Thus, IFN-γ may not be protective in those who die of CM [10]

If IFN-γ and interleukin 12 (IL-12) have significant protective effects against SM [10, 11], then cytokines that inhibit Th1 cell differentiation or that interfere with IFN-γ-mediated activation of phagocytes—such as interleukin 10 and interleukin 4 (IL-4)—may increase the risk of SM. Indeed, children with SM have elevated immunoglobulin E (IgE) levels, and IgE deposits have been observed in brain vessels in which massive sequestration had occurred [12, 13]

Our aim was to use a genetic approach to evaluate whether IL-4 contributes to the pathogenesis of malaria. This type of approach has been used previously to confirm the involvement of cytokines in the pathogenesis of SM [14] and of type 2 T helper cytokines in other parasitic diseases [15, 16]. We report that IL4 alleles that increase IL-4 production are transmitted more to subjects with SM and that plasma concentrations of IL-4 are elevated in these subjects. These findings argue for participation of IL-4 in the pathogenesis of malaria and identify mutations in IL4 that are associated with a higher risk of disease

Previous SectionNext Section

Methods

Study population and sampling This study included 341 children with SM (either CM or SA) and 42 children with uncomplicated malaria (UM) (Table 1) hospitalized in the pediatric department of Gabriel Toure Hospital in Bamako, Mali [17 -19]

Figure 1
View larger version:
Figure 1

A, Higher plasma concentrations of interleukin 4 (IL-4) in children with severe malaria (SM) than in children with uncomplicated malaria (UM) during the episode. B, Higher plasma concentration of IL-4 in children with cerebral malaria (CM) and in children with severe anemia (SA) than in children with UM during the episode. The nonparametric Mann-Whitney U test was used to assess differences. Horizontal lines within boxes indicate median values, boxes indicate interquartile ranges, and error bars indicate standard deviations

Figure 2
View larger version:
Figure 2

A, Localization of 16 markers used to define blocks of correlation. B, Block of correlation between polymorphisms in IL4, IL13, and KIF3A. C, Correlation values for the 16 polymorphisms analyzed in Malian subjects. Asterisks indicate polymorphisms with a minor allelic frequency >15% used in an association study after the definition of correlation blocks

Figure 3
View larger version:
Figure 3

Higher plasma concentrations of interleukin 4 (IL-4) in children who were homozygous for allele 1 or heterozygous than in children who were homozygous for allele 2. The nonparametric Mann-Whitney U test was used to assess differences. Horizontal lines within boxes indicate median values, boxes indicate interquartile ranges, and error bars indicate standard deviations

Table 1
View larger version:
Table 1

Description of the Children Included in the Study

Children were considered to have CM if they were comatose (Blantyre coma scale [BCS] score, < 3) and had a thick blood film positive for P. falciparum (n=240). Meningitis was ruled out by lumbar puncture. One hundred eighty-seven of these patients rapidly recovered fully after treatment with quinine; 53 died despite the same treatment

Children were considered to have SA if they had a thick blood film positive for P. falciparum, a packed cell volume ⩽15%, and a BCS score ⩾3 (n=101). Of these 101 children, 98 recovered fully after transfusion and treatment with quinine

Children were considered to have UM if they had a thick blood film positive for P. falciparum, a BCS score >4, and hematocrit >21% (n=42). These children did not develop CM at any time. They attended the outpatient clinic because of a bout of febrile malaria

Informed consent was obtained from the parents of each child. The study was approved by the Ethics Committee of the Faculty of Medicine of Bamako, Mali. Recruitment, DNA extraction from blood leukocytes, and analysis of parental inconsistencies were performed as described elsewhere [10]

Cytokine assays IL-4 and interleukin 13 (IL-13) levels were determined by enzyme-linked immunosorbent assay, using pairs of cytokine-specific monoclonal antibodies (Abcys). The detection threshold was 4 pg/mL for IL-4 and 1 pg/mL for IL-13. Data are presented as arithmetic means of duplicate values. IgE was assayed in plasma samples from the patients by the paper radioimmunosorbent technique (Pharmacia); values were expressed in units per milliliter. Cytokines were assayed in plasma samples from 44 children with CM, 16 children with fatal CM, 61 children with SA, and 42 children with UM

Genotyping of the IL4 polymorphisms All the polymorphisms studied are single-nucleotide polymorphisms (SNPs) except the IL4 variable-number tandem repeat (VNTR), which is a 70-bp short tandem repeat [20]. We investigated all these variants in an initial cohort of 198 nuclear families recruited between 2000 and 2001. Markers showing P<.05 have been tested for association in a larger cohort. Then we used 143 additional families recruited between 2002 and 2003. The polymorphisms were studied by polymerase chain reaction (PCR) amplification followed by enzymatic digestion using the primers and the enzymes described in Table 2. The digestion products were analyzed on 10% or 12% acrylamide gel (37.5:1) or 2% agarose gel stained with ethidium bromide solution (1 mg/mL) (Table 2)

Table 2
View larger version:
Table 2

Methodology for Genotyping of Polymorphisms Used in the Study

Blocks of correlation (r2>0.7) were determined by genotyping 16 polymorphisms in 80 independent subjects (as described in Table 2) or by TaqMan allelic discrimination (Applied Biosystems) for rs2243266 (G/A), rs2243267 (G/C), and rs2243282 (C/A), in accordance with the manufacturer’s instructions

IL4 sequencing IL4 gene sequences from 10 subjects (4 with CM, 3 with SA, and 3 with UM) were determined using PCR-amplified products (Table 3). DNA fragments were sequenced by GATC Biotech. Chromas (version 1.45) and ClustalW (version 1.83) software were used for screening and fragment alignments

Table 3
View larger version:
Table 3

Primers Used for Sequencing

Statistical analysis The nonparametric Wilcoxon&amp;rank sum test was used to assess differences between groups. Nonmatched groups were compared by the Mann-Whitney U test (SPSS, version 10.1). Hardy-Weinberg equilibrium was tested with the Genepop program (Web version 3.1c), using the genotypes of 396 or 682 unrelated first-degree relatives. Of 11 polymorphisms tested in familial association studies, only rs2243266 was not in Hardy-Weinberg equilibrium. Associations between individual polymorphisms and SM were analyzed by the family-based association test (FBAT), using FBAT software (version 1.4). The association between IL4 VNTR genotype and IL-4 concentrations was tested by nonparametric analysis (Mann-Whitney U test)

Previous SectionNext Section

Results

Association between SM and high plasma concentrations of IL-4 IL-4 was assayed in plasma samples from 121 children with SM (60 with CM and 61 with SA) and from 42 children with UM. We collected plasma on the day of admission and 4 weeks later except for 16 children with CM (26.7%) who died within 2 days of admission

IL-4 concentrations were significantly higher in children with SM (median, 32 pg/mL) than in children with UM (median, 15 pg/mL) (P=.003) (Figure 1A ). IL-4 concentrations were higher in patients with nonlethal CM (median, 32 pg/mL) and SA (median, 44 pg/mL) than in those with UM (median, 15 pg/mL); the difference between children with SA and those with UM was statistically significant (P<.001), and there was a trend toward higher levels in patients with CM than in those with UM (P=.06) (Figure 1B ). Four weeks after hospital discharge, plasma IL-4 concentrations had returned to low levels (median, 4 pg/mL), confirming that the increased IL-4 levels were due to malaria

The IL-4 concentration in plasma from subjects who died during hospitalization was lower than that in plasma from those with nonlethal CM (median, 20 vs 32 pg/mL) and was no higher than that in those with UM (median, 20 vs 15 pg/mL) (Figure 1B )

Interestingly, the plasma concentration of IL-13, like that of IL-4, was significantly higher in children with SM (median, 12 pg/mL) than in children with UM (median, 5.5 pg/mL) (P<.001). However, there was no statistically significant difference in plasma level of total IgE between children with SM and those with UM (data not shown)

Association between polymorphisms in IL4 and SM We selected polymorphisms associated with an increased risk of allergic disease and with high IgE levels [21 –23]. Polymorphisms in IL4—one at position −590 (rs2243250), one at position −33 (rs2070874), and a VNTR in intron 3 (rs8179190)—were genotyped in 198 trios (2 parents with an affected child). Although all of these markers were informative, only IL4 −33 and IL4 VNTR showed an association with SM: the genotypes IL4 −33 C/T and IL4 VNTR 1/2 were overtransmitted to children with SM (P=.009 and P=.003, respectively). We genotyped 143 additional trios for these 2 polymorphisms (IL4 −33 and IL4 VNTR) showing a significant association. In the total sample set of 341 families, the most significant association was obtained between the heterozygous IL4 VNTR genotype and SM (P<.001); an association was also observed between IL4 −33 C/T and the phenotype (P=.01) (Table 4). These results confirm that children heterozygous for the IL4 VNTR are susceptible to SM

Table 4
View larger version:
Table 4

Associations between IL4 −33 (rs2070874), rs2243267, rs2243268, IL4 VNTR (rs8179190), and rs2243282 polymorphisms and Severe Malaria in the Whole Study Population

Associations between IL4 VNTR and −33 genotypes and CM or SA We tested whether IL4 VNTR and −33 genotypes were associated with either CM or SA in the whole population. IL4 VNTR 1/2 and IL4 −33 C/T were associated with CM (P=.001 and P=.02, respectively). The genotyping data for subjects with SA demonstrated an association between SA and IL4 VNTR 1/2 (P=.03)

Definition of 3 correlation blocks in the IL4 gene The association between the IL4 VNTR and SM indicates either that this polymorphism is involved in pathogenesis or that it is in linkage disequilibrium with another polymorphism involved in pathogenesis. We sequenced the IL4 gene (FJ807883) and defined the blocks of correlation for selected polymorphisms with a minor allelic frequency (MAF) >20%

We detected 35 polymorphisms in the IL4 gene sequence: 15 polymorphisms had a MAF >20%, 15 had a MAF of ∼15%, and 5 had a MAF <10%. We selected 16 polymorphisms to define correlation groups (r2>0.7); 13 (including IL4 −590, −33, and VNTR polymorphisms) map in the IL4 gene, 1 in IL13, and 2 in KIF3A (Figure 2A ). These genetic variants were genotyped in 80 subjects. Three major correlation groups were observed: (1) IL4 −33 (rs2070874) and rs11479198, (2) rs2243251 and rs2243255, and (3) rs2243266, rs2243267, VNTR, and rs2243282 (Figure 2B ). The correlation values for the 16 polymorphisms in the Malian subjects are shown in Figure 2C

Only weak associations between SM and polymorphisms in linkage disequilibrium with IL4 VNTR and −33 We selected 8 additional polymorphisms with a MAF >15% (rs2243251, rs11479198, rs2243255, rs2243266, rs2243267, rs2243268, rs2243274, and rs2243282) for an association study. Of these 8 polymorphisms (indicated by an asterisk in Figure 2), 3 were in linkage disequilibrium with IL4 VNTR, and 1 was in linkage disequilibrium with IL4 −33. We conducted FBAT analysis on 198 trios. Only 5 of the polymorphisms showed an association with SM. A heterozygous genotype for each of the polymorphisms rs11479198, rs2243266, rs2243267, rs2243268, and rs2243282 was more prevalent among children with SM than expected (P=.02, P=.05, P=.05, P=.009, and P=.03, respectively). These markers were then analyzed using the total sample set (341 families). There was an association between SM and being heterozygous for rs2243267, rs2243268, and rs2243282 (P=.03, P=.01, and P=.03, respectively) (Table 4). Hence, the IL4 VNTR polymorphism showed the most significant association with susceptibility to SM

Association between IL4 VNTR 1/1 and 1/2 genotypes and high plasma concentrations of IL-4 and IL-13 We analyzed the association between IL4 VNTR genotypes and plasma IL-4 concentration by univariate nonparametric tests. Among 163 children from all study groups (CM, SA, and UM), IL4 VNTR genotypes showed an association with plasma IL-4 levels: plasma from subjects who were homozygous for allele 1 or were heterozygous had higher plasma IL-4 concentrations than did plasma from subjects who were homozygous for allele 2 (P=.003) (Figure 3). Interestingly, the same IL4 VNTR genotypes were also strongly associated with IL-13 concentration (P=.001); similarly, subjects who were homozygous for allele 1 or were heterozygous exhibited the highest plasma IL-13 concentrations (data not shown)

Previous SectionNext Section

Discussion

In the present study, we report evidence that IL-4 plays an aggravating role in SM—and, more precisely, in CM—in children. First, we confirmed the association between high plasma concentrations of IL-4 and SM, consistent with findings reported by others for IL-4, soluble IL-4 receptor, and IgE [12, 24]. We also observed that IL-4 concentrations in children with SA were higher than those in children with CM. The association between IL-4 level and SA has been explained by Helmby et al [25], who demonstrated that IL-4 is produced by basophils that have been stimulated and/or activated by interleukin 3, which is produced in large amounts as a result of the anemia caused by the disease

To determine whether high IL-4 concentrations were not simply a consequence of the disease, we evaluated whether polymorphisms in IL4, which are believed to be associated with protein abundance, were also associated with SM [21, 26]. We observed that the IL4 VNTR 1/2 genotype was associated with severe disease and that polymorphism IL4 −33 is associated, albeit weakly, with SM. The association between the IL4 VNTR 1/2 genotype and susceptibility to SM is consistent with our observation that plasma concentrations of IL-4 are higher in heterozygous children, whereas the IL4 VNTR 2/2 genotype is correlated with lower IL-4 concentrations. Evaluation of polymorphisms in linkage disequilibrium with IL4 VNTR supports the notion that it is involved in SM

The effects that IL-4 has on antimalarial immunity are complex. IL-4 may reduce immunity to blood-stage parasites and thereby contribute to the growth of parasite mass [27]; however, IL-4 might be required for antisporozoite immunity [28]. IL-4 can reduce blood-stage parasite immunity in several ways—IL-4 interferes with Th1 cell development and reduces the production of IFN-γ [29]. IFN-γ is required for the activation of the microbicidal activity of blood monocytes, which are crucial to the control of blood-stage parasites [2, 4]. IFN-γ is also required for isotype switching and the production of opsonizing antibody, which promote parasite phagocytosis by activated monocytes [8]. IL-4 also acts directly on blood monocytes and macrophages, and the net effects reduce antimalarial immunity and inhibit FcγR membrane expression and FcγR-mediated cytotoxic activity [30], IFN-γ-dependent macrophage activation [31], production of reactive oxygen intermediates, enhanced transcription of inductable nitric oxide synthase via the accumulation of iron [32], and antibody-independent killing of P. falciparum by macrophages [27]. Studies in mice infected with Plasmodium yoelii have shown that IL-4 is required for the development of CD8+ T lymphocytes [28] and for the development of a memory response [33] against liver-stage parasites. This raises the possibility that IL-4 may also exert opposite and indeed positive effects on the control of P. falciparum infections. Once an infection is established, however, IL-4 is expected to facilitate parasite multiplication via its multiple effects on immunity

That SA is associated with malaria is the consequence of both massive lysis of the infected erythrocytes and the inhibition of erythropoiesis [34]; consequently, factors such as IL-4 that facilitate parasite multiplication presumably aggravate the disease. This view was apparently supported by the observation that SA was associated with high plasma IL-4 levels, even higher than those observed for CM. We found only a weak association between SA susceptibility and IL4 VNTR 1/2. This supports 2 interpretations that are not mutually exclusive: first, the prodisease effects of IL-4 (resulting from its action on the mechanisms controlling parasite multiplication) might be balanced by the direct positive effects that IL-4 has on erythropoiesis; second, the number of families in the SA group in the study (101, vs 240 for CM) was insufficient to detect an association. Indeed, IL-4 increases the growth of erythroid precursors [35, 36]—IL-4 acts as a costimulant with erythropoietin or interleukin 6 (IL-6), causing a marked increase in the development of erythroid burst-forming unit colonies [35]. Both IL-6 and erythropoietin were observed in the plasma from children with SA included in our study. IL-12 also synergizes with IL-4 to stimulate erythropoiesis in vitro [37]. Thus, the present findings and data in the literature are altogether consistent with the view that the beneficial effects that IL-4 has on erythropoiesis may balance the aggravating effects that IL-4 has on anemia, which may result from increased parasite multiplication

IL-4 may aggravate malaria and contribute to CM by inhibiting the destruction of blood-stage parasites; it has also specific effects on the vascular endothelium that could further increase the risk of CM by enhancing inflammation in brain microvessels. IL-4 acts synergistically with tumor necrosis factor to substantially increase vascular cell-adhesion molecule 1 (VCAM-1) expression on endothelial cells [38, 39]. IL-4 stabilizes VCAM-1 mRNA and thereby allows the persistence of VCAM-1 on the cell surface, whereas tumor necrosis factor exerts a transcriptional stimulation [40]. VCAM-1 is a key cell-adhesion molecule that arrests monocytes that roll on endothelium venules [41]; both its expression on endothelia and local IL-4 production have been associated with local accumulation of basophils, eosinophils, and monocytes that express the α4 β1 integrin at sites of allergic reactions [42]. IL-4 also stimulates the production by endothelial cells of monocyte chemotactic protein 1, a potent chemotractant for monocytes [39, 43]. Monocytes, eosinophils, and basophils might be activated by immune complexes containing IgE such that they release IL-4 and various inflammatory mediators. This would further increase the IL-4 concentration in tissues, where blood perfusion is decreased by parasite sequestration and red blood cell aggregation. Parasitized erythrocytes adhere to endothelial cell-adhesion molecules, including VCAM-1 [44]. Therefore, increased VCAM-1 expression due to the action of IL-4 is expected to contribute to parasite sequestration and increase both the accumulation of inflammatory cells and the release of inflammatory substances. This would further aggravate local inflammation, reduce tissue blood perfusion, and contribute to tissue hypoxia. Thus, several observations support the hypothesis that IL-4 participates in the aggravation of CM in 3 ways: by increasing parasite mass; by promoting infiltration by monocytes, basophils, and eosinophils; and by increasing parasite sequestration. Consequently, we suggest that IL-4 has much broader aggravating effects on CM than does IgE

Previous SectionNext Section

Acknowledgments

We thank Dr Laurent Argiro, Dr Christophe Chevillard, and the staff of the pediatric wards the Gabriel Toure Hospital in Bamako for their help

Previous SectionNext Section

Footnotes

  • Potential conflicts of interest: none reported

  • Financial support: Institut National de la Santé et de la Recherche Médicale (support to the study); MRTC/DEAP (grants to the study); French Research Ministry (VIH-PAL) Action 2000 (support to the study); VIH-PAL and FRM (fellowship to S.C.)

  • Received March 24, 2009.
  • Accepted June 12, 2009.
Previous Section
 

References

  1. 1.↵
    1. Fernandez V,
    2. Wahlgren M
    . Rosetting and autoagglutination in Plasmodium falciparum . Chem Immunol 2002;80:163-87.
    MedlineWeb of Science
  2. 2.↵
    1. Rockett KA,
    2. Awburn MM,
    3. Cowden WB,
    4. Clark IA
    . Killing of Plasmodium falciparum in vitro by nitric oxide derivatives. Infect Immun 1991;59:3280-3.
    Abstract/FREE Full Text
  3. 3.↵
    1. Artavanis‐Tsakonas K,
    2. Riley EM
    . Innate immune response to malaria: rapid induction of IFN‐gamma from human NK cells by live Plasmodium falciparum‐infected erythrocytes. J Immunol 2002;169:2956-63.
    Abstract/FREE Full Text
  4. 4.↵
    1. Bashyam H
    . IFNgamma: issuing macrophages a license to kill. J Exp Med 2007;204:3.
    Abstract/FREE Full Text
  5. 5.↵
    1. Ringwald P,
    2. Peyron F,
    3. Lepers JP,
    4. et al
    . Parasite virulence factors during falciparum malaria: rosetting, cytoadherence, and modulation of cytoadherence by cytokines. Infect Immun 1993;61:5198-204.
    Abstract/FREE Full Text
  6. 6.↵
    1. Rosenman SJ,
    2. Shrikant P,
    3. Dubb L,
    4. Benveniste EN,
    5. Ransohoff RM
    . Cytokine‐induced expression of vascular cell adhesion molecule‐1 (VCAM‐1) by astrocytes and astrocytoma cell lines. J Immunol 1995;154:1888-99.
    Abstract
  7. 7.↵
    1. Taoufiq Z,
    2. Pino P,
    3. Dugas N,
    4. et al
    . Transient supplementation of superoxide dismutase protects endothelial cells against Plasmodium falciparum‐induced oxidative stress. Mol Biochem Parasitol 2006;150:166-73.
    CrossRefMedlineWeb of Science
  8. 8.↵
    1. Yoneto T,
    2. Waki S,
    3. Takai T,
    4. et al
    . A critical role of Fc receptor‐mediated antibody‐dependent phagocytosis in the host resistance to blood‐stage Plasmodium berghei XAT infection. J Immunol 2001;166:6236-41.
    Abstract/FREE Full Text
  9. 9.↵
    1. Weiser S,
    2. Miu J,
    3. Ball HJ,
    4. Hunt NH
    . Interferon‐gamma synergises with tumour necrosis factor and lymphotoxin‐alpha to enhance the mRNA and protein expression of adhesion molecules in mouse brain endothelial cells. Cytokine 2007;37:84-91.
    CrossRefMedlineWeb of Science
  10. 10.↵
    1. Cabantous S,
    2. Poudiougou B,
    3. Traore A,
    4. et al
    . Evidence that interferon‐γ plays a protective role during cerebral malaria. J Infect Dis 2005;192:854-60.
    Abstract/FREE Full Text
  11. 11.↵
    1. Marquet S,
    2. Doumbo O,
    3. Cabantous S,
    4. et al
    . A functional promoter variant in IL12B predisposes to cerebral malaria. Hum Mol Genet 2008;17:2190-5.
    Abstract/FREE Full Text
  12. 12.↵
    1. Perlmann P,
    2. Perlmann H,
    3. Flyg BW,
    4. et al
    . Immunoglobulin E, a pathogenic factor in Plasmodium falciparum malaria. Infect Immun 1997;65:116-21.
    Abstract/FREE Full Text
  13. 13.↵
    1. Maeno Y,
    2. Perlmann P,
    3. Perlmann H,
    4. et al
    . IgE deposition in brain microvessels and on parasitized erythrocytes from cerebral malaria patients. Am J Trop Med Hyg 2000;63:128-32.
    Abstract
  14. 14.↵
    1. Campino S,
    2. Kwiatkowski D,
    3. Dessein A
    . Mendelian and complex genetics of susceptibility and resistance to parasitic infections. Semin Immunol 2006;18:411-22.
    CrossRefMedlineWeb of Science
  15. 15.↵
    1. Dessein A,
    2. Kouriba B,
    3. Eboumbou C,
    4. et al
    . Interleukin‐13 in the skin and interferon‐gamma in the liver are key players in immune protection in human schistosomiasis. Immunol Rev 2004;201:180-90.
    CrossRefMedlineWeb of Science
  16. 16.↵
    1. Kouriba B,
    2. Chevillard C,
    3. Bream JH,
    4. et al
    . Analysis of the 5q31–q33 locus shows an association between IL13–1055C/T IL‐13‐591A/G polymorphisms and Schistosoma haematobium infections. J Immunol 2005;174:6274-81.
    Abstract/FREE Full Text
  17. 17.↵
    1. Safeukui‐Noubissi I,
    2. Ranque S,
    3. Poudiougou B,
    4. et al
    . Risk factors for severe malaria in Bamako, Mali: a matched case‐control study. Microbes Infect 2004;6:572-8.
    CrossRefMedlineWeb of Science
  18. 18.↵
    1. Ranque S,
    2. Safeukui I,
    3. Poudiougou B,
    4. et al
    . Familial aggregation of cerebral malaria and severe malarial anemia. J Infect Dis 2005;191:799-804.
    Abstract/FREE Full Text
  19. 19.↵
    1. Ranque S,
    2. Poudiougou B,
    3. Traore A,
    4. et al
    . Life‐threatening malaria in African children: a prospective study in a mesoendemic urban setting. Pediatr Infect Dis J 2008;27:130-5.
    MedlineWeb of Science
  20. 20.↵
    1. Mout R,
    2. Willemze R,
    3. Landegent JE
    . Repeat polymorphisms in the interleukin‐4 gene (IL4). Nucleic Acids Res 1991;19:3763.
    FREE Full Text
  21. 21.↵
    1. Suzuki I,
    2. Hizawa N,
    3. Yamaguchi E,
    4. Kawakami Y
    . Association between a C+33T polymorphism in the IL‐4 promoter region and total serum IgE levels. Clin Exp Allergy 2000;30:1746-9.
    CrossRefMedlineWeb of Science
  22. 22.↵
    1. Beghe B,
    2. Barton S,
    3. Rorke S,
    4. et al
    . Polymorphisms in the interleukin‐4 and interleukin‐4 receptor alpha chain genes confer susceptibility to asthma and atopy in a Caucasian population. Clin Exp Allergy 2003;33:1111-7.
    CrossRefMedlineWeb of Science
  23. 23.↵
    1. Kabesch M,
    2. Schedel M,
    3. Carr D,
    4. et al
    . IL‐4/IL‐13 pathway genetics strongly influence serum IgE levels and childhood asthma. J Allergy Clin Immunol 2006;117:269-74.
    CrossRefMedlineWeb of Science
  24. 24.↵
    1. Perkmann T,
    2. Winkler H,
    3. Graninger W,
    4. Kremsner PG,
    5. Winkler S
    . Circulating levels of the interleukin (IL)‐4 receptor and of IL‐18 in patients with Plasmodium falciparum malaria. Cytokine 2005;29:153-8.
    CrossRefMedlineWeb of Science
  25. 25.↵
    1. Helmby H,
    2. Kullberg M,
    3. Troye‐Blomberg M
    . Expansion of IL‐3‐responsive IL‐4‐producing non‐B non‐T cells correlates with anemia and IL‐3 production in mice infected with blood‐stage Plasmodium chabaudi malaria. Eur J Immunol 1998;28:2559-70.
    CrossRefMedlineWeb of Science
  26. 26.↵
    1. Verra F,
    2. Luoni G,
    3. Calissano C,
    4. et al
    . IL4‐589C/T polymorphism and IgE levels in severe malaria. Acta Trop 2004;90:205-9.
    CrossRefMedlineWeb of Science
  27. 27.↵
    1. Kumaratilake LM,
    2. Ferrante A
    . IL‐4 inhibits macrophage‐mediated killing of Plasmodium falciparum in vitro: a possible parasite‐immune evasion mechanism. J Immunol 1992;149:194-9.
    Abstract
  28. 28.↵
    1. Carvalho LH,
    2. Sano G,
    3. Hafalla JC,
    4. Morrot A,
    5. Curotto de Lafaille MA,
    6. Zavala F
    . IL‐4‐secreting CD4+ T cells are crucial to the development of CD8+ T‐cell responses against malaria liver stages. Nat Med 2002;8:166-70.
    CrossRefMedlineWeb of Science
  29. 29.↵
    1. Zhu J,
    2. Yamane H,
    3. Cote‐Sierra J,
    4. Guo L,
    5. Paul WE
    . GATA‐3 promotes Th2 responses through three different mechanisms: induction of Th2 cytokine production, selective growth of Th2 cells and inhibition of Th1 cell‐specific factors. Cell Res 2006;16:3-10.
    CrossRefMedlineWeb of Science
  30. 30.↵
    1. te Velde AA,
    2. Huijbens RJ,
    3. de Vries JE,
    4. Figdor CG
    . IL‐4 decreases Fc gamma R membrane expression and Fc gamma R‐mediated cytotoxic activity of human monocytes. J Immunol 1990;144:3046-51.
    Abstract
  31. 31.↵
    1. Lehn M,
    2. Weiser WY,
    3. Engelhorn S,
    4. Gillis S,
    5. Remold HG
    . IL‐4 inhibits H2O2 production and antileishmanial capacity of human cultured monocytes mediated by IFN‐gamma. J Immunol 1989;143:3020-4.
    Abstract
  32. 32.↵
    1. Fritsche G,
    2. Larcher C,
    3. Schennach H,
    4. Weiss G
    . Regulatory interactions between iron and nitric oxide metabolism for immune defense against Plasmodium falciparum infection. J Infect Dis 2001;183:1388-94.
    Abstract/FREE Full Text
  33. 33.↵
    1. Morrot A,
    2. Hafalla JC,
    3. Cockburn IA,
    4. Carvalho LH,
    5. Zavala F
    . IL‐4 receptor expression on CD8+ T cells is required for the development of protective memory responses against liver stages of malaria parasites. J Exp Med 2005;202:551-60.
    Abstract/FREE Full Text
  34. 34.↵
    1. Chang KH,
    2. Stevenson MM
    . Malarial anaemia: mechanisms and implications of insufficient erythropoiesis during blood‐stage malaria. Int J Parasitol 2004;34:1501-16.
    CrossRefMedlineWeb of Science
  35. 35.↵
    1. Rennick D,
    2. Jackson J,
    3. Yang G,
    4. Wideman J,
    5. Lee F,
    6. Hudak S
    . Interleukin‐6 interacts with interleukin‐4 and other hematopoietic growth factors to selectively enhance the growth of megakaryocytic, erythroid, myeloid, and multipotential progenitor cells. Blood 1989;73:1828-35.
    Abstract/FREE Full Text
  36. 36.↵
    1. Sonoda Y
    . Interleukin‐4—a dual regulatory factor in hematopoiesis. Leuk Lymphoma 1994;14:231-40.
    MedlineWeb of Science
  37. 37.↵
    1. Dybedal I,
    2. Larsen S,
    3. Jacobsen SE
    . IL‐12 directly enhances in vitro murine erythropoiesis in combination with IL‐4 and stem cell factor. J Immunol 1995;154:4950-5.
    Abstract
  38. 38.↵
    1. Barks JL,
    2. McQuillan JJ,
    3. Iademarco MF
    . TNF‐alpha and IL‐4 synergistically increase vascular cell adhesion molecule‐1 expression in cultured vascular smooth muscle cells. J Immunol 1997;159:4532-8.
    Abstract
  39. 39.↵
    1. Lee YW,
    2. Eum SY,
    3. Chen KC,
    4. Hennig B,
    5. Toborek M
    . Gene expression profile in interleukin‐4‐stimulated human vascular endothelial cells. Mol Med 2004;10:19-27.
    CrossRefMedlineWeb of Science
  40. 40.↵
    1. Iademarco MF,
    2. Barks JL,
    3. Dean DC
    . Regulation of vascular cell adhesion molecule‐1 expression by IL‐4 and TNF‐alpha in cultured endothelial cells. J Clin Invest 1995;95:264-71.
    MedlineWeb of Science
  41. 41.↵
    1. Luscinskas FW,
    2. Kansas GS,
    3. Ding H,
    4. et al
    . Monocyte rolling, arrest and spreading on IL‐4‐activated vascular endothelium under flow is mediated via sequential action of L‐selectin, beta 1‐integrins, and beta 2‐integrins. J Cell Biol 1994;125:1417-27.
    Abstract/FREE Full Text
  42. 42.↵
    1. Ying S,
    2. Meng Q,
    3. Barata LT,
    4. Robinson DS,
    5. Durham SR,
    6. Kay AB
    . Associations between IL‐13 and IL‐4 (mRNA and protein), vascular cell adhesion molecule‐1 expression, and the infiltration of eosinophils, macrophages, and T cells in allergen‐induced late‐phase cutaneous reactions in atopic subjects. J Immunol 1997;158:5050-7.
    Abstract
  43. 43.↵
    1. Lee YW,
    2. Hennig B,
    3. Toborek M
    . Redox‐regulated mechanisms of IL‐4‐induced MCP‐1 expression in human vascular endothelial cells. Am J Physiol Heart Circ Physiol 2003;284:H185-92.
    Abstract/FREE Full Text
  44. 44.↵
    1. Ockenhouse CF,
    2. Tegoshi T,
    3. Maeno Y,
    4. et al
    . Human vascular endothelial cell adhesion receptors for Plasmodium falciparum‐infected erythrocytes: roles for endothelial leukocyte adhesion molecule 1 and vascular cell adhesion molecule 1. J Exp Med 1992;176:1183-9.
    Abstract/FREE Full Text
| Table of Contents

This Article

  1. J Infect Dis. (2009) 200 (10): 1530-1539. doi: 10.1086/644600
  1. AbstractFree
  2. » Full Text (HTML)Free
  3. Full Text (PDF)Free

Classifications

Share

  1. Email this article

Navigate This Article

Current Issue

  1. March 1, 2012 205 (5)
  1. Journal of Infectious Diseases
  1. Alert me to new issues

Most