Contact: sedejong [at] stanford.edu
Doctor of Philosophy, Leiden University (2017)
Master of Science, Leiden University (2012)
Bachelor of Science, Leiden University (2009)
Bali Pulendran, Postdoctoral Faculty Sponsor
Longitudinal study of changes in γδ T cells and CD4+ T cells upon asymptomatic malaria infection in Indonesian children.
2017; 7 (1): 8844
Both γδ T cells and CD4+ T cells have been implicated in immunity to malaria, but their association with natural gain or loss of infection has not been studied before. Therefore, we followed up asymptomatic children living in an area endemic for malaria in Indonesia for 21 months. The percentage of γδ T cells was related to both current and previous infection, with higher percentages in infected than uninfected children and declining after infections resolve. Infected children also had higher levels of Th1 and Th17 cells, lower levels of CD25Hi FOXP3+ regulatory T cells (Tregs), but similar levels of Th2 cells as compared to uninfected children. However, TNF, IFN-γ, and IL-17 cytokine responses to Plasmodium falciparum-infected red blood cells (PfRBCs) were similar, while IL-5 and IL-13 responses were lower in infected children. Furthermore, infected children had more phenotypically exhausted PD-1+ CD4+ T cells, more Tregs expressing TNF-RII, and higher IL-10 responses to PfRBCs, which persisted following resolution of infection. Altogether, this study demonstrates that asymptomatic malaria infection is associated with some long-lasting changes in the frequencies and immunoregulation of circulating innate and adaptive T cells, which might in part explain how pre-exposure to malaria affects responses to subsequent immunological challenges.
View details for PubMedID 28821806
View details for PubMedCentralID PMC5562820
Community deworming alleviates geohelminth-induced immune hyporesponsiveness
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
2016; 113 (44): 12526-12531
In cross-sectional studies, chronic helminth infections have been associated with immunological hyporesponsiveness that can affect responses to unrelated antigens. To study the immunological effects of deworming, we conducted a cluster-randomized, double-blind, placebo-controlled trial in Indonesia and assigned 954 households to receive albendazole or placebo once every 3 mo for 2 y. Helminth-specific and nonspecific whole-blood cytokine responses were assessed in 1,059 subjects of all ages, whereas phenotyping of regulatory molecules was undertaken in 121 school-aged children. All measurements were performed before and at 9 and 21 mo after initiation of treatment. Anthelmintic treatment resulted in significant increases in proinflammatory cytokine responses to Plasmodium falciparum-infected red blood cells (PfRBCs) and mitogen, with the largest effect on TNF responses to PfRBCs at 9 mo-estimate [95% confidence interval], 0.37 [0.21-0.53], P value over time (Ptime) < 0.0001. Although the frequency of regulatory T cells did not change after treatment, there was a significant decline in the expression of the inhibitory molecule cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) on CD4+ T cells of albendazole-treated individuals, -0.060 [-0.107 to -0.013] and -0.057 [-0.105 to -0.008] at 9 and 21 mo, respectively; Ptime = 0.017. This trial shows the capacity of helminths to up-regulate inhibitory molecules and to suppress proinflammatory immune responses in humans. This could help to explain the inferior immunological responses to vaccines and lower prevalence of inflammatory diseases in low- compared with high-income countries.
View details for DOI 10.1073/pnas.1604570113
View details for Web of Science ID 000386608200061
View details for PubMedID 27791067
View details for PubMedCentralID PMC5098677
IgG1 Fc N-glycan galactosylation as a biomarker for immune activation
Immunoglobulin G (IgG) Fc N-glycosylation affects antibody-mediated effector functions and varies with inflammation rooted in both communicable and non-communicable diseases. Worldwide, communicable and non-communicable diseases tend to segregate geographically. Therefore, we studied whether IgG Fc N-glycosylation varies in populations with different environmental exposures in different parts of the world. IgG Fc N-glycosylation was analysed in serum/plasma of 700 school-age children from different communities of Gabon, Ghana, Ecuador, the Netherlands and Germany. IgG1 galactosylation levels were generally higher in more affluent countries and in more urban communities. High IgG1 galactosylation levels correlated with low total IgE levels, low C-reactive protein levels and low prevalence of parasitic infections. Linear mixed modelling showed that only positivity for parasitic infections was a significant predictor of reduced IgG1 galactosylation levels. That IgG1 galactosylation is a predictor of immune activation is supported by the observation that asthmatic children seemed to have reduced IgG1 galactosylation levels as well. This indicates that IgG1 galactosylation levels could be used as a biomarker for immune activation of populations, providing a valuable tool for studies examining the epidemiological transition from communicable to non-communicable diseases.
View details for DOI 10.1038/srep28207
View details for Web of Science ID 000378107700001
View details for PubMedID 27306703
View details for PubMedCentralID PMC4910062
CD4(+)CD25(hi)FOXP3(+) Cells in Cord Blood of Neonates Born from Filaria Infected Mother Are Negatively Associated with CD(4+)Tbet(+) and CD4(+)ROR gamma t(+) T Cells
2014; 9 (12)
Children who have been exposed in utero to maternal filarial infection are immunologically less responsive to filarial antigens, have less pathology, and are more susceptible to acquire infection than offspring of uninfected mothers. Moreover children from filaria infected mothers have been shown to be less responsive to vaccination as a consequence of an impairment of their immune response. However, it is not well known how in utero exposure to parasite antigens affects cellular immune responses.Here, 30 pregnant women were examined for the presence of microfilaria of Loa loa and Mansonella perstans in peripheral blood. At delivery, cord blood mononuclear cells (CBMC) were obtained and the CD4+T cells were phenotyped by expression of the transcription factors Tbet, RORγt, and FOXP3.No significant difference was observed between newborns from infected versus uninfected mothers in the frequencies of total CD4+T cells and CD4+T cells subsets including CD4+Tbet+, CD4+RORγt+ T and CD4+CD25hiFOXP3+ T cells. However, there was a negative association between CD4+CD25hiFOXP3+T cells and CD4+Tbet+ as well as CD4+RORγt+ T cells in the infected group only (B = -0.242, P = 0.002; B = -0.178, P = 0.013 respectively).Our results suggest that filarial infection during pregnancy leads to an expansion of functionally active regulatory T cells that keep TH1 and TH17 in check.
View details for DOI 10.1371/journal.pone.0114630
View details for Web of Science ID 000348845100021
View details for PubMedID 25531674
View details for PubMedCentralID PMC4273973
Changes in immunological profile as a function of urbanization and lifestyle
2014; 143 (4): 569-577
Differences in lifestyle and break with natural environment appear to be associated with changes in the immune system resulting in various adverse health effects. Although genetics can have a major impact on the immune system and disease susceptibility, the contribution of environmental factors is thought to be substantial. Here, we investigated the immunological profile of healthy volunteers living in a rural and an urban area of a developing African country (Senegal), and in a European country (the Netherlands). Using flow cytometry, we investigated T helper type 1 (Th1), Th2, Th17, Th22 and regulatory T cells, as well as CD4(+) T-cell and B-cell activation markers, and subsets of memory T and B cells in the peripheral blood. Rural Senegalese had significantly higher frequencies of Th1, Th2 and Th22 cells, memory CD4(+) T and B cells, as well as activated CD4(+) T and B cells compared with urban Senegalese and urban Dutch people. Within the Senegalese population, rural paritcipants displayed significantly higher frequencies of Th2 and Th22 cells, as well as higher pro-inflammatory and T-cell activation and memory profiles compared with the urban population. The greater magnitude of immune activation and the enlarged memory pool, together with Th2 polarization, seen in rural participants from Africa, followed by urban Africans and Europeans suggest that environmental changes may define immunological footprints, which could have consequences for disease patterns in general and vaccine responses in particular.
View details for DOI 10.1111/imm.12335
View details for Web of Science ID 000344781200008
View details for PubMedID 24924958
View details for PubMedCentralID PMC4253505
Differences in Innate Cytokine Responses between European and African Children
2014; 9 (4)
Although differences in immunological responses between populations have been found in terms of vaccine efficacy, immune responses to infections and prevalence of chronic inflammatory diseases, the mechanisms responsible for these differences are not well understood. Therefore, innate cytokine responses mediated by various classes of pattern-recognition receptors including Toll-like receptors (TLR), C-type lectin receptors (CLRs) and nucleotide-binding oligomerisation domain-like receptors (NLRs) were compared between Dutch (European), semi-urban and rural Gabonese (African) children. Whole blood was stimulated for 24 hours and the pro-inflammatory tumor necrosis factor (TNF) and the anti-inflammatory/regulatory interleukin-10 (IL-10) cytokines in culture supernatant were measured by enzyme-linked immunosorbent assay (ELISA). Gabonese children had a lower pro-inflammatory response to poly(I:C) (TLR3 ligand), but a higher pro-inflammatory response to FSL-1 (TLR2/6 ligand), Pam3 (TLR2/1 ligand) and LPS (TLR4 ligand) compared to Dutch children. Anti-inflammatory responses to Pam3 were also higher in Gabonese children. Non-TLR ligands did not induce substantial cytokine production on their own. Interaction between various TLR and non-TLR receptors was further assessed, but no differences were found between the three populations. In conclusion, using a field applicable assay, significant differences were observed in cytokine responses between European and African children to TLR ligands, but not to non-TLR ligands.
View details for DOI 10.1371/journal.pone.0095241
View details for Web of Science ID 000335309100094
View details for PubMedID 24743542
View details for PubMedCentralID PMC3990610
T-Helper 17 Cells Are Associated With Pathology in Human Schistosomiasis
JOURNAL OF INFECTIOUS DISEASES
2013; 207 (1): 186-195
Schistosome infections are often clinically silent, but some individuals develop severe pathological reactions. In several disease processes, T-helper 17 (Th17) cells have been linked to tissue injuries, while regulatory T cells (Tregs) are thought to downmodulate inflammatory reactions. We assessed whether bladder pathology in human Schistosoma haematobium infection is related to the balance of Th17 cells and Tregs. We used a murine model of Schistosoma mansoni infection to further investigate whether the peripheral profiles reflected ongoing events in tissues.We characterized T-helper cell subsets in the peripheral blood of children residing in a S. haematobium-endemic area and in the peripheral blood, spleen, and hepatic granulomas of S. mansoni-infected high-pathology CBA mice and low-pathology C57BL/6 mice.S. haematobium-infected children with bladder pathology had a significantly higher percentage of Th17 cells than those without pathology. Moreover, the Th17/Treg ratios were significantly higher in infected children with pathology, compared with infected children without pathology. Percentages of interleukin 17-producing cells were significantly higher in spleen and granulomas of CBA mice, compared with C57BL/6 mice. This difference was also reflected in the peripheral blood.This is the first study to indicate that Th17 cells may be involved in the pathogenesis of human schistosomiasis.
View details for DOI 10.1093/infdis/jis654
View details for Web of Science ID 000312604200023
View details for PubMedID 23087431
View details for PubMedCentralID PMC3571236
Changes in Antigen-specific IgG1 Fc N-glycosylation Upon Influenza and Tetanus Vaccination
MOLECULAR & CELLULAR PROTEOMICS
2012; 11 (4)
Antibody effector functions have been shown to be influenced by the structure of the Fc N-glycans. Here we studied the changes in plasma or serum IgG Fc N-glycosylation upon vaccination of 10 Caucasian adults and 10 African children. Serum/plasma IgG was purified by affinity chromatography prior to and at two time points after vaccination. Fc N-glycosylation profiles of individual IgG subclasses were determined for both total IgG and affinity-purified anti-vaccine IgG using a recently developed fast nanoliquid chromatography-electrospray ionization MS (LC-ESI-MS) method. While vaccination had no effect on the glycosylation of total IgG, anti-vaccine IgG showed increased levels of galactosylation and sialylation upon active immunization. Interestingly, the number of sialic acids per galactose increased during the vaccination time course, suggesting a distinct regulation of galactosylation and sialylation. In addition we observed a decrease in the level of IgG1 bisecting N-acetylglucosamine whereas no significant changes were observed for the level of fucosylation. Our data indicate that dependent on the vaccination time point the infectious agent will encounter IgGs with different glycosylation profiles, which are expected to influence the antibody effector functions relevant in immunity.
View details for DOI 10.1074/mcp.M111.014563
View details for Web of Science ID 000302786500015
View details for PubMedID 22184099
View details for PubMedCentralID PMC3322571