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  • 1. Achidi, E. A.
    et al.
    Apinjoh, T. O.
    Mbunwe, E.
    Besingi, R.
    Yafi, C.
    Awah, N. Wenjighe
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Ajua, A.
    Anchang, J. K.
    Febrile status, malarial parasitaemia and gastro-intestinal helminthiases in schoolchildren resident at different altitudes, in south-western Cameroon2008In: Annals of Tropical Medicine and Parasitology, ISSN 0003-4983, E-ISSN 1364-8594, Vol. 102, no 2, p. 103-118Article in journal (Refereed)
    Abstract [en]

    In the many areas where human malaria and helminthiases are co-endemic, schoolchildren often harbour the heaviest infections and suffer much of the associated morbidity, especially when co-infected. In one such area, the Buea district, in south-western Cameroon, two cross-sectional surveys, together covering 263 apparently healthy schoolchildren aged 4-12 years, were recently conducted. The prevalences of fever, malarial parasitaemia and intestinal helminth infections, the seroprevalences of anti-Plasmodium falciparum IgG and IgE and anti-glycosylphosphatidylinositol (anti-GPI) IgG, plasma concentrations of total IgE, and the incidence of anaemia were all investigated. The mean (S.D.) age of the study children was 7.56 (1.82) years. Overall, 156 (59.3%) of the children were found parasitaemic, with a geometric mean parasitaemia of 565 parasites/mu l. Parasitaemia and fever were significantly associated (P=0.042). The children who lived at low altitude, attending schools that lay 400-650 m above sea level, had significantly higher parasitaemias than their high-altitude counterparts (P < 0.01). At low altitude, the children attending government schools had significantly higher parasitaemias than their mission-school counterparts (P=0.010). Of the 31 children (11.9%) found anaemic, 22 (70.4%) had mild anaemia and none had severe anaemia. A significant negative correlation (r=-0.224; P=0.005) was observed between haemoglobin concentration and level of parasitaemia. Infection with Plasmodium appeared to reduce erythrocyte counts (P=0.045), a condition that was exacerbated by co-infection with helminths (P=0.035). Plasma concentrations of total IgE were higher in the children found to be excreting helminth eggs than in those who appeared helminth-free, while levels of anti-P. falciparum IgE were higher in the children with low-grade parasitaemias than in those with more intense parasitaemias. Levels of anti-GPI IgG increased with age and were relatively high in the children who lived at low altitude and in those who were aparasitaemic. The survey results confirm that asymptomatic malarial parasitaemia frequently co-exists with helminth infections in schoolchildren and indicate links with fever, altitude and school type. Immunoglobulin E may play a role in immune protection against helminthiasis whereas anti-GPI antibodies may be important in the development of antimalarial immunity in such children. In Cameroon, as in other areas with endemic malaria, control programmes to reduce the prevalences of infections with intestinal helminths and malarial parasites in schoolchildren, which may effectively reduce the incidence of anaemia, are clearly needed.

  • 2.
    Ahlborg, Niklas
    Stockholm University, Faculty of Science, The Wenner-Gren Institute, Immunology.
    Immune responses to repeat sequences of the Plasmodium falciparum malaria antigen Pf3321995Doctoral thesis, comprehensive summary (Other academic)
  • 3. Amodu, O. K.
    et al.
    Olaniyan, S. A.
    Adeyemo, A. A.
    Troye-Blomberg, Marita
    Stockholm University, Faculty of Science, The Wenner-Gren Institute, Immunology.
    Olumese, P. E.
    Omotade, O. O.
    Association of the sickle cell trait and the ABO blood group with clinical severity of malaria in southwest Nigeria2012In: Acta Tropica, ISSN 0001-706X, E-ISSN 1873-6254, Vol. 123, no 2, p. 72-77Article in journal (Refereed)
    Abstract [en]

    In regions of high Plasmodium falciparum malaria endemicity, certain erythrocyte polymorphisms confer resistance to severe disease. In this study, we evaluate the role of the sickle cell trait (HbS) and ABO blood groups in the clinical manifestations of childhood malaria in Southwest Nigeria. The subjects comprised 3100 children (53% males, median age 39 months), including 1400 children with uncomplicated malaria, 1000 children with asymptomatic malaria and 700 with severe malaria. Haemoglobin (Hb) types were determined using electrophoresis and serum agglutination techniques were used to determine ABO blood groups. Blood group O was the commonest ABO blood group (47.7%) in the study population, the others were A (22.5%), B (25.2%) and AB (4.6%). The frequencies of the HbAS and HbAC were 14.4% and 5.8%, respectively. In regression models adjusting for age, gender, parasite density and blood group, HbAS was associated with a reduced risk of severe malaria OR=0.46 (CI95%: 0.273-0.773). Among severe malaria subjects, HbAS was associated with significantly lower parasite densities. The protective effect of blood group 0 was demonstrated with a decreased risk of severe malaria OR=0.743 (CI95%: 0.566-0.976) after adjusting for age, gender and parasite density and Hb genotype. Blood group B was associated with increased risk of severe malaria OR=1.638 (CI95%: 1.128-2.380) after adjusting for age, gender, packed cell volume, parasite density and Hb genotype. We have confirmed from this large study of Nigerian children the major protective effective of the sickle cell heterozygous state against both cerebral malaria and severe malarial anaemia. We also show that the B blood group is associated with an increased risk of severe malaria. In conclusion, the sickle cell haemoglobin type and ABO groups modulate the risk of severe malaria in Nigerian children.

  • 4. Anchang-Kimbi, Judith K
    et al.
    Achidi, Eric A
    Nkegoum, Blaise
    Sverremark-Ekström, Eva
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Troye-Blomberg, Marita
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Diagnostic comparison of malaria infection in peripheral blood, placental blood and placental biopsies in Cameroonian parturient women.2009In: Malaria Journal, ISSN 1475-2875, E-ISSN 1475-2875, Vol. 8, p. 126-Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: In sub-Saharan Africa, Plasmodium falciparum malaria in pregnancy presents an enormous diagnostic challenge. The epidemiological and clinical relevance of the different types of malaria diagnosis as well as risk factors associated with malaria infection at delivery were investigated. METHOD: In a cross-sectional survey, 306 women reporting for delivery in the Mutenegene maternity clinic, Fako division, South West province, Cameroon were screened for P. falciparum in peripheral blood, placental blood and placental tissue sections by microscopy. Information relating to the use of intermittent preventive treatment in pregnancy with sulphadoxine/pyrimethamine, history of fever attack, infant birth weights and maternal anaemia were recorded. RESULTS: Among these women, P. falciparum infection was detected in 5.6%, 25.5% and 60.5% of the cases in peripheral blood, placental blood and placental histological sections respectively. Placental histology was more sensitive (97.4%) than placental blood film (41.5%) and peripheral blood (8.0%) microscopy. In multivariate analysis, age (< or = 20 years old) (OR = 4.61, 95% CI = 1.47 - 14.70), history of fever attack (OR = 2.98, 95% CI = 1.58 - 5.73) were significant risk factors associated with microscopically detected parasitaemia. The use of > or = 2 SP doses (OR = 0.18, 95% CI = 0.06 - 0.52) was associated with a significant reduction in the prevalence of microscopic parasitaemia at delivery. Age (>20 years) (OR = 0.34, 95% CI = 0.15 - 0.75) was the only significant risk factor associated with parasitaemia diagnosed by histology only in univariate analysis. Microscopic parasitaemia (OR = 2.74, 95% CI = 1.33-5.62) was a significant risk factor for maternal anaemia at delivery, but neither infection detected by histology only, nor past infection were associated with increased risk of anaemia. CONCLUSION: Placenta histological examination was the most sensitive indicator of malaria infection at delivery. Microscopically detected parasitaemia was associated with increased risk of maternal anaemia at delivery, but not low-grade parasitaemia detected by placental histology only.

  • 5.
    Arama, Charles
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Understanding the immunobiology of DC subsets for rational design of novel malaria vaccines2011Licentiate thesis, monograph (Other academic)
  • 6.
    Arama, Charles
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Assefaw-Redda, Y.
    Rodriguez, A.
    Fernández, C.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Corradin, G.
    Kaufmann, S. H.
    Reece, S. T.
    Troye-Blomberg, Marita
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Heterologous prime–boost regimen adenovector 35-circumsporozoite protein vaccine/recombinant Bacillus Calmette-Guérin expressing the Plasmodium falciparum circumsporozoite induces enhanced long-term memory immunity in BALB/c miceManuscript (preprint) (Other academic)
  • 7.
    Arama, Charles
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Assefaw-Redda, Yohannes
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Rodriguez, Ariane
    Fernández, Carmen
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Corradin, Giampietro
    Kaufmann, Stefan H. E.
    Reece, Stephen T.
    Troye-Blomberg, Marita
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Heterologous prime-boost regimen adenovector 35-circumsporozoite protein vaccine/recombinant Bacillus Calmette-Guerin expressing the Plasmodium falciparum circumsporozoite induces enhanced long-term memory immunity in BALB/c mice2012In: Vaccine, ISSN 0264-410X, E-ISSN 1873-2518, Vol. 30, no 27, p. 4040-4045Article in journal (Refereed)
    Abstract [en]

    Background: Sustained antibody levels are a hallmark of immunity against many pathogens, and induction of long-term durable antibody titers is an essential feature of effective vaccines. Heterologous prime-boost approaches with vectors are optimal strategies to improve a broad and prolonged immunogenicity of malaria vaccines. Results: In this study, we demonstrate that the heterologous prime-boost regimen Ad35-CS/BCG-CS induces stronger immune responses by enhancing type 1 cellular producing-cells with high levels of CSp-specific IFN-gamma and cytophilic IgG2a antibodies as compared to a homologous BCG-CS and a heterologous BCG-CS/CSp prime-boost regimen. Moreover, the heterologous prime-boost regimen elicits the highest level of LLPC-mediated immune responses. Conclusion: The increased IFN-gamma-producing cell responses induced by the combination of Ad35-CS/BCG-CS and sustained type 1 antibody profile together with high levels of LLPCs may be essential for the development of long-term protective immunity against liver-stage parasites.

  • 8.
    Arama, Charles
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Giusti, Pablo
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Boström, Stephanie
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Varani, Stefania
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Troye Blomberg, Marita
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Interethnic Differences in Antigen-Presenting Cell Activation and TLR Responses in Malian Children during Plasmodium falciparum Malaria2011In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 6, no 3, p. e18319-Article in journal (Refereed)
    Abstract [en]

    The Fulani ethnic group from West Africa is relatively better protected against Plasmodium falciparum malaria as compared to other sympatric ethnic groups, such as the Dogon. However, the mechanisms behind this lower susceptibility to malaria are largely unknown, particularly those concerning innate immunity. Antigen-presenting cells (APCs), and in particular dendritic cells (DCs) are important components of the innate and adaptive immune systems. Therefore, in this study we investigated whether APCs obtained from Fulani and Dogon children exhibited differences in terms of activation status and toll-like receptor (TLR) responses during malaria infection. Lower frequency and increased activation was observed in circulating plasmacytoid DCs and BDCA-3+ myeloid DCs of infected Fulani as compared to their uninfected counterparts. Conversely, a higher frequency and reduced activation was observed in the same DC subsets obtained from peripheral blood of P. falciparum-infected Dogon children as compared to their uninfected peers. Moreover, infected individuals of both ethnic groups exhibited higher percentages of both classical and inflammatory monocytes that were less activated as compared to their non-infected counterparts. In line with APC impairment during malaria infection, TLR4, TLR7 and TLR9 responses were strongly inhibited by P. falciparum infection in Dogon children, while no such TLR inhibition was observed in the Fulani children. Strikingly, the TLR-induced IFN-γ release was completely abolished in the Dogon undergoing infection while no difference was seen within infected and non-infected Fulani. Thus, P. falciparum infection is associated with altered activation status of important APC subsets and strongly inhibited TLR responses in peripheral blood of Dogon children. In contrast, P. falciparum induces DC activation and does not affect the innate response to specific TLR ligands in Fulani children. These findings suggest that DCs and TLR signalling may be of importance for the protective immunity against malaria observed in the Fulani.

  • 9. Arama, Charles
    et al.
    Skinner, Jeff
    Doumtabe, Didier
    Portugal, Silvia
    Tran, Tuan M.
    Jain, Aarti
    Traore, Boubacar
    Doumbo, Ogobara K.
    Davies, David Huw
    Troye-Blomberg, Marita
    Stockholm University, Faculty of Science, The Wenner-Gren Institute, Immunology.
    Dolo, Amagana
    Felgner, Philip L.
    Crompton, Peter D.
    Genetic Resistance to Malaria Is Associated With Greater Enhancement of Immunoglobulin (Ig)M Than IgG Responses to a Broad Array of Plasmodium falciparum Antigens2015In: Open forum infectious diseases, ISSN 2328-8957, Vol. 2, no 3Article in journal (Refereed)
    Abstract [en]

    Background. People of the Fulani ethnic group are more resistant to malaria compared with genetically distinct ethnic groups, such as the Dogon people, in West Africa, and studies suggest that this resistance is mediated by enhanced antibody responses to Plasmodium falciparum antigens. However, prior studies measured antibody responses to < 0.1% of P falciparum proteins, so whether the Fulani mount an enhanced and broadly reactive immunoglobulin (Ig) M and IgG response to P falciparum remains unknown. In general, little is known about the extent to which host genetics influence the overall antigen specificity of IgM and IgG responses to natural infections. Methods. In a cross-sectional study in Mali, we collected plasma from asymptomatic, age-matched Fulani (n = 24) and Dogon (n = 22) adults with or without concurrent P falciparum infection. We probed plasma against a protein microarray containing 1087 P falciparum antigens and compared IgM and IgG profiles by ethnicity. Results. We found that the breadth and magnitude of P falciparum-specific IgM and IgG responses were significantly higher in the malaria-resistant Fulani versus the malaria-susceptible Dogon, and, unexpectedly, P falciparum-specific IgM responses more strongly distinguished the 2 ethnic groups. Conclusions. These findings point to an underappreciated role for IgM in protection from malaria, and they suggest that host genetics may influence the antigen specificity of IgM and IgG responses to infection.

  • 10.
    Arama, Charles
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute, Immunology.
    Waseem, Shahid
    Stockholm University, Faculty of Science, The Wenner-Gren Institute, Immunology.
    Fernández, Carmen
    Stockholm University, Faculty of Science, The Wenner-Gren Institute, Immunology.
    Assefaw-Redda, Yohannes
    Stockholm University, Faculty of Science, The Wenner-Gren Institute, Immunology.
    You, Liya
    Stockholm University, Faculty of Science, The Wenner-Gren Institute, Immunology.
    Rodriguez, Ariane
    Radošević, Katarina
    Goudsmit, Jaap
    Kaufmann, Stefan H E
    Reece, Stephen T
    Troye-Blomberg, Marita
    Stockholm University, Faculty of Science, The Wenner-Gren Institute, Immunology.
    A recombinant Bacille Calmette-Guerin construct expressing the Plasmodium falciparum circumsporozoite protein enhances dendritic cell activation and primes for circumsporozoite-specific memory cells in BALB/c mice2012In: Vaccine, ISSN 0264-410X, E-ISSN 1873-2518, Vol. 30, no 37, p. 5578-5584Article in journal (Refereed)
    Abstract [en]

    A protective malaria vaccine may induce both high levels of neutralising antibodies and strong T-cell responses. The Plasmodium falciparum circumsporozoite protein (CSp) is a leading pre-erythrocytic vaccine candidate. CSp is a week immunogen per se, but Mycobacterium bovis Bacille Calmette-Guérin (BCG) has excellent adjuvant activity and has been utilized as a vector to deliver heterologous vaccine candidate antigens. It is safe in immunocompetent individuals and inexpensive to produce. We assessed in vitro and in vivo a recombinant BCG-expressing CSp (BCG-CS) as malaria vaccine candidate. Immunisation of BALB/c mice with BCG-CS augmented numbers of dendritic cells (DCs) in draining lymph nodes and in the spleen. The activation markers MHC-class-II, CD40, CD80 and CD86 on DCs were significantly upregulated by BCG-CS as compared to wild-type BCG (wt-BCG). In vitro stimulation of bone marrow-derived DCs and macrophages with BCG-CS induced IL-12 and TNF-α production. BCG-CS induced higher phagocytic activity in macrophages as compared to wt-BCG. Immunogenicity studies show that BCG-CS induced CS-specific antibodies and IFN-γ-producing memory cells. In conclusion, BCG-CS is highly efficient in activating antigen-presenting cells (APCs) for priming of adaptive immunity. Implications for the rational design of novel vaccines against malaria and TB, the two major devastating poverty-related diseases, are discussed.

  • 11. Arestrom, Irene
    et al.
    Zuber, Bartek
    Bengtsson, Theresa
    Ahlborg, Niklas
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Measurement of human latent transforming growth factor beta 1 using a latency associated protein reactive elisa2012In: JIM - Journal of Immunological Methods, ISSN 0022-1759, E-ISSN 1872-7905, Vol. 379, no 1-2, p. 23-29Article in journal (Refereed)
    Abstract [en]

    Human Transforming Growth Factor (TGF)-beta 1, one of three TGF-beta isoforms, is a pleotropic cytokine critical for many physiological and immunological processes. TGF-beta 1 is secreted in a latent form, linked to Latency Associated Protein (LAP). Analysis of Latent TGF-beta 1 by TGF-ELISA requires dissociation of TGF-beta 1 from LAP, e.g. by acidification of samples. The ELISA then measures total TGF-beta 1, equivalent to dissociated Latent TGF-beta 1 plus any free TGF-beta 1 present prior to acidification. Evolutionary conservation of TGF-beta 1 across mammals also renders TGF-beta 1 ELISAs reactive with TGF-beta 1 in bovine serum often used in human cell cultures. To enable a direct analysis of Latent TGF-beta 1, monoclonal antibodies were made against LAP from human latent TGF-beta 1 and used to develop a LAP ELISA detecting Latent TGF-beta 1. The ELISA did not react with LAP from human Latent TGF-beta 2 or 3, respectively, nor with Latent TGF-beta in bovine serum. EDTA-containing plasma from healthy subjects (n = 20) was analyzed by conventional TGF-beta 1 ELISA and LAP ELISA. By TGF-beta 1 ELISA, total TGF-beta 1 were detected in all samples (median 133 pM, range 34-348 pM); low levels of free TGF-beta 1 found in 8/20 non-addified samples showed that >98.5% of the total TGF-beta 1 derived from Latent TGF-beta 1. Latent TGF-beta 1 found in non-acidified samples by LAP ELISA (median 154 pM, range 48-403 pM) was comparable in molar levels to, and correlated with, total TGF-beta 1 (r(s) 0.96, p<0.0001). A similar agreement between the total TGF-beta 1 and the LAP ELISA was found with citrate- and heparin-containing plasma. The LAP ELISA facilitates analysis of Latent TGF-beta 1 without sample acidification and is not compromised by the presence of bovine serum in human cell supernatants.

  • 12. Arkestål, Kurt
    et al.
    Sibanda, Elopy
    Thors, Cecilia
    Troye-Blomberg, Marita
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Mduluza, Takafira
    Valenta, Rudolf
    Grönlund, Hans
    van Hage, Marianne
    Impaired allergy diagnostics among parasite-infected patients caused by IgE antibodies to the carbohydrate epitope galactose-alpha 1,3-galactose2011In: Journal of Allergy and Clinical Immunology, ISSN 0091-6749, E-ISSN 1097-6825, Vol. 127, no 4, p. 1024-1028Article in journal (Refereed)
    Abstract [en]

    Background: The carbohydrate epitope galactose-alpha 1,3galactose (a-Gal) is abundantly expressed on nonprimate mammalian proteins. We have recently shown that alpha-Gal is responsible for the IgE binding to cat IgA, a newly identified cat allergen (Fel d 5). Objective: We sought to investigate the diagnostic relevance of IgE antibodies to Fel d 5 and a-Gal among parasite-infected patients from central Africa without cat allergy compared with patients with cat allergy from the same region. Methods: Sera from 47 parasite-infected patients and 31 patients with cat allergy were analyzed for total IgE and IgE antibodies against cat dander extract (CDE) by using the ImmunoCAP system. Inhibition assay was performed with a-Gal on solid phase-bound CDE. The presence of IgE specific for the major cat allergen Fel d 1, Fel d 5, and alpha-Gal was analyzed by means of ELISA. Results: Among the 47 parasite-infected patients, 85% had IgE antibodies against alpha-Gal (OD; median, 0.175; range, 0.1021.466) and 66% against Fel d 5 (OD; median, 0.13; range, 0.1031.285). Twenty-four of the parasite-infected patients were sensitized to CDE, and 21 of them had IgE antibodies to Fel d 5 and a-Gal. There was no correlation between IgE levels to CDE and rFel d 1 among the parasite-infected patients but a strong correlation between CDE and Fel d 5 and alpha-Gal (P <. 001). Among the group with cat allergy, only 5 patients had IgE to alpha-Gal, and nearly 75% (n 5 23) had IgE to rFel d 1 (median, 7.07 kU(A)/L; range, 0.51-148.5 kUA/ L). In contrast, among the patients with cat allergy, there was a correlation between IgE levels to CDE and rFel d 1 (P <.05) but no correlation between CDE and Fel d 5 and alpha-Gal. Conclusion: IgE to alpha-Gal causes impaired allergy diagnostics in parasite-infected patients. Screening for IgE to rFel d 1 and other allergens without carbohydrates might identify patients with true cat sensitization/ allergy in parasite-infested areas.

  • 13.
    Arko-Mensah, John
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Rahman, Muhammad J
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Dégano, Irene R
    Chuquimia, Olga D
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Fotio, Agathe L
    Garcia, Irene
    Fernández, Carmen
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Resistance to mycobacterial infection: a pattern of early immune responses leads to a better control of pulmonary infection in C57BL/6 compared with BALB/c mice.2009In: Vaccine, ISSN 0264-410X, E-ISSN 1873-2518, Vol. 27, no 52, p. 7418-27Article in journal (Refereed)
    Abstract [en]

    In this study, we have compared the immunological responses associated with early pulmonary mycobacterial infection in two mouse strains, BALB/c and C57BL/6 known to exhibit distinct differences in susceptibility to infection with several pathogens. We infected mice via the intranasal route. We have demonstrated that BALB/c was less able to control mycobacterial growth in the lungs during the early phase of pulmonary infection. Our results showed that during the early phase (day 3 to week 1), BALB/c mice exhibited a delay in the production of TNF and IFN-gamma in the lungs compared to C57BL/6 mice. Levels of IL-12 and soluble TNF receptors (sTNFR) were comparable between the mouse strains. The cellular subset distribution in these mice before and after infection showed a higher increase in CD11b+ cells in the lungs of C57BL/6, compared to BALB/c as early as day 3 postinfection. At early time points, higher levels of monocyte chemoattractant protein (MCP)-1 and macrophage inflammatory protein 1 (MIP)-alpha were detected in C57BL/6 than BALB/c mice. In vitro, BCG-infected bone marrow derived macrophages (BMM) from both mouse strains displayed similar capacities to either phagocytose bacteria or produce soluble mediators such as TNF, IL-12 and nitric oxide (NO). Although IFN-gamma stimulation of infected BMM in both mouse strains resulted in the induction of antimycobacterial activity, BALB/c mice had a reduced capacity to kill ingested bacteria. The above observations indicate that the chain of early, possibly innate immunological events occurring during pulmonary mycobacterial infection may directly impact on increased susceptibility or resistance to infection.

  • 14. Arko-Mensah, John
    et al.
    Rahman, Muhammad Jubayer
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Julián, Eshter
    Horner, Gudron
    Singh, Mahavir
    Fernández, Carmen
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Increased levels of immunological markers in the respiratory tract but not in serum correlate with active pulmonary mycobacterial infection in mice2009In: Clinical Microbiology and Infection, ISSN 1198-743X, E-ISSN 1469-0691, Vol. 15, no 8, p. 777-786Article in journal (Refereed)
    Abstract [en]

    Immunological tests for the diagnosis of tuberculosis (TB) have relied mostly on detection of immune markers in serum or release of cytokines by mononuclear cells in vitro. These tests, although useful, sometimes fail to discriminate between active infection and contact with mycobacteria or vaccination. TB is primarily a disease of the lung, and therefore identification of immunological markers in the respiratory tract will be more likely to reflect the infection status or disease activity. In this study, it is demonstrated that active infection of mice with Mycobacterium bovis bacille Calmette-Guérin (BCG), but not exposure to heat-killed BCG, induced production of interleukin-12 (IL-12), interferon-gamma (IFN-gamma) or soluble tumour necrosis factor receptors (sTNFRs) locally in the lungs, as detected in bronchoalveolar lavage (BAL) fluid. There was a strong correlation between bacterial growth in the lung and levels of sTNFRs, and to some extent IL-12 and IFN-gamma, in BAL fluid. Furthermore, sTNFR levels increased significantly in BAL fluid after reactivation of controlled infection with dexamethasone, and this correlated with increased bacterial growth in the lungs. Finally, infection, but not exposure to non-replicating mycobacteria, induced specific IgG and IgA in BAL fluid. Elevated levels of all biomarkers measured were also detected in the serum, but correlation with infection was not as clear as in the case of BAL fluid. Taken together, the detection of sTNFRs and mycobacterium-specific antibodies, especially IgA, locally in the lungs could be used as immunological markers for the diagnosis of TB.

  • 15.
    Awah, Nancy
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Balogun, Halima
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Achidi, E.
    Mariuba, L. A.
    Nogueira, P. A.
    Orlandi, P.
    Troye-Blomberg, Marita
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Gysin, J.
    Berzins, Klavs
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Antibodies to the Plasmodium falciparum rhoptry protein RAP-2/RSP-2 in relation to anaemia in Cameroonian children2011In: Parasite immunology (Print), ISSN 0141-9838, E-ISSN 1365-3024, Vol. 33, no 2, p. 104-115Article in journal (Refereed)
    Abstract [en]

    Previous studies have implicated reactive antibodies to the low molecular weight rhoptry-associated proteins (RAP-1, RAP-2/RSP-2 and RAP-3) in erythroid cell destruction during Plasmodium falciparum infection. In this pilot study, the frequency, specificity and functional capacity of naturally acquired anti-RAP-2/RSP-2 antibodies were investigated in the sera of anaemic and nonanaemic malaria-infected Cameroonian children. All sera recognized RAP-2/RSP-2 by FACS, irrespective of the clinical status of the subjects. However, the anaemic children showed higher levels of IgG antibodies than the nonanaemic group, while both groups showed similar levels of IgM antibodies. Only few individuals had detectable levels of RAP-2/RSP-2-specific IgG1 and IgG3 subclass antibodies, while no IgG2 and IgG4 subclass antibodies were detected in these subjects. By ELISA, the anaemic group tended to show higher levels of antibodies to RAP-2/RSP-2 regarding all antibody classes tested, except for IgG4 and IgE. Unexpectedly, sera from the nonanaemic group activated complement to a greater extent than those from the anaemic group. These results need to be confirmed in extended studies but indicate that the effector functions of the RAP-2/RSP-2-reactive antibodies may be more important than their amounts. Such antibodies could play a role in both immunity and pathogenesis during P. falciparum infection.

  • 16.
    Awah, Nancy W.
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Troye-Blomberg, Marita
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Berzins, Klavs
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Gysin, Jürg
    Unité de Parasitologie Expérimentale, URA Institut Pasteur/Univ-Med.
    Mechanisms of malarial anaemia: potential involvement of the Plasmodium falciparum low molecular weight rhoptry-associated proteins.2009In: Acta Tropica, ISSN 0001-706X, E-ISSN 1873-6254, Vol. 112, no 3, p. 295-302Article in journal (Refereed)
    Abstract [en]

    Plasmodium falciparum malaria is a major cause of morbidity and mortality throughout the tropics. Anaemia is a constant feature of the disease. Pregnant women mostly primigravidae and children below the age of 5 years are the most afflicted. Its pathogenesis is multifactorial and incompletely understood. Among several factors, the destruction of erythrocytes (RBCs) is the most frequently observed cause of severe malarial anaemia and the removal of non-parasitized RBCs (nEs) is thought to be the most important, accounting for approximately 90% of the reduction in haematocrit in acute malaria. Previous studies demonstrated that the tagging of nEs with the parasite antigen RAP-2 (rhoptry-associated protein-2; also designated RSP-2) due to either failed or aborted invasion by merozoites resulted in the destruction of these cells. In this study we further investigated the mechanisms mediating the destruction of nEs in the development of severe malarial anaemia and the possible involvement of RAP-2/RSP-2 and other members of the low molecular weight rhoptry complex (RAP-1: rhoptry-associated protein-1 and RAP-3: rhoptry-associated protein-3). Antibodies to the rhoptry-associated proteins were found to recognise the surface of nEs in a parasitaemia-dependent manner after merozoite release in P. falciparumin vitro cultures. These cells, as well as erythroblasts co-cultured with infected RBCs (IEs), could then be destroyed by either phagocytosis or lysis after complement activation. The ability of anti-rhoptry antibodies to mediate the destruction of RAP-2/RSP-2-tagged erythroblasts in the presence of effector cells was also investigated. Data obtained suggest that mouse monoclonal antibodies to the low molecular weight RAP proteins mediate the death of RAP-2/RSP-2-tagged erythroblasts on interaction with adherent monocytes. The mechanism of cell death is not yet fully known, but seems to involve primarily apoptosis. The above observations suggest that the antibody response against RAP-2/RSP-2 and other members of the complex could trigger the destruction of RAP-2/RSP-2-tagged host cells. Taken together it appears that during severe anaemia a defective bone marrow or dyserythropoiesis possibly due to erythroblast cell death, may overlap with the accelerated destruction of normal erythroid cells, either by opsonisation or complement activation further aggravating the anaemia which may become fatal. These observations could therefore have implications in the design, development and deployment of future therapeutic interventions against malaria.

  • 17. Bachmayer, Nora
    et al.
    Sohlberg, Ebba
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Sundström, Yvonne
    Hamad, Rangeen Rafik
    Berg, Louise
    Bremme, Katarina
    Sverremark-Ekström, Eva
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Women with pre-eclampsia have an altered NKG2A and NKG2C receptor expression on peripheral blood natural killer cells.2009In: American Journal of Reproductive Immunology and Microbiology, ISSN 8755-8920, Vol. 62, no 3, p. 147-57Article in journal (Refereed)
    Abstract [en]

    PROBLEM: Preeclampsia, a pregnancy disorder, is associated with exaggerated inflammation and increased serum monokines. Uterine natural killer (NK) cells are implicated in preeclampsia pathology, but little is known regarding peripheral NK cells in the disease. METHOD OF STUDY: We examined blood NK cells at delivery in women with preeclampsia, in healthy pregnant women and in healthy non-pregnant blood donors as a reference. RESULTS: Although the percentages of both NKG2A- and NKG2C-positive NK cells were normal in preeclamptic women, the levels of NKG2A and NKG2C on NK cells were significantly up-regulated in these women. In vitro stimulation of PBMCs from healthy pregnant women and blood donors with monokines resulted in increased percentage of NKG2A(+) NK cells and increased NKG2A levels, while levels of NKG2C were decreased. CONCLUSIONS: Our results suggest that the peripheral NK-cell pool is skewed in preeclampsia and possibly under the influence of monokines like interleukin (IL)-15 and IL-12.

  • 18.
    Balogun, Halima A.
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Awah, Nancy W.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Farouk, Salah E.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Berzins, Klavs
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Pf332-C231-reactive antibodies affect growth and development of intra-erythrocytic Plasmodium falciparum parasites2011In: Vaccine, ISSN 0264-410X, E-ISSN 1873-2518, Vol. 30, no 1, p. 21-28Article in journal (Refereed)
    Abstract [en]

    The Plasmodium falciparum antigen 332 (Pf332), is a megadalton parasite protein expressed at the surface of infected red cells during later stages of the parasite's developmental cycle. Antibodies to different parts of this antigen have been shown to inhibit parasite growth and adherence to host cells with or without ancillary cells. However, the mechanisms involved in these inhibitions remain largely unknown. We further analysed the activities of specific antibodies with regard to their specific mechanisms of action. For these analyses, affinity purified human antibodies against epitopes in the C-terminal fragment of Pf332 (Pf332-C231) were employed. All purified antibodies recognized Pf332-C231 both by immunofluorescence and ELISA. IgG was the main antibody isotype detected, although all sera investigated had varying proportions of IgG and IgM content. All the antibodies showed a capacity to inhibit parasite growth in P. falciparum cultures to different extents, mainly by acting on the more mature parasite stages. Morphological analysis revealed the antibody effects to be characterized by the presence of a high proportion of abnormal schizonts (15-30%) and pyknotic parasites. There was also an apparent antibody effect on the red cell integrity, as many developing parasites (up to 10% of trophozoites and schizonts) were extracellular. In some cases, the infected red cells appeared to be disintegrating/fading, staining paler than surrounding infected and uninfected cells. Antigen reversal of inhibition confirmed that these inhibitions were antigen specific. Furthermore, the growth of parasites after 22-42 h exposure to antibodies was investigated. Following the removal of antibody pressure, a decreased growth rate of these parasites was seen compared to that of control parasites. The present study confirms the potential of Pf332 as a target antigen for parasite neutralizing antibodies, and further indicates that epitopes within the C231 region of Pf332 should constitute important tools in the dissection of the role of Pf332 in the biology of the malaria parasite, as well as in the design of a malaria vaccine.

  • 19.
    Balogun, Halima A.
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Vasconcelos, N.-M.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Lindberg, R.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Haeggström, M.
    Moll, K.
    Chen, Q.
    Wahlgren, M.
    Berzins, Klavs
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Immunogenicity and antigenic properties of Pf332-C231, a fragment of a non-repeat region of the Plasmodium falciparum antigen Pf332 2009In: Vaccine, ISSN 0264-410X, E-ISSN 1873-2518, Vol. 28, no 1, p. 90-97Article in journal (Refereed)
    Abstract [en]

    Antigen Pf332, a megadalton protein has been shown to be associated with the membrane of infected erythrocytes. Detailed functional studies on the antigen have remained hampered by the cross-reactive nature of antibodies generated to Pf332. Pf332-C231, identified in the C-terminal region of Pf332 was cloned and antibodies against the C231 fragment were shown to react with intact Pf332 antigen by both immunofluorescence and immunoblotting analyses. Antibodies to C231 inhibited in vitro Plasmodium falciparum growth efficiently. In addition, human sera from malaria-exposed individuals reacted with recombinant C231. We show that Pf332-C231 represents a functional domain and is expected to facilitate further studies on Pf332 as a potential target for protective immune responses and the function of the antigen.

  • 20.
    Balogun, Halima
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Awah, Nancy
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Farouk, S.
    Berzins, Klavs
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Pf332-C231- reactive antibodies affect growth and development of intraerythrocytic Plasmodium falciparum parasitesArticle in journal (Refereed)
  • 21.
    Balogun, Halima
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Awah, Nancy
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Nilsson, S.
    Rousillhon, C.
    Rogier, C.
    Trape, J. F.
    Chen, Q.
    Berzins, Klavs
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Pattern of antibodies to the Duffy binding-like domain of Plasmodium falciparum antigen Pf332 in Senegalese individualsManuscript (preprint) (Other academic)
  • 22. Bemark, Mats
    et al.
    Friskopp, Linda
    Saghafian-Hedengren, Shanie
    Stockholm University, Faculty of Science, The Wenner-Gren Institute, Immunology.
    Koethe, Susanne
    Fasth, Anders
    Abrahamsson, Jonas
    Sverremark-Ekström, Eva
    Stockholm University, Faculty of Science, The Wenner-Gren Institute, Immunology.
    Andersson, Bengt A.
    Mellgren, Karin
    A glycosylation-dependent CD45RB epitope defines previously unacknowledged CD27(-)IgM(high) B cell subpopulations enriched in young children and after hematopoietic stem cell transplantation2013In: Clinical Immunology, ISSN 1521-6616, E-ISSN 1521-7035, Vol. 149, no 3, p. 421-431Article in journal (Refereed)
    Abstract [en]

    The immune system is dysfunctional for years after hematopoietic stem cell transplantation (HSCT). A potential cause is an intrinsic B cell deficiency. In a cohort of pediatric HSCT patients few CD27(+) B cells formed after transplantation with the number of CD27(+)IgM(high) cells more affected than class-switched ones. A previously unacknowledged population of CD27(-)IgM(high) cells made up the majority of B cells and this population was also enlarged in healthy children compared to adults. Only a minority of these CD27(-)IgM(high) B cells expressed markers typical for transitional B cells, and the non-transitional CD27(-)IgM(high) cells could be further divided into subpopulations based on their ability to extrude the dye Rhodamine 123 and their expression of CD45RB(MEM55), a glycosylation-dependent epitope. Thus, we define several novel human CD27(-)IgM(high) B cell subpopulations in blood, all of which are present in higher frequencies and numbers in young children and after HSCT than in adults.

  • 23.
    Björkander, Sofia
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Bremme, K.
    Persson, Jan-Olov
    Stockholm University, Faculty of Science, Department of Mathematics.
    van Vollenhoven, R. F.
    Sverremark-Ekström, Eva
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Holmlund, Ulrika
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Pregnancy-associated inflammatory markers are elevated in pregnant women with systemic lupus erythematosus2012In: Cytokine, ISSN 1043-4666, E-ISSN 1096-0023, Vol. 59, no 2, p. 392-399Article in journal (Refereed)
    Abstract [en]

    During normal pregnancy a dampening in T cell-mediated immunity is compensated by an increased pro-inflammatory activity. Likewise, the autoimmune disease systemic lupus erythematosus (SLE) is associated with inflammatory activity and pregnancy complications occur frequently in women with SLE. The aim of this study was to elucidate how SLE influences the chemokine and cytokine balance during and after pregnancy. Blood samples were taken from pregnant women with or without SLE at second and third trimester and 8-12 weeks after pregnancy. Cytokines (interleukin (IL)-1 beta, IL-2, IL-4, IL-6, IL-10, IL-12p70, IL-17A, TNF, IFN-gamma and IFN-alpha), chemokines (CXCL8/IL-8, CXCL9/MIG, CXCL10/IP-10, CCL2/MCP-1, CCL5/RANTES and CCL17/TARC), soluble IL-6 receptor (sIL-6R) and soluble glycoprotein 130 (gp130) were measured in serum using cytometric bead array (CBA) or enzyme-linked immunosorbent assay (ELISA). Women with SLE had increased serum concentrations of CXCL8/IL-8, CXCL9/MIG, CXCL10/IP-10 and IL-10 compared to controls both during and after pregnancy. Further, when dividing the patients based on disease activity, the women with active disease had the highest levels. Importantly, women with SLE seemed to respond to pregnancy in a similar way as controls, since the changes of cytokines and chemokines over the course of pregnancy were similar but with overall higher levels in the patient group. In conclusion, changes in pro- and anti-inflammatory serum components during pregnancy in women with SLE, occurring on top of already more pro-inflammatory levels, might increase their risk for pregnancy complications and flares. How their children are affected by this heightened inflammatory milieu during pregnancy needs further investigation.

  • 24.
    Boström, Stéphanie
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Inflammatory responses due to Plasmodium falciparum infection during pregnancy and childhood2012Licentiate thesis, comprehensive summary (Other academic)
  • 25.
    Calla-Magarinos, Jacqueline
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute, Immunology. National University Hospital of Iceland.
    Fernandez, Carmen
    Stockholm University, Faculty of Science, The Wenner-Gren Institute, Immunology.
    Troye-Blomberg, Marita
    Stockholm University, Faculty of Science, The Wenner-Gren Institute, Immunology.
    Freysdottir, Jona
    Alkaloids from Galipea longiflora Krause modify the maturation of human dendritic cells and their ability to stimulate allogeneic CD4(+) T cells2013In: International Immunopharmacology, ISSN 1567-5769, E-ISSN 1878-1705, Vol. 16, no 1, p. 79-84Article in journal (Refereed)
    Abstract [en]

    Alkaloids obtained from the plant Evanta have been shown to have dual effects in Leishmania infection; a direct leishmanicidal effect on the parasite and more importantly, the alkaloids affect both polyclonal and Leishmania-specific stimulation of T-cells. Dendritic cells (DCs) play a pivotal role in stimulation and polarization of naive T cells towards a Th1, Th2, Th17 or regulatory phenotype. In leishmaniasis, the interactions between the parasites and DCs are complex and involve contradictory functions that can stimulate or suppress T cell responses, leading to the control of infection or progression of disease. In this study the effect of an alkaloid extract of Evanta (AEE) or the purified alkaloid 2-phenilquinoline (2Ph) on the activation of human DCs and their ability to stimulate allogeneic CD4(+) T cells was analyzed. The expression of surface activation molecules was not affected on DCs stimulated in the presence of AEE or 2Ph nor did AEE-DCs or 2Ph-CDs affect the expression of activation surface molecules on allogeneic CD4(+) T cells. In contrast, as compared with control, the secretion of IL-12p40, IL-23 and IL-6 was lower from AEE-DCs and 2Ph-CDs and allogeneic CD4(+) T cells co-cultured with these DCs secreted lower levels of IFN-gamma and IL-10 but the same levels of IL-17. These results demonstrate that AEE and 2Ph affect the stimulation of DCs and their ability to stimulate allogeneic CD4(+) T cells by reducing the production of IFN-gamma, IL-12 p40, IL-6 and IL-23. This suggests that AEE and 2Ph may take part in regulation of inflammation.

  • 26.
    Cardell, Susanna
    Stockholm University, Faculty of Science, The Wenner-Gren Institute, Immunology.
    T lymphocyte subsets: a study on heterogeneity based on lymphokine production1992Doctoral thesis, comprehensive summary (Other academic)
  • 27. Cherif, M. K.
    et al.
    Sanou, G. S.
    Maiga, B.
    Israelsson, E.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Ouedraogo, A. L.
    Bougouma, E. C.
    Diarra, A.
    Ouedraogo, A.
    Ouattara, A. S.
    Troye-Blomberg, Marita
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Dolo, A.
    Cavanagh, D. R.
    Theisen, M.
    Modiano, D.
    Sirima, S. B.
    Nebie, I.
    Fc gamma RIIa Polymorphism and Anti-Malaria-Specific IgG and IgG Subclass Responses in Populations Differing in Susceptibility to Malaria in Burkina Faso2012In: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 75, no 6, p. 606-613Article in journal (Refereed)
    Abstract [en]

    Fc?RIIa is known to be polymorphic; and certain variants are associated with different susceptibilities to malaria. Studies involving the Fulani ethnic group reported an ethnic difference in Fc?RIIa-R131H genotype frequencies between the Fulani and other sympatric groups. No previous studies have addressed these questions in Burkina Faso. This study aimed to assess the influence of Fc?RIIa-R131H polymorphism on anti-falciparum malaria IgG and IgG subclass responses in the Fulani and the Mossi ethnic groups living in Burkina Faso. Healthy adults more than 20 years old belonging to the Mossi or the Fulani ethnic groups were enrolled for the assessment of selected parasitological, immunological and genetic variables in relation to their susceptibility to malaria. The prevalence of the Plasmodium falciparum infection frequency was relatively low in the Fulani ethnic group compared to the Mossi ethnic group. For all tested antigens, the Fulani had higher antibody levels than the Mossi group. In both ethnic groups, a similar distribution of Fc?RIIa R131H polymorphism was found. Individuals with the R allele of Fc?RIIa had higher antibody levels than those with the H allele. This study confirmed that malaria infection affected less the Fulani group than the Mossi group. Fc?RIIa-R131H allele distribution is similar in both ethnic groups, and higher antibody levels are associated with the Fc?RIIa R allele compared to the H allele.

  • 28. Chuangchaiya, S
    et al.
    Jangpatarapongsa, K
    Chootong, P
    Sirichaisinthop, J
    Sattabongkot, J
    Pattanapanyasat, K
    Chotivanich, K
    Troye-Blomberg, Marita
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Cui, L
    Udomsangpetch, R
    Immune response to Plasmodium vivax has a potential to reduce malaria severity2010In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 160, no 2, p. 233-239Article in journal (Refereed)
    Abstract [en]

    Summary Plasmodium falciparum infection causes transient immunosuppression during the parasitaemic stage. However, the immune response during simultaneous infections with both P. vivax and P. falciparum has been investigated rarely. In particular, it is not clear whether the host's immune response to malaria will be different when infected with a single or mixed malaria species. Phenotypes of T cells from mixed P. vivax-P. falciparum (PV-PF) infection were characterized by flow cytometry, and anti-malarial antibodies in the plasma were determined by an enzyme-linked immunosorbent assay. We found the percentage of CD3(+)delta2(+)-T cell receptor (TCR) T cells in the acute-mixed PV-PF infection and single P. vivax infection three times higher than in the single P. falciparum infection. This implied that P. vivax might lead to the host immune response to the production of effector T killer cells. During the parasitaemic stage, the mixed PV-PF infection had the highest number of plasma antibodies against both P. vivax and P. falciparum. Interestingly, plasma from the group of single P. vivax or P. falciparum malaria infections had both anti-P. vivax and anti-P. falciparum antibodies. In addition, antigenic cross-reactivity of P. vivax or P. falciparum resulting in antibodies against both malaria species was shown in the supernatant of lymphocyte cultures cross-stimulated with either antigen of P. vivax or P. falciparum. The role of delta2 +/- TCR T cells and the antibodies against both species during acute mixed malaria infection could have an impact on the immunity to malaria infection.

  • 29.
    Chuquimia Flores, Olga Daniela
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Innate and adaptive immune responses in the lungs. Contribution to protection against mycobacterial infections2011Licentiate thesis, monograph (Other academic)
    Abstract [en]

    Host defense against Mycobacterium tuberculosis (Mtb) is mediated by a combination of innate and adaptive immunity. In this thesis we investigated the role of components of innate system such as TLR2 signalling and alveolar epithelial cells type II (AEC II) in the immune responses against mycobacterial infections.

    Since TLR2 has been shown to be important in the defense against mycobacterial infections; in paper I we investigated the role of TLR2 to generate acquired immune responses. We compared both humoral and cellular immune responses in TLR2-/- and WT (wild type) mice immunized with the mycobacterial antigens 19kDa (TLR2 ligand) or Ag85A (non-TLR2 ligand). We did not find any differences in the humoral responses in both mouse strains. However, we found some deficiencies in the T cell memory compartment of TLR2-/- mice immunized with 19kDa. In addition, the antigen presenting cells (APC) compartment in TLR2-/- mice, for instance bone marrow derived macrophages (BMM) and pulmonary macrophages (PM) in this study, has also shown deficiencies. This effect was more evident when PM were used as APC. We next evaluated the responses in both BMM and PM upon stimulation with anti-CD40 and TLR ligands where PM were the low responders to TLR2 ligand and to anti-CD40 both in the production of different cytokines and in the up-regulation of the co-stimulatory molecules. Together, our results have demonstrated the importance of TLR2 in the generation of specific immune responses.

    In paper II, we investigated the role of AEC II in the defense against mycobacterial infections. AEC II have been suggested to play an important role in the local immune responses to inhaled pathogens. First, we compared murine AEC II with PM in their ability to take up and control mycobacterial growth and their capacity as APCs. AEC II were able to internalize and control bacterial growth as well as presenting antigen to memory T cells. In addition, both cells types were compared in their capacity to produce cytokines, chemokines and other factors where AEC II exhibited a different pattern of secretion than PM. Also, a more complete profile of AEC II responses reveled that AEC II were able to secrete different factors important to generated various effects in others cells. The major finding in this study was that upon TNF, AEC II produced MCP-1 a chemokine involved in the recruitment monocytes/macrophages to the sites of infection. Since TNF is predominantely produced by macrophages, we speculate that both cell types may communicate and influence each other. In conclusion, our results provide more evidence of the important role of AEC II in the immune responses in the respiratory tract.

  • 30.
    Chuquimia, Olga D.
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute, Immunology.
    Petursdottir, Dagbjort H.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute, Immunology.
    Periolo, Natalia
    Stockholm University, Faculty of Science, The Wenner-Gren Institute, Immunology.
    Fernandéz, Carmen
    Stockholm University, Faculty of Science, The Wenner-Gren Institute, Immunology.
    Alveolar epithelial cells are critical in protection of the respiratory tract by secretion of factors able to modulate the activity of pulmonary macrophages and directly control bacterial growth2013In: Infection and Immunity, ISSN 0019-9567, E-ISSN 1098-5522, Vol. 81, no 1, p. 381-389Article in journal (Refereed)
    Abstract [en]

    The respiratory epithelium is a physical and functional barrier actively involved in the clearance of environmental agents. The alveolar compartment is lined with membranous pneumocytes known as type I alveolar epithelial cells (AEC I), and granular pneumocytes, type II alveolar epithelial cells (AEC II). AEC II are responsible for epithelial reparation upon injury and ion transport and are very active immunologically contributing to lung defense by secreting antimicrobial factors. AEC II also secrete a broad variety of factors such as cytokines and chemokines involved in activation and differentiation of immune cells and are able to present antigen to specific T cells. Another cell type important in lung defense is the pulmonary macrophage (PuM). Considering the architecture of the alveoli, a good communication between the external and the internal compartments is crucial to mount effective responses. Our hypothesis is that being in the interface; AEC may play an important role in transmitting signals from the external to the internal compartment and in modulating the activity of PuM. For this, we collected supernatants from AEC unstimulated or stimulated in vitro with lipopolysaccharide (LPS). These AEC-conditioned media were used in various setups to test for the effect on a number of macrophage functions: a) migration; b) phagocytosis and intracellular control of bacterial growth and c) phenotypic changes and morphology. Finally, we tested the direct effect of AEC-conditioned media on bacterial growth. We found that AEC-secreted factors had a dual effect, in one hand controlling bacterial growth and on the other hand increasing macrophage activity.

  • 31.
    Chuquimia, Olga D.
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute, Immunology.
    Petursdottir, Dagbjort H.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute, Immunology.
    Rahman, Muhammad J.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute, Immunology.
    Hartl, Katharina
    Stockholm University, Faculty of Science, The Wenner-Gren Institute, Immunology.
    Singh, Mahavir
    Fernandez, Carmen
    Stockholm University, Faculty of Science, The Wenner-Gren Institute, Immunology.
    The Role of Alveolar Epithelial Cells in Initiating and Shaping Pulmonary Immune Responses: Communication between Innate and Adaptive Immune Systems2012In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 2, p. e32125-Article in journal (Refereed)
    Abstract [en]

    Macrophages and dendritic cells have been recognized as key players in the defense against mycobacterial infection. However, more recently, other cells in the lungs such as alveolar epithelial cells (AEC) have been found to play important roles in the defense and pathogenesis of infection. In the present study we first compared AEC with pulmonary macrophages (PuM) isolated from mice in their ability to internalize and control Bacillus Calmette-Guerin (BCG) growth and their capacity as APCs. AEC were able to internalize and control bacterial growth as well as present antigen to primed T cells. Secondly, we compared both cell types in their capacity to secrete cytokines and chemokines upon stimulation with various molecules including mycobacterial products. Activated PuM and AEC displayed different patterns of secretion. Finally, we analyzed the profile of response of AEC to diverse stimuli. AEC responded to both microbial and internal stimuli exemplified by TLR ligands and IFNs, respectively. The response included synthesis by AEC of several factors, known to have various effects in other cells. Interestingly, TNF could stimulate the production of CCL2/MCP-1. Since MCP-1 plays a role in the recruitment of monocytes and macrophages to sites of infection and macrophages are the main producers of TNF, we speculate that both cell types can stimulate each other. Also, another cell-cell interaction was suggested when IFNs (produced mainly by lymphocytes) were able to induce expression of chemokines (IP-10 and RANTES) by AEC involved in the recruitment of circulating lymphocytes to areas of injury, inflammation, or viral infection. In the current paper we confirm previous data on the capacity of AEC regarding internalization of mycobacteria and their role as APC, and extend the knowledge of AEC as a multifunctional cell type by assessing the secretion of a broad array of factors in response to several different types of stimuli.

  • 32. Costa, Giulia
    et al.
    Loizon, Séverine
    Guenot, Marianne
    Mocan, Iulia
    Halary, Franck
    de Saint-Basile, Geneviève
    Pitard, Vincent
    Déchanet-Merville, Julie
    Moreau, Jean-François
    Troye-Blomberg, Marita
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Mercereau-Puijalon, Odile
    Behr, Charlotte
    Control of Plasmodium falciparum erythrocytic cycle: gamma-delta T cells target the red blood cell-invasive merozoites2011In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 118, no 26, p. 6952--6962Article in journal (Refereed)
    Abstract [en]

    The control of Plasmodium falciparum erythrocytic parasite density is essential for protection against malaria, as it prevents pathogenesis and progression towards severe disease. P.falciparum blood-stage parasite cultures are inhibited by human Vγ9Vδ2 gamma-delta T cells, but the underlying mechanism remains poorly understood. Here, we show that both intra-erythrocytic parasites and the extracellular red blood cell-invasive merozoites specifically activate Vγ9Vδ2 T cells in a γδ T cell receptor dependent manner and trigger their degranulation. In contrast, the γδ T cell-mediated anti-parasitic activity only targets the extracellular merozoites. Using perforin-deficient and granulysin-silenced T cell lines, we demonstrate that granulysin is essential for the in vitro anti-plasmodial process, whereas perforin is dispensable. Patients infected with P.falciparum exhibited elevated granulysin plasma levels associated with high levels of granulysin-expressing Vδ2(+) T cells endowed with parasite-specific degranulation capacity. This indicates in vivo activation of Vγ9Vδ2 T cells along with granulysin triggering and discharge during primary acute falciparum malaria. Altogether, this work identifies Vγ9Vδ2 T cells as unconventional immune effectors targeting the red blood cell-invasive extracellular P.falciparum merozoites and opens novel perspectives for immune interventions harnessing the anti-parasitic activity of Vγ9Vδ2 T cells to control parasite density in malaria patients.

  • 33. Courtin, David
    et al.
    Milet, Jacqueline
    Bertin, Gwladys
    Vafa, Manijeh
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Sarr, Jean Birame
    Watier, Laurence
    Deloron, Philippe
    Troye-Blomberg, Marita
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Garcia, André
    Migot-Nabias, Florence
    G6PD A-variant influences the antibody responses to Plasmodium falciparum MSP2.2011In: Infection, Genetics and Evolution, ISSN 1567-1348, E-ISSN 1567-7257, Vol. 11, no 6, p. 1287-1292Article in journal (Refereed)
    Abstract [en]

    High antibody levels directed to Plasmodium falciparum merozoite surface proteins (MSP), including MSP2, as well as genetically related red blood cell defects, have previously been found to be associated with protection against malaria. Here, our main objective was to study the changes in MSP2-specific total IgG, IgG1 and IgG3 responses during a malaria transmission season in order to assess the impact of sickle-cell, α(+)-thalassemia and G6PD variants on antibody kinetics. Repeated parasitological assessments of a cohort of children were conducted during an 8-month period. Antibody responses to recombinant MSP2/3D7 and MSP2/FC27 proteins were measured at the beginning and at the end of transmission season. We found that (i) the period of last Plasmodium falciparum infection during the transmission season was associated with IgG3 anti-MSP2 change. Compared to the IgG3 levels of children infected in January 2003 (end of transmission season), the IgG3 level of children decreased with the length of the period without infection, (ii) G6PD A- carriers had a lower increase of IgG3 levels to MSP2/FC27 and MSP2/3D7 during the transmission season than the noncarriers. This latter finding is suggestive of qualitative and/or quantitative reduction of exposure to malarial antigens related to this genetic variant, leading to weaker stimulation of specific antibody responses. We speculate that cell-mediated immune activity may explain the clinical protection afforded by this genetic trait.

  • 34. Curbo, Sophie
    et al.
    Gaudin, Raphael
    Carlsten, Mattias
    Malmberg, Karl-Johan
    Troye-Blomberg, Marita
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Ahlborg, Niklas
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Karlsson, Anna
    Johansson, Magnus
    Lundberg, Mathias
    Regulation of interleukin-4 signaling by extracellular reduction of intramolecular disulfides2009In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 390, no 4, p. 1272-1277Article in journal (Refereed)
    Abstract [en]

    Interleukin-4 (IL-4) contains three structurally important intramolecular disulfides that are required for the bioactivity of the cytokine. We show that the cell surface of HeLa cells and endotoxin-activated monocytes can reduce IL-4 intramolecular disulfides in the extracellular space and inhibit binding of IL-4 to the IL-4R alpha receptor. IL-4 disulfides were in vitro reduced by thioredoxin 1 (Trx1) and protein disulfide isomerase (PDI). Reduction of IL-4 disulfides by the cell surface of HeLa cells was inhibited by auranofin, an inhibitor of thioredoxin reductase that is an electron donor to both Trx1 and PDI. Both Trx1 and PDI have been shown to be located at the cell surface and our data suggests that these enzymes are involved in catalyzing reduction of IL-4 disulfides. The pro-drug N-acetylcysteine (NAC) that promotes T-helper type 1 responses was also shown to mediate the reduction of IL-4 disulfides. Our data provides evidence for a novel redox dependent pathway for regulation of cytokine activity by extracellular reduction of intramolecular disulfides at the cell surface by members of the thioredoxin enzyme family. 

  • 35.
    Dubicke, Aurelija
    et al.
    Department of Woman and Child Health, Karolinska Institute,Stockholm, Sweden.
    Andersson, Peter
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Fransson, Emma
    Department of Woman and Child Health, Karolinska Institute, Stockholm, Sweden.
    Andersson, Eva
    Department of Woman and Child Health, Karolinska Institute,Stockholm, Sweden.
    Sioutas, Angelos
    Malmström, Anders
    Department of Experimental Medical Science, University of Lund, Sweden.
    Sverremark-Ekström, Eva
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Ekman-Ordeberg, Gunvor
    Department of Woman and Child Health, Karolinska Institute, Stockholm, Sweden.
    High-mobility group box protein 1 and its signalling receptors in human preterm and term cervix2010In: Journal of Reproductive Immunology, ISSN 0165-0378, E-ISSN 1872-7603, Vol. 84, no 1, p. 86-94Article in journal (Refereed)
    Abstract [en]

    The objective of this study was to identify possible changes in mRNA and protein expression of high-mobility group box protein 1 (HMGB1) and its suggested receptors - receptor for advanced glycation end-products (RAGE) and Toll-like receptor 2 (TLR2) and TLR4 - in human cervix during pregnancy, term and preterm labor. Cervical biopsies were taken from 58 women: 20 at preterm labor, 24 at term labor, 10 at term not in labor and 4 from non-pregnant women. Real-time RT-PCR was used to quantify mRNA expression, and immunohistochemistry and ELISA for protein analysis. HMGB1, RAGE, TLR2 and TLR4 proteins were localized and their mRNA expression was detected in the cervix. There was more extranuclear HMGB1 in the cervical epithelium and stroma in preterm and term labor compared to the term not in labor. TLR2 mRNA expression was upregulated 5-fold in term labor and 3-fold in preterm labor compared to term not in labor and non-pregnant controls. There was lower expression of TLR2 and TLR4 mRNAs in preterm labor compared to term. Lower mRNA expression of HMGB1 was found in the subgroup with preterm premature rupture of membranes than in the rest of the preterm group, where levels were significantly higher than in term labor. In conclusion, extranuclear expression of HMGB1 during labor suggests a possible role of HMGB1 during the process of cervical ripening. Changes in expression of mRNAs encoding HMGB1, TLR2 and TLR4 in preterm labor suggest differences in the mechanism of cervical ripening at preterm and term delivery.

  • 36. Ekstrom, Mattias
    et al.
    Liska, Jan
    Eriksson, Per
    Sverremark-Ekström, Eva
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Tornvall, Per
    Stimulated in vivo synthesis of plasminogen activator inhibitor 1 in human adipose tissue2012In: Thrombosis and Haemostasis, ISSN 0340-6245, Vol. 108, no 3, p. 485-492Article in journal (Refereed)
    Abstract [en]

    Plasminogen activator inhibitor type-1 (PAI-1) is one of the most important inhibitors of endogenous fibrinolysis. Adipose tissue is a suggested source of the elevated plasma levels o(-) PAI-1 in obesity. The relation between PAI-1 and inflammation is of particular interest, but current knowledge regarding regulation of PAI-1 in adipose tissue is mainly based on animal studies or ex vivo experiments on human cultured adipocytes. So far, no study has described stimulated gene expression and protein synthesis of PAI-1 in vivo in human adipose tissue. We used open heart surgery as a model of acute systemic inflammation. Twenty-two male patients underwent blood sampling and omental and subcutaneous adipose tissue biopsies for gene expression studies before and after surgery. Expression and localisation of PAI-1 antigen was evaluated by immunohistochemistry. After surgery gene expression of PAI-1 increased 27-fold in omental adipose tissue and three-fold in subcutaneous adipose tissue, but no differences were found in tissue-type plasminogen activator (t-PA) mRNA. PAI-1 antigen was localised within endothelial cells and in the adipose tissue interstitium close to vessels. The upregulated gene expression and protein synthesis in adipose tissue was followed by increased concentrations of PAI-1 antigen in plasma. In conclusion, we present for the first time that an acute systemic inflammation in humans increased gene expression and protein synthesis of PAI-1 in adipose tissue and that this increase was most prominent in omental adipose tissue. PAI-1 synthesis in adipose tissue due to acute systemic inflammation may be a link between inflammation and impaired endogenous fibrinolysis.

  • 37.
    Elenström-Magnusson, Carina
    Stockholm University, Faculty of Science, The Wenner-Gren Institute, Immunology.
    Regulation of B lymphocyte adhesion and migration by interleukin 41995Doctoral thesis, comprehensive summary (Other academic)
  • 38. Fernando Chaves, Luis
    et al.
    Taleo, George
    Kalkoa, Morris
    Kaneko, Akira
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Spleen rates in children: an old and new surveillance tool for malaria elimination initiatives in island settings2011In: Transactions of the Royal Society of Tropical Medicine and Hygiene, ISSN 0035-9203, E-ISSN 1878-3503, Vol. 105, no 4, p. 226-231Article in journal (Refereed)
    Abstract [en]

    Spleen rates (SR) have been traditionally used to estimate the burden of malaria transmission. Results are presented from 51 surveys, which measured SR and parasite rates (PR) in 29 962 individuals in the archipelago of Vanuatu. Indices for spleen size computed with multivariate statistical tools outperformed the WHO average spleen index and showed that spleen sizes in a population can track shifts in malaria transmission. In general, a positive linear relationship between Plasmodium spp. PR and SR was found for the archipelago. In the context of malaria elimination and for the specific setting of this study we found that spleen examination is a useful tool in post-malaria elimination surveillance. Finally, results highlight the value of measuring spleen sizes to rapidly assess the impact of intervention packages aimed at malaria elimination or control.

  • 39. Ferwerda, Bart
    et al.
    Alonso, Santos
    Banahan, Kathy
    McCall, Matthew B B
    Giamarellos-Bourboulis, Evangelos J
    Ramakers, Bart P
    Mouktaroudi, Maria
    Fain, Pamela R
    Izagirre, Neskuts
    Syafruddin, Din
    Cristea, Tudor
    Mockenhaupt, Frank P
    Troye-Blomberg, Marita
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Kumpf, Oliver
    Maiga, Boubacar
    Dolo, Amagana
    Doumbo, Ogobara
    Sundaresan, Santhosh
    Bedu-Addo, George
    van Crevel, Reinout
    Hamann, Lutz
    Oh, Djin-Ye
    Schumann, Ralf R
    Joosten, Leo A B
    de la Rúa, Concepcion
    Sauerwein, Robert
    Drenth, Joost P H
    Kullberg, Bart-Jan
    van der Ven, André J A M
    Hill, Adrian V
    Pickkers, Peter
    van der Meer, Jos W M
    O'Neill, Luke A J
    Netea, Mihai G
    Functional and genetic evidence that the Mal/TIRAP allele variant 180L has been selected by providing protection against septic shock.2009In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 106, no 25, p. 10272-10277Article in journal (Refereed)
    Abstract [en]

    Adequate responses by our innate immune system toward invading pathogens were of vital importance for surviving infections, especially before the antibiotic era. Recently, a polymorphism in Mal (Ser180Leu, TIRAP rs8177374), an important adaptor protein downstream of the Toll-like receptor (TLR) 2 and 4 pathways, has been described to provide protection against a broad range of infectious pathogens. We assessed the functional effects of this polymorphism in human experimental endotoxemia, and we demonstrate that individuals bearing the TIRAP 180L allele display an increased, innate immune response to TLR4 and TLR2 ligands, but not to TLR9 stimulation. This phenotype has been related to an increased resistance to infection. However, an overshoot in the release of proinflammatory cytokines by TIRAP 180L homozygous individuals suggests a scenario of balanced evolution. We have also investigated the worldwide distribution of the Ser180Leu polymorphism in 14 populations around the globe to correlate the genetic makeup of TIRAP with the local infectious pressures. Based on the immunological, clinical, and genetic data, we propose that this mutation might have been selected in West Eurasia during the early settlement of this region after the out-of-Africa migration of modern Homo sapiens. This combination of functional and genetic data provides unique insights to our understanding of the pathogenesis of sepsis.

  • 40. Gbedande, K.
    et al.
    Ezinmegnon, S.
    Adeothy, A. -L
    Agbowai, C.
    Nouatin, O. P.
    Ibitokou, S.
    Borgella, S.
    Moutairou, K.
    Massougbodji, A.
    Varani, S.
    Troye-Blomberg, Marita
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Luty, A. J. F.
    Deloron, P.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Fievet, N.
    Consequences of malaria during pregnancy on neonatal antigen presenting cell activation and on responses to toll-like receptors and P. falciparum antigens in Benin2011In: Tropical medicine & international health, ISSN 1360-2276, E-ISSN 1365-3156, Vol. 16, no Special issue, supplement 1, p. 304-304Article in journal (Refereed)
  • 41. Geels, Mark J
    et al.
    Imoukhuede, Egeruan B
    Imbault, Nathalie
    van Schooten, Harry
    McWade, Terry
    Troye-Blomberg, Marita
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Dobbelaer, Roland
    Craig, Alister G
    Leroy, Odile
    European Vaccine Initiative: lessons from developing malaria vaccines2011In: Expert Review of Vaccines, ISSN 1476-0584, E-ISSN 1744-8395, Vol. 10, no 12, p. 1697-1708Article in journal (Refereed)
    Abstract [en]

    For over 10 years, the European Vaccine Initiative (EVI; European Malaria Vaccine Initiative until 2009) has contributed to the development of 24 malaria candidate vaccine antigens with 13 vaccine candidates being advanced into Phase I clinical trials, two of which have been transitioned for further clinical development in sub-Saharan Africa. Since its inception the EVI organization has operated as a funding agency, but with a clear service-oriented strategy. The scientific successes and difficulties encountered during these years and how these efforts have led to standardization and harmonization in vaccine development through large-scale European consortia are discussed. In the future, the EVI will remain instrumental in the pharmaceutical and clinical development of vaccines against ?diseases of poverty? with a continued focus on malaria. EVI will continue to focus on funding and managing preclinical evaluation up to Phase I/II clinical trials and strengthening the vaccine-development infrastructure in Europe, albeit with a global orientation.

  • 42. Giha, Hayder A
    et al.
    ElGhazali, Gehad
    Nasr, Amre
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Iriemenam, Nnaemeka C
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Berzins, Klavs
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Troye-Blomberg, Marita
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Physiology.
    Theander, Thor G
    Arnot, David
    Clustering of malaria treatment failure (TF) in Daraweesh: hints for host genetic susceptibility to TF with emphasis on immune-modulating SNPs2010In: Infection, Genetics and Evolution, ISSN 1567-1348, E-ISSN 1567-7257, Vol. 10, no 4, p. 481-6Article in journal (Refereed)
    Abstract [en]

    In malaria, drug resistance and treatment failure (TF) are not synonymous, although are escalating together. Over 9 years of surveillances for malaria morbidity and TF in Daraweesh village in eastern Sudan (1991-2004), 136 donors (15-78 years) from 43 households, treated for 278 malaria episodes and had experienced 46 incident of TF, were included in this study. Blood obtained from the donors in 2005, was used for measurement of IgG subclasses against Pf332-C231 antigen and GM/KM allotyping and for genotyping of the donors for; FcgammaRIIA 131 (HH, RH, RR), CRP 286 (C

  • 43. Giha, Hayder A
    et al.
    Nasr, Amre
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Ekström, Mattias
    Israelsson, Elisabeth
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Arambepola, Gishanthi
    Arnot, David
    Theander, Thor G
    Troye-Blomberg, Marita
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Berzins, Klavs
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Tornvall, Per
    ElGhazali, Gehad
    Association of a single nucleotide polymorphism in the C-reactive protein gene (-286) with susceptibility to Plasmodium falciparum malaria2010In: Molecular medicine (Cambridge, Mass. Print), ISSN 1076-1551, E-ISSN 1528-3658, Vol. 16, no 1-2, p. 27-33Article in journal (Refereed)
    Abstract [en]

    The role of inflammation in malaria pathogenesis is not fully understood, although C-reactive protein (CRP) may have a negative influence on host immunity to infections. An upstream polymorphism, -286 (C > T > A), in the CRP gene is known to influence CRP levels. In this study, a cohort of 192 Sudanese donors, followed for malaria infection for 9 years, had their CRP -286 gene locus genotyped by pyrosequencing. The number of malaria episodes experienced by each individual over the study period was used as an index for malaria susceptibility. The prevalence of the CRP alleles A, C and T were 21%, 52% and 27%, respectively. Importantly, the A-allele, unlike the C- and T-alleles or CRP genotypes, was significantly associated with an increased number of malaria episodes, P = 0.007. The proportion of A-allele carriers among donors not known to have had malaria during the study period was 18%, whereas it was 43% and 63% among donors who had experienced 1-4 and > or =5 malaria episodes, respectively, over the same period (P = 0.002). Furthermore, the A-allele was associated with higher parasite counts. In conclusion, the CRP -286 A-allele was associated with an increased susceptibility to uncomplicated Plasmodium falciparum malaria.

  • 44. Giha, Hayder A
    et al.
    Nasr, Amre
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Iriemenam, Nnaemeka C
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Arnot, David
    Troye-Blomberg, Marita
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Theander, Thor G
    Berzins, Klavs
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Elghazali, Gehad
    Pandey, Janardan P
    Antigen-specific influence of GM/KM allotypes on IgG isotypes and association of GM allotypes with susceptibility to Plasmodium falciparum malaria.2009In: Malaria journal, ISSN 1475-2875, Vol. 8, no 1, p. 306-Article in journal (Refereed)
    Abstract [en]

    ABSTRACT: BACKGROUND: Plasmodium falciparum malaria is a complex disease in which genetic and environmental factors influence susceptibility. IgG isotypes are in part genetically controlled, and GM/KM allotypes are believed to be involved in this control. METHODS: In this study, 216 individuals from Daraweesh, an area of seasonal malaria transmission in Sudan, were followed for nine years for malaria infection. Total IgG and IgG isotypes against four malaria antigens, MSP2-3D7, MSP2-FC27, AMA1, and Pf332-C231 were measured in plasma obtained from the cohort at the end of the study, during the dry malaria-free period. The GM/KM allotypes of the donors were determined. RESULTS: The GM 1,17 5,13,14,6 phenotype was associated with a higher incidence of malaria compared with the non-1,17 5,13,14,6 phenotypes (P = 0.037). Paradoxically, the carriers of the GM 1,17 5,13,14,6 phenotype had significantly higher baseline levels of total IgG and non-cytophilic IgG isotypes as compared to non-carriers. The KM allotypes influence on IgG isotypes level was limited. Finally, the differences in the baseline concentrations of total IgG and IgG isotypes between the different GK/KM phenotype carriers were antigen-dependent. DISCUSSION: The results show that GM but not KM allotypes appeared to influence host susceptibility to uncomplicated malaria as well as the antibody profile of the donors, and the carriers of the GM 1,17 5,13,14,6 phenotype were the most susceptible CONCLUSIONS: The GM allotypes have significant influence on susceptibility to uncomplicated P. falciparum malaria and antigen-dependent influence on total IgG and IgG subclasses.

  • 45. Giha, Hayder A
    et al.
    Nasr, Amre
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Iriemenam, Nnaemeka C
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Balogun, Halima A
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Arnot, David
    Theander, Thor G
    Troye-Blomberg, Marita
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Berzins, Klavs
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Elghazali, Gehad
    Age-dependent association between IgG2 and IgG3 subclasses to Pf332-C231 antigen and protection from malaria, and induction of protective antibodies by sub-patent malaria infections, in Daraweesh2010In: Vaccine, ISSN 0264-410X, E-ISSN 1873-2518, Vol. 28, no 7, p. 1732-1739Article in journal (Refereed)
    Abstract [en]

    The certainty of the protective role of acquired immunity in malaria is the major drive for malaria vaccine development. In this study, we measured the levels of total IgG and IgG subclasses to four candidate malaria vaccine antigens; MSP2-3D7, MSP2-FC27, AMA-1 and Pf332-C231, in plasma obtained from a cohort of 136 donors from Daraweesh in Sudan. The cohort was followed for malaria infection for 9 years. After an initial analysis, the immune response to Pf332-C231 antigen was the only one found associated with protection, thus taken for further analysis. The number of previous clinical malaria episodes experienced by the donors was used as an index for relative protection. The number of these episodes was found to be negatively correlated with the levels of pre-existing total IgG, IgG2 and IgG3 to Pf332-C231 (correlation coefficient, CC - 0.215, p=0.012; CC - 0.195, p=0.023 and CC - 0.211, p=0.014, respectively), and also with age (CC - 0.311, p<0.001). Unexpectedly, equal levels of Pf332-C231 antibodies were induced by both patent and sub-patent infections regardless of the number of previous malaria episodes (1-7). Combining the correlation analysis with a multi-linear regression, three variable markers for protection were emerged, two age-dependent, the antibody response to Pf332-C231 and an unidentified marker (likely immune response to other antigens), and the third was an age-independent unidentified marker (possibly gene polymorphisms). In conclusion, this report suggests a protective effect for IgG subclasses to Pf332-C231 antigen against malaria.

  • 46. Giha, Hayder A.
    et al.
    Nasr, Amre
    Iriemenam, Nnaemeka C.
    Troye-Blomberg, Marita
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Berzins, Klavs
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    ElGhazali, Gehad
    Lack of significant influence for Fc gamma RIIa-RH131 or hemoglobin AA/AS polymorphisms on immunity and susceptibility to uncomplicated malaria and existence of marked linkage between the two polymorphisms in Daraweesh2012In: Microbes and infection, ISSN 1286-4579, E-ISSN 1769-714X, Vol. 14, no 6, p. 537-544Article in journal (Refereed)
    Abstract [en]

    Malaria signature on human genome is marked by several gene polymorphisms. HemoglobinAS (HbAS) is known to protect against severe malaria, but barely proved to protect against uncomplicated malaria (UM). Similarly, the influence of Fc gamma RIIa-RH131 polymorphism on malaria is controversial. Polymorphisms in both genes were examined and levels of IgG subclasses against four malaria antigens were measured for 250 Fulani's from Daraweesh, eastern Sudan. Morbidity data for up to nine years was available for 214 donors. Number of malaria episodes experienced by each individual during the study period was used as indicator for susceptibility to UM. PCR and RFLP were used for donors DNA genotyping and ELISA for antibodies measurement. Results revealed that neither Fc gamma RIIa-RH131 alleles/genotypes nor HbAA/AS was significantly associated with malaria morbidity or with levels of IgG to test antigens. Both polymorphisms were in Hardy-Weinberg Equilibrium, interestingly, there was strong association between the two polymorphisms (linkage disequilibrium - LD) with D' = 0.89. The association between the two polymorphisms was confirmed by analysis of independent material from a neighboring village. In conclusion, in Daraweesh both Fc gamma RIIa-RH131 and HbAA/AS genotypes, independently or together, were not major markers for UM susceptibility, however, marked LD was observed between the two polymorphisms.

  • 47. Giha, Hayder A
    et al.
    Nasr, Amre
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Iriemenam, Nnaemeka C
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Troye-Blomberg, Marita
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Berzins, Klavs
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Pandey, Janardan P
    Elghazali, Gehad
    Associations of multi-locus polymorphisms in an immune network with susceptibility to uncomplicated Plasmodium falciparum malaria in Daraweesh village, Eastern Sudan2011In: Infection, Genetics and Evolution, ISSN 1567-1348, E-ISSN 1567-7257, Vol. 11, no 7, p. 1674-1681Article in journal (Refereed)
    Abstract [en]

    Susceptibility to uncomplicated malaria (UM), as to other forms of the disease, is genetically determined. Over 9-years of clinical and parasitological follow up of inhabitants of Daraweesh, in Eastern Sudan, the relative susceptibility to UM was estimated in terms of number of episodes experienced by each individual. Previously, we reported that the levels of IgG2 and IgG3 to Pf332-C231 malaria antigen are negatively correlated with number of malaria episodes. In addition, four molecular markers for malaria susceptibility (CRP -286, GM/KM haplotypes, FcγRIIa131 and HbAS) were tested. In this study, the above data were combined and reanalysed. The CRP -286A allele and GM 1,17 5,13,14,6 phenotype were previously found to be associated with increased susceptibility to malaria; however, individuals have both polymorphism together were not more susceptible to UM than the non-carriers of the same double polymorphism. The FcγRIIa-RR131 and HbAA genotypes taken individually or as double polymorphism were not associated with malaria susceptibility; however, their combination with any or both of the former polymorphisms was mostly associated with increased susceptibility to malaria. None of the four markers were associated with the levels of IgG2 and IgG3 against Pf332-C231. In conclusion, while our data support the polygenic nature of susceptibility to UM and highlighted the role of immune markers polymorphisms, the combinations of these markers were not predictable, i.e. the combination of the susceptibility markers will not necessarily render the carriers more susceptible to UM.

  • 48.
    Giusti, Pablo
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Dendritic cells and Plasmodium falciparum: studies in vitro and in the human host2009Licentiate thesis, comprehensive summary (Other academic)
    Abstract [en]

    Malaria is one of the world’s most threatening diseases. About half the world’s population is at risk of infection and the infection claims a million lives each year. A vast majority of the deaths occur in children below the age of 5 in sub-Saharan Africa. Survivors typically acquire immunity only after long time of repeated exposure and immunity is rapidly lost. Immunity is created by the activation of naive T cells and their differentiation into effector cells. The most potent activators of naive T cells are dendritic cells (DCs). The life cycle of DCs is adapted to find and process microbes in order to be able to present their antigens to T cells and thereby activate them. Antigen presentation typically takes place in the lymph nodes and that is why migration to these areas is an essential part of the DC life cycle. Various studies have shown that DC function may be hampered by the malaria parasite or its components.

    We have investigated activation and migratory capacities of DCs upon in vitro exposure of the malarial pigment hemozoin and Plasmodium falciparum infected red blood cells. Furthermore, we have assessed the activation status of blood DCs in the Fulani, a traditionally nomadic population that respond better to malaria infection and exhibit less clinical symptoms than other ethnicities living under similar conditions, and a neighbouring ethnic group, the Dogon, in Mali.

    Our results indicate that DCs are semi-activated upon malaria exposure in vitro, including enhanced migratory capacity, partial up-regulation of co-stimulatory markers and no IL-12, which may lead to inappropriate T-cell priming. We also observed that DCs from the Fulani have a higher degree of activation than DCs from the Dogon upon malaria exposure in vivo.

    We hypothesize that this increased DC activation may be the reason for the relatively increased protection against malaria.

    Taken together, our findings suggest that improper DC activation may contribute to poor immunity in Malaria.

  • 49.
    Giusti, Pablo
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    The novel anti-rheumatic compound Rabeximod impairs differentiation and function of human pro-inflammatory dendritic cells and macrophages2011In: Immunobiology, ISSN 0171-2985, E-ISSN 1878-3279, Vol. 216, no 1-2, p. 243-250Article in journal (Refereed)
    Abstract [en]

    Rabeximod (9-chloro-2,3-dimethyl-6-(N,N-dimethylaminoethylamino-2-oxoethyl)-6H-indolo[2,3-b]quinoxaline) is a synthetic compound that is currently being developed for the treatment of rheumatoid arthritis (RA). Here, we investigated the effects of Rabeximod on the functionality of human antigen-presenting cells (APCs) of myeloid origin. Different subsets of professional APCs were generated from human monocytes in vitro and simultaneously treated with different doses of Rabeximod. Although Rabeximod had no effect on the differentiation of monocytes into anti-inflammatory macrophages (AI-Ms), this compound impaired monocyte differentiation into monocyte-derived dendritic cells (MDCs) and pro-inflammatory allostimulated macrophages (Allo-Ms). MDCs that were treated with Rabeximod resulted in a significant decrease in their ability to pinocytose antigens, while no effect was exerted by the drug on the ability of Allo-Ms and AI-Ms to phagocytose. Furthermore, we observed a significant reduction in the allostimulatory ability of MDCs and Allo-Ms after treatment with Rabeximod, although this compound did not affect the low immunostimulatory capacity of AI-Ms. Conversely, the effect of Rabeximod in influencing cytokine secretion by APCs appeared to be limited. In conclusion, Rabeximod impairs differentiation of monocytes into different pro-inflammatory APCs, leading to impaired immunostimulatory abilities of these cells. Our observations shed light on the cellular mode of action and the immunomodulatory effect of Rabeximod.

  • 50.
    Giusti, Pablo
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Troye Blomberg, Marita
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Varani, Stefania
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Plasmodium falciparum-Infected Erythrocytes and beta-Hematin Induce Partial Maturation of Human Dendritic Cells and Increase Their Migratory Ability in Response to Lymphoid Chemokines2011In: Infection and Immunity, ISSN 0019-9567, E-ISSN 1098-5522, Vol. 79, no 7, p. 2727-2736Article in journal (Refereed)
    Abstract [en]

    Acute and chronic Plasmodium falciparum infections alter theimmune competence of the host possibly through changes in dendriticcell (DC) functionality. DCs are the most potent activatorsof T cells, and migration is integral to their function. MatureDCs express lymphoid chemokine receptors (CCRs), expressionof which enables them to migrate to the lymph nodes, where theyencounter naïve T cells. The present study aimed to investigatethe impact of the synthetic analog to malaria parasite pigmenthemozoin, i.e., β-hematin, or infected erythrocytes (iRBCs)on the activation status of human monocyte-derived DCs and ontheir expression of CCRs. Human monocyte-derived DCs partiallymatured upon incubation with β-hematin as indicated byan increased expression of CD80 and CD83. Both β-hematinand iRBCs provoked the release of proinflammatory and anti-inflammatorycytokines, such as interleukin-6 (IL-6), IL-10, and tumor necrosisfactor alpha, but not IL-12, and induced upregulation of thelymphoid chemokine receptor CXCR4, which was coupled to an increasedmigration to lymphoid ligands. Taken together, these resultssuggest that the partial and transient maturation of human myeloidDCs upon stimulation with malaria parasite-derived productsand the increased IL-10 but lack of IL-12 secretion may leadto suboptimal activation of T cells. This may in turn lead toimpaired adaptive immune responses and therefore insufficientclearance of the parasites.

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