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  • 51. Giha, Hayder A.
    et al.
    Nasr, Amre
    Iriemenam, Nnaemeka C.
    Troye-Blomberg, Marita
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för immunologi.
    Berzins, Klavs
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för immunologi.
    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 Daraweesh2012Ingår i: Microbes and infection, ISSN 1286-4579, E-ISSN 1769-714X, Vol. 14, nr 6, s. 537-544Artikel i tidskrift (Refereegranskat)
    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.

  • 52. Giha, Hayder A.
    et al.
    Nasr, Amre
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för immunologi.
    Iriemenam, Nnaemeka C.
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för immunologi.
    Troye-Blomberg, Marita
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för immunologi.
    Berzins, Klavs
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för immunologi.
    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 Sudan2011Ingår i: Infection, Genetics and Evolution, ISSN 1567-1348, E-ISSN 1567-7257, Vol. 11, nr 7, s. 1674-1681Artikel i tidskrift (Refereegranskat)
    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.

  • 53.
    Giusti, Pablo
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för immunologi.
    Troye Blomberg, Marita
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för immunologi.
    Varani, Stefania
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för immunologi.
    Plasmodium falciparum-Infected Erythrocytes and beta-Hematin Induce Partial Maturation of Human Dendritic Cells and Increase Their Migratory Ability in Response to Lymphoid Chemokines2011Ingår i: Infection and Immunity, ISSN 0019-9567, E-ISSN 1098-5522, Vol. 79, nr 7, s. 2727-2736Artikel i tidskrift (Refereegranskat)
    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.

  • 54.
    Giusti, Pablo
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för immunologi.
    Urban, Britta C
    Frascaroli, Giada
    Albrecht, Letusa
    Tinti, Anna
    Troye-Blomberg, Marita
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för immunologi.
    Varani, Stefania
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för immunologi.
    Plasmodium falciparum-infected erythrocytes and beta-hematin induce partial maturation of human dendritic cells and increase their migratory ability in response to lymphoid chemokines.2011Ingår i: Infection and Immunity, ISSN 0019-9567, E-ISSN 1098-5522, Vol. 79, nr 7, s. 2727-2736Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Acute and chronic Plasmodium falciparum infections alter the immune competence of the host possibly through changes in dendritic cell (DC) functionality. DCs are the most potent activators of T cells, and migration is integral to their function. Mature DCs express lymphoid chemokine receptors (CCRs), expression of which enables them to migrate to the lymph nodes, where they encounter naïve T cells. The present study aimed to investigate the impact of the synthetic analog to malaria parasite pigment hemozoin, i.e., β-hematin, or infected erythrocytes (iRBCs) on the activation status of human monocyte-derived DCs and on their expression of CCRs. Human monocyte-derived DCs partially matured upon incubation with β-hematin as indicated by an increased expression of CD80 and CD83. Both β-hematin and iRBCs provoked the release of proinflammatory and anti-inflammatory cytokines, such as interleukin-6 (IL-6), IL-10, and tumor necrosis factor alpha, but not IL-12, and induced upregulation of the lymphoid chemokine receptor CXCR4, which was coupled to an increased migration to lymphoid ligands. Taken together, these results suggest that the partial and transient maturation of human myeloid DCs upon stimulation with malaria parasite-derived products and the increased IL-10 but lack of IL-12 secretion may lead to suboptimal activation of T cells. This may in turn lead to impaired adaptive immune responses and therefore insufficient clearance of the parasites.

  • 55. Gryseels, Bruno
    et al.
    Zumla, Alimuddin
    Troye-Blomberg, Marita
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för immunologi.
    Kieny, Marie Paule
    Quaglio, Gianluca
    Holtel, Andreas
    Laang, Hannu
    Romaris, Manuel
    De Magistris, Maria Teresa
    Nuez, Ana Nieto
    Olesen, Ole F
    Ghalouci, Rachida
    Lönnroth, Anna
    European Union conference on poverty-related diseases research.2009Ingår i: The Lancet Infectious Diseases, ISSN 1474-4457, Vol. 9, nr 6, s. 334-7Artikel i tidskrift (Refereegranskat)
  • 56. Guenot, Marianne
    et al.
    Loizon, Séverine
    Howard, Jennifer
    Costa, Giulia
    Baker, David A.
    Mohabeer, Shaneel Y.
    Troye-Blomberg, Marita
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Moreau, Jean-Francois
    Dechanet-Merville, Julie
    Mercereau-Puijalon, Odile
    Mamani-Matsuda, Maria
    Behr, Charlotte
    Phosphoantigen Burst upon Plasmodium falciparum Schizont Rupture Can Distantly Activate V gamma 9V delta 2 T Cells2015Ingår i: Infection and Immunity, ISSN 0019-9567, E-ISSN 1098-5522, Vol. 83, nr 10, s. 3816-3824Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Malaria induces potent activation and expansion of the V gamma 9V delta 2 subpopulation of gamma delta T cells, which inhibit the Plasmodium falciparum blood cycle through soluble cytotoxic mediators, abrogating merozoite invasion capacity. Intraerythrocytic stages efficiently trigger V gamma 9V delta 2 T-cell activation and degranulation through poorly understood mechanisms. P. falciparum blood-stage extracts are known to contain phosphoantigens able to stimulate V gamma 9V delta 2 T cells, but how these are presented by intact infected red blood cells (iRBCs) remains elusive. Here we show that, unlike activation by phosphoantigen-expressing cells, V gamma 9V delta 2 T-cell activation by intact iRBCs is independent of butyrophilin expression by the iRBC, and contact with an intact iRBC is not required. Moreover, blood-stage culture supernatants proved to be as potent activators of V gamma 9V delta 2 T cells as iRBCs. Bioactivity in the microenvironment is attributable to phosphoantigens, as it is dependent on the parasite DOXP pathway, on V gamma 9V delta 2 TCR signaling, and on butyrophilin expression by V gamma 9V delta 2 T cells. Kinetic studies showed that the phosphoantigens were released at the end of the intraerythrocytic cycle at the time of parasite egress. We document exquisite sensitivity of V gamma 9V delta 2 T cells, which respond to a few thousand parasites. These data unravel a novel framework, whereby release of phosphoantigens into the extracellular milieu by sequestered parasites likely promotes activation of distant V gamma 9V delta 2 T cells that in turn exert remote antiparasitic functions.

  • 57. Holtel, Andreas
    et al.
    Troye-Blomberg, Marita
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för immunologi.
    Penas-Jimenez, Inmaculada
    EU-funded malaria research under the 6th and 7th Framework Programmes for research and technological development.2011Ingår i: Malaria Journal, ISSN 1475-2875, E-ISSN 1475-2875, Vol. 10, s. 11-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    While malaria research has traditionally been strong in Europe, targeted and sustained support for cooperative malaria research at EU level, namely through the EU's 6th and 7th Framework Programmes for research and technological development, FP6 (2002-2006) and FP7 (2007-2013), has boosted both impact and visibility of European malaria research. Most of the European malaria research community is now organized under a number of comprehensive and complementary research networks and projects, assembled around four key areas: (1) fundamental research on the malaria parasite and the disease, (2) development of new malaria drugs, (3) research and development of a malaria vaccine, and (4) research to control the malaria-transmitting mosquito vector. Considerable efforts were undertaken to ensure adequate participation of research groups from disease-endemic countries, in particular from Africa, with the long-term aim to strengthen cooperative links and research capacities in these countries. The concept of organizing European research through major strategic projects to form a "European Research Area" (ERA) was originally developed in the preparation of FP6, and ERA formation has now turned into a major EU policy objective explicitly inscribed into the Lisbon Treaty. EU-funded malaria research may serve as a showcase to demonstrate how ERA formation can successfully be implemented in a given area of science when several surrounding parameters converge to support implementation of this strategic concept: timely coincidence of political stimuli, responsive programming, a clearly defined--and well confined--area of research, and the readiness of the targeted research community who is well familiar with transnational cooperation at EU level. Major EU-funded malaria projects have evolved into thematic and organizational platforms that can collaborate with other global players. Europe may thus contribute more, and better, to addressing the global research agenda for malaria.

  • 58. Howard, Jennifer
    et al.
    Loizon, Séverine
    Tyler, Christopher J.
    Duluc, Dorothée
    Moser, Bernhard
    Mechain, Matthieu
    Duvignaud, Alexandre
    Malvy, Denis
    Troye-Blomberg, Marita
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Moreau, Jean-Francois
    Eberl, Matthias
    Mercereau-Puijalon, Odile
    Déchanet-Merville, Julie
    Behr, Charlotte
    Mamani-Matsuda, Maria
    The Antigen-Presenting Potential of V gamma 9V delta 2 T Cells During Plasmodium falciparum Blood-Stage Infection2017Ingår i: Journal of Infectious Diseases, ISSN 0022-1899, E-ISSN 1537-6613, Vol. 215, nr 10, s. 1569-1579Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    During Plasmodium falciparum infections, erythrocyte-stage parasites inhibit dendritic cell maturation and function, compromising effective antimalarial adaptive immunity. Human V gamma 9V delta 2 T cells can act in vitro as antigen-presenting cells (APCs) and induce alpha beta T-cell activation. However, the relevance of this activity in vivo has remained elusive. Because V gamma 9V delta 2 T cells are activated during the early immune response against P. falciparum infection, we investigated whether they could contribute to the instruction of adaptive immune responses toward malaria parasites. In P. falciparum-infected patients, V gamma 9V delta 2 T cells presented increased surface expression of APC-associated markers HLA-DR and CD86. In response to infected red blood cells in vitro, V gamma 9V delta 2 T cells upregulated surface expression of HLA-DR, HLA-ABC, CD40, CD80, CD83, and CD86, induced naive alpha beta T-cell responses, and cross-presented soluble prototypical protein to antigen-specific CD8(+) T cells. Our findings qualify V gamma 9V delta 2 T cells as alternative APCs, which could be harnessed for therapeutic interventions and vaccine design.

  • 59. Ibitokou, Samad A.
    et al.
    Boström, Stephanie
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Brutus, Laurent
    Ndam, Nicaise Tuikue
    Vianou, Bertin
    Agbowai, Carine
    Amadoudji Zin, Martin
    Huynh, Bich Tram
    Massougbodji, Achille
    Deloron, Philippe
    Troye-Blomberg, Marita
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Fievet, Nadine
    Luty, Adrian J. F.
    Submicroscopic Infections with Plasmodium falciparum during Pregnancy and Their Association with Circulating Cytokine, Chemokine, and Cellular Profiles2014Ingår i: Clinical and Vaccine Immunology, ISSN 1556-6811, E-ISSN 1556-679X, Vol. 21, nr 6, s. 859-866Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The immunological consequences of pregnancy-associated malaria (PAM) due to Plasmodium falciparum have been extensively investigated in cross-sectional studies conducted at delivery, but there have been very few longitudinal studies of changes due to PAM during pregnancy. We conducted a prospective study in Benin to investigate the changes associated with PAM in groups of 131 and 111 women at inclusion in the second trimester and at delivery, respectively. Infected women were identified by standard microscopic examinations of blood smears and by quantitative PCR (qPCR) assays and were matched to uninfected control women by age, gestational age, and gravidity. We quantified plasma levels of a panel of soluble immunological mediators and other mediators, as well as the frequencies of peripheral blood mononuclear cell types. Comparisons of these variables in infected and uninfected women used multivariate analyses, and we also assessed the predictive value of variables measured at inclusion for pregnancy outcomes at delivery. In multivariate analyses, peripheral plasma interleukin 10 (IL-10) and gamma interferon-inducible protein 10 (IP-10) levels were associated with PAM at inclusion and at delivery, while higher IL-10 levels distinguished qPCR-detectable submicroscopic infections at inclusion but not at delivery. Maternal anemia at delivery was associated with markers of proinflammatory (increased frequency of monocytes) and anti-inflammatory (increased IL-10 levels and increased activation of regulatory T cells) activity measured at inclusion. Elevated concentrations of IL-10 are associated with the majority of P. falciparum infections during pregnancy, but this marker alone does not identify all submicroscopic infections. Reliably identifying such occult infections will require more sensitive and specific methods.

  • 60. Ibitokou, Samad
    et al.
    Boström, Stéphanie
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Brutus, Laurent
    Ndam, Nicaise
    Vianou, Bertin
    Agbowai, Carine
    Zin, Martin
    Huynh, Bich
    Massougbodji, Achille
    Deloron, Philippe
    Troye-Blomberg, Marita
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Fievet, Nadine
    Luty, Adrian
    Sub-microscopic infections with Plasmodium falciparum during pregnancy and their association with circulating cytokine, chemokine and cellular profilesManuskript (preprint) (Övrigt vetenskapligt)
  • 61. Ibitokou, Samad
    et al.
    Brutus, Laurent
    Vianou, Bertin
    Oesterholt, Mayke
    Massougbodji, Achille
    Deloron, Philippe
    Troye-Blomberg, Marita
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Fievet, Nadine
    Luty, Adrian J. F.
    Gestational age-related changes in the peripheral blood cell composition of sub-Saharan African women2013Ingår i: Journal of Reproductive Immunology, ISSN 0165-0378, E-ISSN 1872-7603, Vol. 98, nr 1-2, s. 21-28Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Gestational age-related changes in the cellular composition of peripheral blood have not been described in sub-Saharan African settings. We conducted longitudinal cohort studies in Beninese and Tanzanian mothers with quantification of peripheral blood mononuclear cell-types ex vivo using flow cytometry. Between the second trimester and delivery the frequency of CD4(+) T cells declined significantly, contrasting with a non-significant increase in CD8(+) T cells, but no changes in T-regulatory, NK or NKT cell frequencies. Antigen-presenting cell profiles were also unaltered, although non-significant trends were evident. These changes resemble in some respects those reported during pregnancies in developed countries, but differ in others.

  • 62. Ibitokou, Samad
    et al.
    Oesterholt, Mayke
    Brutus, Laurent
    Borgella, Sophie
    Agbowaï, Carine
    Ezinmègnon, Sèm
    Lusingu, John
    Schmiegelow, Christentze
    Massougbodji, Achille
    Deloron, Philippe
    Troye-Blomberg, Marita
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut.
    Varani, Stefania
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut.
    Luty, Adrian J. F.
    Fievet, Nadine
    Peripheral Blood Cell Signatures of Plasmodium falciparum Infection during Pregnancy2012Ingår i: PLOS ONE, E-ISSN 1932-6203, Vol. 7, nr 12, s. e49621-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Sequestration of Plasmodium falciparum-infected erythrocytes in placental intervillous spaces causes inflammation and pathology. Knowledge of the profiles of immune cells associated with the physiopathology of pregnancy-associated malaria (PAM) is scarce. We conducted a longitudinal, prospective study, both in Benin and Tanzania, including ∼1000 pregnant women in each site with systematic follow-up at scheduled antenatal visits until delivery. We used ex vivo flow cytometry to identify peripheral blood mononuclear cell (PBMC) profiles that are associated with PAM and anaemia, determining the phenotypic composition and activation status of PBMC in selected sub-groups with and without PAM both at inclusion and at delivery in a total of 302 women. Both at inclusion and at delivery PAM was associated with significantly increased frequencies both of B cells overall and of activated B cells. Infection-related profiles were otherwise quite distinct at the two different time-points. At inclusion, PAM was associated with anaemia, with an increased frequency of immature monocytes and with a decreased frequency of regulatory T cells (Treg). At delivery, infected women presented with significantly fewer plasmacytoid dendritic cells (DC), more myeloid DC expressing low levels of HLA-DR, and more effector T cells (Teff) compared to uninfected women. Independent associations with an increased risk of anaemia were found for altered antigen-presenting cell frequencies at inclusion, but for an increased frequency of Teff at delivery. Our findings emphasize the prominent role played by B cells during PAM whenever it arises during pregnancy, whilst also revealing signature changes in other circulating cell types that, we conclude, primarily reflect the relative duration of the infections. Thus, the acute, recently-acquired infections present at delivery were marked by changes in DC and Teff frequencies, contrasting with infections at inclusion, considered chronic in nature, that were characterized by an abundance of immature monocytes and a paucity of Treg in PBMC.

  • 63.
    Iriemenam, Nnaemeka C.
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut.
    Khirelsied, Atif H.
    Nasr, Amre
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut.
    ElGhazali, Gehad
    Giha, Haider A.
    Elhassan A-Elgadir, Thoraya
    Agab-Aldour, Ahmed A.
    Montgomery, Scott M.
    Anders, Robin F.
    Theisen, Michael
    Troye-Blomberg, Marita
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut.
    Elbashir, Mustafa I.
    Berzins, Klavs
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut.
    Antibody responses to a panel of Plasmodium falciparum malaria blood-stage antigens in relation to clinical disease outcome in Sudan2009Ingår i: Vaccine, ISSN 0264-410X, E-ISSN 1873-2518, Vol. 27, nr 1, s. 62-71Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Despite many intervention programmes aimed at curtailing the scourge, malaria remains a formidable problem of human health. Immunity to asexual blood-stage of Plasmodium falciparum malaria is thought to be associated with protective antibodies of certain immunoglobulin classes and subclasses. We have analysed immunoglobulin G profiles to six leading blood-stage antigens in relation to clinical malaria outcome in a hospital-based study in Sudan. Our results revealed a linear association with anti-AMA-1-IgG1 antibodies in children <5 years and reduced risk of severe malaria, while the responses of the IgG3 antibodies against MSP-2, MSP-3, GLURP in individuals above 5 years were bi-modal. A dominance of IgG3 antibodies in >5 years was also observed. In the final combined model, the highest levels of IgG1 antibodies to AMA-1, GLURP-R0, and the highest levels of IgG3 antibodies to 3D7 MSP-2 were independently associated with protection from clinical malaria. The study provides further support for the potential importance of the studied merozoite vaccine candidate antigens as targets for parasite neutralizing antibody responses of the IgG1 and IgG3 subclasses.

  • 64.
    Iriemenam, Nnaemeka C
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för immunologi.
    Okafor, Christian M F
    Balogun, Halima A
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för immunologi.
    Ayede, Idowu
    Omosun, Yusuf
    Persson, Jan-Olov
    Hagstedt, Margareta
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för immunologi.
    Anumudu, Chiaka I
    Nwuba, Roseangela I
    Troye-Blomberg, Marita
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för immunologi.
    Berzins, Klavs
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för immunologi.
    Cytokine profiles and antibody responses to Plasmodium falciparum malaria infection in individuals living in Ibadan, southwest Nigeria.2009Ingår i: African Health Sciences, ISSN 1680-6905, E-ISSN 1729-0503, Vol. 9, nr 2, s. 66-74Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND: The ability of the host immune system to efficiently clear Plasmodium falciparum parasites during a malaria infection depends on the type of immune response mounted by the host. STUDY DESIGN: In a cross-sectional study, we investigated the cellular-and antibody responses in individuals with P. falciparum infection, in an attempt to identify immunological signs indicative of the development of natural immunity against malaria in Ibadan, Nigeria. Levels of IL-10, IL-12(p70), IFN-gamma, and IgM, IgG and IgG1-4 subclasses in the serum of 36 symptomatic children with microscopically confirmed malaria parasitaemia and 54 asymptomatic controls were analysed by ELISA. RESULTS: IFN-gamma and IL-10 were significantly higher in the symptomatic children (p=0.009, p=0.025 respectively) than in the asymptomatic controls but no differences were seen for IL-12(p70). Estimated higher ratios of IFN-gamma/IL-10 and IFN-gamma/IL-12 were also observed in the symptomatic children while the asymptomatic controls had higher IL-12/IL-10 ratio. The mean concentration levels of anti-P. falciparum IgG1, IgG2, IgG3 antibodies were statistically significantly higher in the individuals >5 years of age than <5 years while anti-P. falciparum IgG3 antibodies were notably low in <5 years category. Children <5 years had higher IgM antibodies than IgG and the expression of IgG subclasses increased with age. CONCLUSION: Taken together, malaria infection is on a delicate balance of pro- and anti-inflammatory cytokines. The higher levels of IFN-gamma seen in the symptomatic children (<6 months) may be instrumental in immune-protection against malaria by limiting parasite replication. The observed variations in immunoglobulin subclass levels were age-dependent and exposure-related.

  • 65.
    Israelsson, Elisabeth
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för immunologi.
    Ekström, Mattias
    Nasr, Amre
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för immunologi.
    Dolo, Amagana
    Kearsley, Susannah
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för immunologi.
    Arambepola, Gishanthi
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för immunologi.
    Homann, Manijeh V.
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för immunologi.
    Maiga, Bakary
    Doumbo, Ogobara K.
    ElGhazali, Gehad
    Giha, Hayder A.
    Troye-Blomberg, Marita
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för immunologi.
    Berzins, Klavs
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för immunologi.
    Tornvall, Per
    Marked differences in CRP genotype frequencies between the Fulani and sympatric ethnic groups in Africa2009Ingår i: Malaria Journal, ISSN 1475-2875, E-ISSN 1475-2875, Vol. 8, nr 136Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background

    C-reactive protein (CRP) is an acute phase protein that can activate various immune cells and bind to certain Fcγ receptors. The latter may compete with the binding of IgG antibodies to these receptors and could thereby interfere with the antigen-specific immune response. Polymorphisms in the promoter region of the CRP gene have been strongly associated with the plasma concentration of CRP. The known lower susceptibility to malaria in the Fulani ethnic group, as compared to their sympatric neighbours in Africa, has been linked to different genetic backgrounds. The present study was performed to investigate if polymorphisms in the CRP gene could contribute to the lower susceptibility to malaria seen in the Fulani ethnic group.

    Methods

    The CRP -717 T>C, -286 C>T>A, and +1444 C>T polymorphisms were analysed in asymptomatic Fulani and non-Fulani individuals from Mali and Sudan using Pyrosequencing T and TaqMan r MGB probes.

    Results

    The rare -286 A allele, previously shown to be associated with increased CRP expression and plasma levels, was shown to be more frequent in the non-Fulani ethnic groups as compared to the sympatric Fulani ethnic group both in Mali and Sudan. The common -717 T allele was more prevalent in the non-Fulani ethnic group compared to the sympatric Fulani ethnic group, but only in Mali. The parasite prevalence was increased for the -286 A allele, but not for the -717 T allele. No differences regarding genotype frequency or parasite prevalence were seen for +1444 C>T.

    Conclusion

    This study indicate that CRP may play an important role in the immune responses to malaria, and that the -286 C/T/A CRP polymorphism may be a contributing factor to the lower susceptibility to malaria seen in the Fulani.

  • 66.
    Israelsson, Elisabeth
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för immunologi.
    Maiga, Bakary
    Kearsley, Susannah
    Dolo, Amagana
    Homann, Manijeh Vafa
    Doumbo, Ogobara K
    Troye-Blomberg, Marita
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för immunologi.
    Tornvall, Per
    Berzins, Klavs
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för immunologi.
    Cytokine gene haplotypes with a potential effect on susceptibility to malaria in sympatric ethnic groups in Mali2011Ingår i: Infection, Genetics and Evolution, ISSN 1567-1348, E-ISSN 1567-7257, Vol. 11, nr 7, s. 1608-1615Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Cytokines are important players in the immune responses, and an unbalance in pro- and anti-inflammatory cytokine responses may affect parasitemia and pathology in a Plasmodium falciparum infection. Polymorphisms in cytokine genes may affect not only the levels of the protein, but many down-stream functions, such as production of C-reactive protein and immunoglobulin isotype switching. Susceptibility to malaria has been shown to differ between individuals with different genetic backgrounds, as indicated by studies in Fulani and non-Fulani ethnic groups. The aim of this study was to investigate possible interethnic differences in totally twelve single nucleotide polymorphisms (SNPs) in the genes encoding the cytokines IL-1β, IL-6, IL-10 and TNF. These SNPs are present in the promoter region of the genes, and have previously been associated with cytokine expression and with disease outcome in malaria. The results from the present study suggest that the Fulani ethnic group has a more pro-inflammatory response, due to high frequencies of high-producing alleles of IL1β and low-producing alleles of IL10. IL-6 could potentially also contribute to the relatively lower susceptibility to malaria in the Fulani ethnic group, whereas the TNF polymorphisms analysed in this study rather seem to associate with the severity of the infection and not the susceptibility for the infection itself. We therefore suggest that the polymorphisms analysed in this study all show a potential to influence the relatively lower susceptibility to malaria seen in the Fulani ethnic group as compared to the other sympatric ethnic groups.

  • 67.
    Israelsson, Elisabeth
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut.
    Vafa, Manijeh
    Maiga, Bakary
    Lysén, Anna
    Iriemenam, Nnaemeka C.
    Dolo, Amagana
    Doumbo, Ogobara K.
    Troye-Blomberg, Marita
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut.
    Berzins, Klavs
    Differences in Fcγ receptor IIa genotypes and IgG subclass pattern of anti-malarial antibodies between sympatric ethnic groups in Mali2008Ingår i: Malaria Journal, ISSN 1475-2875, E-ISSN 1475-2875, Vol. 7, nr 175Artikel i tidskrift (Refereegranskat)
  • 68. Jallow, Muminatou
    et al.
    Teo, Yik Ying
    Small, Kerrin S
    Rockett, Kirk A
    Deloukas, Panos
    Clark, Taane G
    Kivinen, Katja
    Bojang, Kalifa A
    Conway, David J
    Pinder, Margaret
    Sirugo, Giorgio
    Sisay-Joof, Fatou
    Usen, Stanley
    Auburn, Sarah
    Bumpstead, Suzannah J
    Campino, Susana
    Coffey, Alison
    Dunham, Andrew
    Fry, Andrew E
    Green, Angela
    Gwilliam, Rhian
    Hunt, Sarah E
    Inouye, Michael
    Jeffreys, Anna E
    Mendy, Alieu
    Palotie, Aarno
    Potter, Simon
    Ragoussis, Jiannis
    Rogers, Jane
    Rowlands, Kate
    Somaskantharajah, Elilan
    Whittaker, Pamela
    Widden, Claire
    Donnelly, Peter
    Howie, Bryan
    Marchini, Jonathan
    Morris, Andrew
    Sanjoaquin, Miguel
    Achidi, Eric Akum
    Agbenyega, Tsiri
    Allen, Angela
    Amodu, Olukemi
    Corran, Patrick
    Djimde, Abdoulaye
    Dolo, Amagana
    Doumbo, Ogobara K
    Drakeley, Chris
    Dunstan, Sarah
    Evans, Jennifer
    Farrar, Jeremy
    Fernando, Deepika
    Hien, Tran Tinh
    Horstmann, Rolf D
    Ibrahim, Muntaser
    Karunaweera, Nadira
    Kokwaro, Gilbert
    Koram, Kwadwo A
    Lemnge, Martha
    Makani, Julie
    Marsh, Kevin
    Michon, Pascal
    Modiano, David
    Molyneux, Malcolm E
    Mueller, Ivo
    Parker, Michael
    Peshu, Norbert
    Plowe, Christopher V
    Puijalon, Odile
    Reeder, John
    Reyburn, Hugh
    Riley, Eleanor M
    Sakuntabhai, Anavaj
    Singhasivanon, Pratap
    Sirima, Sodiomon
    Tall, Adama
    Taylor, Terrie E
    Thera, Mahamadou
    Troye-Blomberg, Marita
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för immunologi.
    Williams, Thomas N
    Wilson, Michael
    Kwiatkowski, Dominic P
    Genome-wide and fine-resolution association analysis of malaria in West Africa.2009Ingår i: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, s. 657-665Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    We report a genome-wide association (GWA) study of severe malaria in The Gambia. The initial GWA scan included 2,500 children genotyped on the Affymetrix 500K GeneChip, and a replication study included 3,400 children. We used this to examine the performance of GWA methods in Africa. We found considerable population stratification, and also that signals of association at known malaria resistance loci were greatly attenuated owing to weak linkage disequilibrium (LD). To investigate possible solutions to the problem of low LD, we focused on the HbS locus, sequencing this region of the genome in 62 Gambian individuals and then using these data to conduct multipoint imputation in the GWA samples. This increased the signal of association, from P = 4 x 10(-7) to P = 4 x 10(-14), with the peak of the signal located precisely at the HbS causal variant. Our findings provide proof of principle that fine-resolution multipoint imputation, based on population-specific sequencing data, can substantially boost authentic GWA signals and enable fine mapping of causal variants in African populations.

  • 69.
    Johansson, Maria A
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för immunologi.
    Saghafian-Hedengren, Shanie
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för immunologi.
    Haileselassie, Yeneneh
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för immunologi.
    Roos, Stefan
    Troye-Blomberg, Marita
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för immunologi.
    Nilsson, Caroline
    Sverremark-Ekström, Eva
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för immunologi.
    Early-Life Gut Bacteria Associate with IL-4-, IL-10- and IFN-γ Production at Two Years of Age2012Ingår i: PLOS ONE, E-ISSN 1932-6203, Vol. 7, nr 11, s. e49315-(9 pp)Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Microbial exposure early in life influences immune maturation and potentially also the development of immune-mediated disease. Here we studied early-life gut colonization in relation to cytokine responses at two years of age. Fecal samples were collected from infants during the first two months of life. DNA was extracted from the fecal samples and Bifidobacterium (B.) adolescentis, B. breve, B. bifidum, a group of lactobacilli (L. casei, L. paracasei and L. rhamnosus) as well as Staphylococcus (S.) aureus were detected with real time PCR. Peripheral mononuclear cells were stimulated with phytohaemagglutinin (PHA) and numbers of IL-4-, IL-10- and IFN-γ secreting cells were evaluated using ELISpot. We further stimulated peripheral blood mononuclear cells with bacterial supernatants in vitro and assessed the IL-4-, IL-10- and IFN-γ inducing capacity by flow cytometry and ELISA. Early S. aureus colonization associated with higher numbers of IL-4- (p = 0.022) and IL-10 (p = 0.016) producing cells at two years of age. In contrast to colonization with S. aureus alone, co-colonization with lactobacilli associated with suppression of IL-4- (p = 0.004), IL-10- (p = 0.004) and IFN-γ (p = 0.034) secreting cells. In vitro stimulations of mononuclear cells with bacterial supernatants supported a suppressive role of L. rhamnosus GG on S. aureus-induced cytokine responses. We demonstrate that the early gut colonization pattern associates with the PHA-induced cytokine profile at two years of age and our in vitro findings support that specific bacterial species influence the T helper cell subsets. This suggests that dysbiosis in the early microbiota may modulate the risk of developing inflammatory conditions like allergy.

  • 70. Kaneko, Akira
    et al.
    Chaves, Luis F.
    Taleo, George
    Kalkoa, Morris
    Isozumi, Rie
    Wickremasinghe, Renu
    Perlmann, Hedvig
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Takeo, Satoru
    Tsuboi, Takafumi
    Tachibana, Shin-Ichiro
    Kimura, Masatsugu
    Björkman, Anders
    Troye-Blomberg, Marita
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Tanabe, Kazuyuki
    Drakeley, Chris
    Characteristic Age Distribution of Plasmodium vivax Infections after Malaria Elimination on Aneityum Island, Vanuatu2014Ingår i: Infection and Immunity, ISSN 0019-9567, E-ISSN 1098-5522, Vol. 82, nr 1, s. 243-252Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Resurgence is a major concern after malaria elimination. After the initiation of the elimination program on Aneityum Island in 1991, microscopy showed that Plasmodium falciparum disappeared immediately, whereas P. vivax disappeared from 1996 onward, until P. vivax cases were reported in January 2002. By conducting malariometric surveys of the entire population of Aneityum, we investigated the age distribution of individuals with parasites during this epidemic in the context of antimalarial antibody levels and parasite antigen diversity. In July 2002, P. vivax infections were detected by microscopy in 22/759 individuals: 20/298 born after the beginning of the elimination program in 1991, 2/126 born between 1982 and 1991, and none of 335 born before 1982. PCR increased the number of infections detected to 77, distributed among all age groups. Prevalences were 12.1%, 16.7%, and 6.0%, respectively (P<0.001). In November, a similar age pattern was found, but with fewer infections: 6/746 and 39/741 individuals were found to be infected by microscopy and PCR, respectively. The frequencies of antibody responses to P. vivax were significantly higher in individuals born before 1991 than in younger age groups and were similar to those on Malakula Island, an area of endemicity. Remarkably low antigen diversity (h, 0.15) of P. vivax infections was observed on Aneityum compared with the other islands (h, 0.89 to 1.0). A P. vivax resurgence was observed among children and teenagers on Aneityum, an age distribution similar to those before elimination and on islands where P. vivax is endemic, suggesting that in the absence of significant exposure, immunity may persist, limiting infection levels in adults. The limited parasite gene pool on islands may contribute to this protection.

  • 71. Kulpraneet, M.
    et al.
    Limtrakul, A.
    Thanomtham, P.
    Taemaitree, N.
    Puttikamonkul, S.
    Pongsunk, S.
    Srisurapanon, S.
    Troye-Blomberg, Marita
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Tangteerawatana, P.
    Analysis of IL-4 promoter and VNTR polymorphisms in Thai patients with pulmonary tuberculosis2019Ingår i: Tropical Biomedicine, ISSN 0127-5720, Vol. 36, nr 4, s. 874-882Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Tuberculosis (TB) is a leading cause of morbidity and mortality in Thailand. Cytokines play important roles in defense against Mycobacterium tuberculosis infection. Interleukin (IL)-4 is one of the anti-inflammatory cytokines and has been found to be elevated in TB patients. The common polymorphisms in IL-4 gene, including IL-4-590C/T, IL-4-33C/T, and IL-4-variable number of tandem repeats (VNTR) intron 3 have been reported to be associated with risk for some diseases. The purpose of this study was to investigate possible associations between the above mentioned three common functional polymorphisms in the IL-4 gene in patients with pulmonary tuberculosis (PTB) in a Thai population. Forty three patients with PTB and 90 healthy control subjects were studied. The three common polymorphisms of the IL-4 gene were determined using polymerase chain reaction (PCR) and PCR-restriction fragment length polymorphism (PCR-RFLP). The allele and genotype frequencies of IL-4-590 C/T, -33 C/T, VNTR intron 3 polymorphisms did not show significant differences between PTB patients and healthy controls ( genotype: p=0.88, p=0.92, p=0.40; allele: p=0.38, p=0.44, p=0.53, respectively). However, the allele distribution of the IL-4 -590 C, -33 C, and VNTR R3 was higher among PTB patients (25.58%, 25.58%, 25.58%, respectively) than among control subjects (20%, 20.48%, 19.44%, respectively). This may suggest that IL-4-590C/T, -33C/T and VNTR intron 3 might play a role in susceptibility to PTB. A larger cohort may possibly help conclude our findings.

  • 72. Kumsiri, Ratchanok
    et al.
    Troye-Blomberg, Marita
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Pattanapanyasat, Kovit
    Krudsood, Srivicha
    Maneerat, Yaowapa
    IgE low affinity receptor (CD23) expression, Plasmodium falciparum specific IgE and tumor necrosis factor-alpha production in Thai uncomplicated and severe falciparum malaria patients2016Ingår i: Acta Tropica, ISSN 0001-706X, E-ISSN 1873-6254, Vol. 154, s. 25-33Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Previous studies have suggested that Plasmodium falciparum (P. falciparum) specific IgE in the form of immune complexes crosslinking the low-affinity receptor (CD23) on monocyte results in tumor necrosis factor (TNF)-alpha and nitric oxide (NO) production. However, the roles of these parameters in severity and immune protection are still unclear. This study aimed to determine the association between CD23 expression on monocytes, plasma soluble CD23 (sCD23), total IgE, malaria-specific IgE and IgG, and TNF-alpha levels in P. falciparum infected patients. We evaluated 64 uncomplicated (UC) and 25 severe patients (S), admitted at the Hospital for Tropical Diseases, Mahidol University, and 34 healthy controls (C) enrolled in 2001. Flow cytometry and enzyme linked immunosorbent assays (ELISA) demonstrated that trends of the CD23 expression, levels of sCD23 and specific IgE were higher in the S group as compared to those in the UC and C groups. Plasma levels of P. falciparum specific IgE in the UC (p = 0.011) and S groups (p = 0.025) were significantly higher than those in C group. In contrast the TNF-alpha levels tended to be higher in the UC than those in the S (p = 0343) and significantly higher than those in C (p = 0.004) groups. The specific IgG levels in UC were significantly higher than those in S and C (p < 0.001) groups. At admission, a strong significant negative correlation was found between specific IgG and sCD23 (r = -0.762, p = 0.028), and TNF-alpha and IgE-IgG complexes (r=-0.715, p = 0.002). Significant positive correlations between levels of specific IgE and TNF-alpha (r=0.575, p = 0.010); and sCD23 (r=0.597, p = 0.000) were also observed. In conclusion, our data suggest that CD23 expression and malaria-specific IgE levels may be involved in the severity of the disease while TNF-alpha and the malaria-specific IgG may correlate with protection against falciparum malaria.

  • 73. Lokki, A Inkeri
    et al.
    Järvelä, Irma
    Israelsson, Elisabeth
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för immunologi.
    Maiga, Bakary
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för immunologi.
    Troye-Blomberg, Marita
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för immunologi.
    Dolo, Amagana
    Doumbo, Ogobara K
    Meri, Seppo
    Holmberg, Ville
    Lactase persistence genotypes and malaria susceptibility in Fulani of Mali.2011Ingår i: Malaria Journal, ISSN 1475-2875, E-ISSN 1475-2875, Vol. 10, s. 9-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND: Fulani are a widely spread African ethnic group characterized by lower susceptibility to Plasmodium falciparum, clinical malaria morbidity and higher rate of lactase persistence compared to sympatric tribes. Lactase non-persistence, often called lactose intolerance, is the normal condition where lactase activity in the intestinal wall declines after weaning. Lactase persistence, common in Europe, and in certain African people with traditions of raising cattle, is caused by polymorphisms in the enhancer region approximately 14 kb upstream of the lactase gene.

    METHODS: To evaluate the relationship between malaria and lactase persistence genotypes, a 400 bp region surrounding the main European C/T-13910 polymorphism upstream of the lactase gene was sequenced. DNA samples used in the study originated from 162 Fulani and 79 Dogon individuals from Mali.

    RESULTS: Among 79 Dogon only one heterozygote of the lactase enhancer polymorphism was detected, whereas all others were homozygous for the ancestral C allele. Among the Fulani, the main European polymorphism at locus C/T-13910 was by far the most common polymorphism, with an allele frequency of 37%. Three other single-nucleotide polymorphisms were found with allele frequencies of 3.7%, 1.9% and 0.6% each. The novel DNA polymorphism T/C-13906 was seen in six heterozygous Fulani. Among the Fulani with lactase non-persistence CC genotypes at the C/T-13910 locus, 24% had malaria parasites detectable by microscopy compared to 18% for lactase persistent genotypes (P = 0.29). Pooling the lactase enhancer polymorphisms to a common presumptive genotype gave 28% microscopy positives for non-persistent and 17% for others (P = 0.11).

    CONCLUSIONS: Plasmodium falciparum parasitaemia in asymptomatic Fulani is more common in individuals with lactase non-persistence genotypes, but this difference is not statistically significant. The potential immunoprotective properties of dietary cow milk as a reason for the partial malaria resistance of Fulani warrant further investigation.

  • 74.
    Maiga, Bakary
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut. Malaria Research and Training Center, Department of Epidemiology of Parasitic Diseases/Faculty of Medicine, Pharmacy and Odonto, Stomatology, Bamako, Mali.
    Dolo, A
    Touré, O
    Dara, V
    Tapily, A
    Campino, S
    Sepulveda, N
    Corran, P
    Rockett, K
    Clark, T G
    Troye Blomberg, Marita
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Doumbo, O K
    Fc gamma Receptor IIa-H131R Polymorphism and Malaria Susceptibility in Sympatric Ethnic Groups, Fulani and Dogon of Mali2014Ingår i: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 79, nr 1, s. 43-50Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    It has been previously shown that there are some interethnic differences in susceptibility to malaria between two sympatric ethnic groups of Mali, the Fulani and the Dogon. The lower susceptibility to Plasmodium falciparum malaria seen in the Fulani has not been fully explained by genetic polymorphisms previously known to be associated with malaria resistance, including haemoglobin S (HbS), haemoglobin C (HbC), alpha-thalassaemia and glucose-6-phosphate dehydrogenase (G6PD) deficiency. Given the observed differences in the distribution of FcγRIIa allotypes among different ethnic groups and with malaria susceptibility that have been reported, we analysed the rs1801274-R131H polymorphism in the FcγRIIa gene in a study of Dogon and Fulani in Mali (n = 939). We confirm that the Fulani have less parasite densities, less parasite prevalence, more spleen enlargement and higher levels of total IgG antibodies (anti-CSP, anti-AMA1, anti-MSP1 and anti-MSP2) and more total IgE (P < 0.05) compared with the Dogon ethnic group. Furthermore, the Fulani exhibit higher frequencies of the blood group O (56.5%) compared with the Dogon (43.5%) (P < 0.001). With regard to the FcγRIIa polymorphism and allele frequency, the Fulani group have a higher frequency of the H allele (Fulani 0.474, Dogon 0.341, P < 0.0001), which was associated with greater total IgE production (P = 0.004). Our findings show that the FcγRIIa polymorphism might have an implication in the relative protection seen in the Fulani tribe, with confirmatory studies required in other malaria endemic settings.

  • 75.
    Maiga, Bakary
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut. Universités de Bamako, Bali.
    Dolo, Amagana
    Campino, Susana
    Sepulveda, Nuno
    Corran, Patrick
    Rockett, Kirk A.
    Troye-Blomberg, Marita
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Doumbo, Ogobara K.
    Clark, Taane G.
    Glucose-6-phosphate dehydrogenase polymorphisms and susceptibility to mild malaria in Dogon and Fulani, Mali2014Ingår i: Malaria Journal, ISSN 1475-2875, E-ISSN 1475-2875, Vol. 13, s. 270-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Glucose-6-phosphate dehydrogenase (G6PD) deficiency is associated with protection from severe malaria, and potentially uncomplicated malaria phenotypes. It has been documented that G6PD deficiency in sub-Saharan Africa is due to the 202A/376G G6PD A-allele, and association studies have used genotyping as a convenient technique for epidemiological studies. However, recent studies have shown discrepancies in G6PD202/376 associations with severe malaria. There is evidence to suggest that other G6PD deficiency alleles may be common in some regions of West Africa, and that allelic heterogeneity could explain these discrepancies. Methods: A cross-sectional epidemiological study of malaria susceptibility was conducted during 2006 and 2007 in the Sahel meso-endemic malaria zone of Mali. The study included Dogon (n = 375) and Fulani (n = 337) sympatric ethnic groups, where the latter group is characterized by lower susceptibility to Plasmodium falciparum malaria. Fifty-three G6PD polymorphisms, including 202/376, were genotyped across the 712 samples. Evidence of association of these G6PD polymorphisms and mild malaria was assessed in both ethnic groups using genotypic and haplotypic statistical tests. Results: It was confirmed that the Fulani are less susceptible to malaria, and the 202A mutation is rare in this group (< 1% versus Dogon 7.9%). The Betica-Selma 968C/376G (similar to 11% enzymatic activity) was more common in Fulani (6.1% vs Dogon 0.0%). There are differences in haplotype frequencies between Dogon and Fulani, and association analysis did not reveal strong evidence of protective G6PD genetic effects against uncomplicated malaria in both ethnic groups and gender. However, there was some evidence of increased risk of mild malaria in Dogon with the 202A mutation, attaining borderline statistical significance in females. The rs915942 polymorphism was found to be associated with asymptomatic malaria in Dogon females, and the rs61042368 polymorphism was associated with clinical malaria in Fulani males. Conclusions: The results highlight the need to consider markers in addition to G6PD202 in studies of deficiency. Further, large genetic epidemiological studies of multi-ethnic groups in West Africa across a spectrum of malaria severity phenotypes are required to establish who receives protection from G6PD deficiency.

  • 76.
    Maiga, Bakary
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut. University of Science, Technique and Technologies of Bamako (USTTB), Mali.
    Dolo, Amagana
    Toure, Ousmane
    Dara, Victor
    Tapily, Amadou
    Campino, Susana
    Sepulveda, Nuno
    Risley, Paul
    Silva, Nipula
    Corran, Patrick
    Rockett, Kirk A.
    Kwiatkowski, Dominic
    Clark, Taane G.
    Troye-Blomberg, Marita
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Doumbo, Ogobara K.
    Human Candidate Polymorphisms in Sympatric Ethnic Groups Differing in Malaria Susceptibility in Mali2013Ingår i: PLOS ONE, E-ISSN 1932-6203, Vol. 8, nr 10, artikel-id e75675Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Malaria still remains a major public health problem in Mali, although disease susceptibility varies between ethnic groups, particularly between the Fulani and Dogon. These two sympatric groups share similar socio-cultural factors and malaria transmission rates, but Fulani individuals tend to show significantly higher spleen enlargement scores, lower parasite prevalence, and seem less affected by the disease than their Dogon neighbours. We have used genetic polymorphisms from malaria-associated genes to investigate associations with various malaria metrics between the Fulanai and Dogon groups. Two cross sectional surveys (transmission season 2006, dry season 2007) were performed. Healthy volunteers from the both ethnic groups (n=939) were recruited in a rural setting. In each survey, clinical (spleen enlargement, axillary temperature, weight) and parasitological data (malaria parasite densities and species) were collected, as well as blood samples. One hundred and sixty six SNPs were genotyped and 5 immunoassays (AMA1, CSP, MSP1, MSP2, total IgE) were performed on the DNA and serum samples respectively. The data confirm the reduced malaria susceptibility in the Fulani, with a higher level of the protective O-blood group, and increased circulating antibody levels to several malaria antigens (p<10(-15)). We identified SNP allele frequency differences between the 2 ethnic groups in CD36, IL4, RTN3 and ADCY9. Moreover, polymorphisms in FCER1A, RAD50, TNF, SLC22A4, and IL13 genes were correlated with antibody production (p-value<0.003). Further work is required to understand the mechanisms underpinning these genetic factors.

  • 77. McCall, Matthew B B
    et al.
    Ferwerda, Bart
    Hopman, Joost
    Ploemen, Ivo
    Maiga, Boubacar
    Daou, Modibo
    Dolo, Amagana
    Hermsen, Cornelus C
    Doumbo, Ogobara K
    Bedu-Addo, George
    van der Meer, Jos W
    Troye-Blomberg, Marita
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för immunologi.
    van der Ven, André J A M
    Schumann, Ralf R
    Sauerwein, Robert W
    Mockenhaupt, Frank P
    Netea, Mihai G
    Persistence of full-length caspase-12 and its relation to malaria in West and Central African populations2010Ingår i: European Cytokine Network, ISSN 1148-5493, E-ISSN 1952-4005, Vol. 21, nr 2, s. 77-83Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background. The full-length (L-) variant of caspase-12 is believed to predispose to sepsis. It has been replaced in the genome of most human populations by the (S-) variant, which leads to premature termination of translation. Strikingly, the L-allele is still widely prevalent in African populations, presumably due to a counterbalancing selective force specific to this continent, for which malaria is a prime candidate.

    Methods. We investigated associations between caspase-12 genotype and malarial parameters in three West-African populations, in studies encompassing immunological, clinical and obstetric data. Results. The caspase-12 L-allele was found at frequencies of 11-34%. Plasmodium falciparum-stimulated mononuclear cells from S/L heterozygote donors produced stronger interferon-γ and interleukin-10 responses than S/S homozygotes (p = 0.011 and p = 0.023 in uninfected and infected donors respectively). Nevertheless, we found no association between caspase-12 genotype and either the presentation of severe malaria or individual clinical parameters in sick children. Amongst pregnant women, the caspase-12 genotype did not influence peripheral or placental malaria infection, or basic obstetric parameters. Interestingly, perinatal mortality was more frequent in children of both S/S and L/L than S/L mothers, independent of placental P. falciparum-infection.

    Conclusion. We find little clinical or epidemiological evidence that malaria has contributed to the persistence of functional caspase-12 in Africa, suggesting either that alternative selective forces are at work or that genetic drift underlies its current global distribution.

  • 78. McCall, Matthew B B
    et al.
    Hopman, Joost
    Daou, Modibo
    Maiga, Boubacar
    Dara, Victor
    Ploemen, Ivo
    Nganou-Makamdop, Krystelle
    Niangaly, Amadou
    Tolo, Youssouf
    Arama, Charles
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för immunologi.
    Bousema, J Teun
    van der Meer, Jos W
    van der Ven, André J A M
    Troye-Blomberg, Marita
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för immunologi.
    Dolo, Amagana
    Doumbo, Ogobara K
    Sauerwein, Robert W
    Early interferon-gamma response against Plasmodium falciparum correlates with interethnic differences in susceptibility to parasitemia between sympatric Fulani and Dogon in Mali.2010Ingår i: Journal of Infectious Diseases, ISSN 0022-1899, E-ISSN 1537-6613, Vol. 201, nr 1, s. 142-52Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    INTRODUCTION: Interethnic differences in susceptibility to malaria provide a unique opportunity to explore immunological correlates of protection. The Fulani of Sahelian Africa are known for their reduced susceptibility to Plasmodium falciparum, compared with surrounding tribes, yet the immunology underlying this is still poorly understood. METHODS AND RESULTS: Here, we show that mononuclear cells from Fulani elicit >10-fold stronger interferon (IFN)-gamma production following a 24-h in vitro coincubation with asexual parasites than cells from sympatric Dogon. This response appears to be specific for P. falciparum among a panel of other human pathogens and is independent of the lower number of regulatory T cell counts present in Fulani. IFN-gamma responses in both tribes were inversely correlated with peripheral parasite density as quantified by nucleic acid sequenced-based amplification, but responses of Fulani remained significantly stronger than those of Dogon after adjustment for concurrent parasitemia, suggesting that hard-wired immunological differences underlie the observed protection. CONCLUSIONS: These results underscore the value of early IFN-gamma responses to P. falciparum as a correlate of anti-parasite immunity, not only in this setting but also in the wider context of malaria, and support the development of malaria vaccines aimed at inducing such responses.

  • 79. Nasr, A.
    et al.
    Iriemenam, N. C.
    Troye-Blomberg, Marita
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för immunologi.
    Arnot, D.
    Theander, T. G.
    Berzins, Klavs
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för immunologi.
    Giha, H. A.
    ElGhazali, G.
    Pattern of Pre-existing IgG Subclass Responses to a Panel of Asexual Stage Malaria Antigens Reported During the Lengthy Dry Season in Daraweesh, Sudan2011Ingår i: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 74, nr 4, s. 390-396Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The anti-malarial IgG immune response during the lengthy and dry season in areas of low malaria transmission as in Eastern Sudan is largely unknown. In this study, ELISA was used for the measurement of pre-existing total IgG and IgG subclasses to a panel of malaria antigens, MSP2-3D7, MSP2-FC27, AMA-1 and Pf332-C231. The results showed that the antibody responses were predominantly age dependent, antigen specific, and their lifespan was at least 5-6 month long. Generally, the IgG3 was most abundant IgG subclass, and the most recognized antigen was Pf332-C231. Furthermore, the correlation between the levels of IgG subclasses was strongest between IgG1 and IgG3, which were more predictive to the total IgG levels. Finally, the response pattern of each of the IgG subclasses to the different test antigens that were spanning the dry season and the correlation between these responses were described in details for the first time.

  • 80.
    Nasr, A.
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut.
    Iriemenam, N.C.
    Troye-Blomberg, M.
    Giha, H.A.
    Balogun, H.A.
    Osman, O.F.
    Montgomery, S.M
    ElGhazali, G.
    Berzins, K.
    Fc gamma Receptor IIa (CD32) Polymorphism and Antibody responses to Asexual Blood-stage Antigens of Plasmodium falciparum Malaria in Sudanese Patients2007Ingår i: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 66, nr 1, s. 87-96Artikel i tidskrift (Refereegranskat)
  • 81. Nasr, Amre
    et al.
    Iriemenam, Nnaemeka C.
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut.
    Giha, Hayder
    Balogun, Halima A.
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut.
    Anders, Robin F.
    Troye-Blomberg, Marita
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut.
    ElGhazali, Gehad
    Berzins, Klavs
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut.
    FcgammaRIIa (CD32) polymorphism and anti-malarial IgG subclass pattern among Fulani and sympatric ethnic groups living in eastern Sudan2009Ingår i: Malaria Journal, ISSN 1475-2875, E-ISSN 1475-2875, Vol. 8, nr 43, s. 1-10Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND: A SNP at position 131, in the FcgammaRIIa gene, affects the binding of the different IgG subclasses and may influence the clinical variation seen in patients with falciparum malaria. This study confirms and extends previous findings, analysing the FcgammaRIIa (CD32) polymorphism in relation to the IgG subclass distribution seen among two sympatric tribes living in eastern Sudan, characterized by marked differences in susceptibility to Plasmodium falciparum malaria. METHODS: Two hundred and fifty Fulani subjects living in an area of meso-endemic P. falciparum malaria infection were genotyped for the FcgammaRIIa-131 polymorphism. For comparison, 101 non-Fulani donors - (Masaleit, Hausa and Four) - living in the same study area, were genotyped. The levels of plasma antibodies (IgG and subclasses) to four malaria antigens (AMA-1, MSP 2 - 3D7 & FC27, Pf332-C231) were measured using indirect enzyme-linked immunosorbent assays. RESULTS: The FcgammaRIIa-H/H131 genotype was found to be significantly more prevalent in the Fulani as compared to the non-Fulani ethnic groups (36.0% for Fulani versus 17.8% for non-Fulani, adjusted OR 3.10, 95% CI 1.61-5.97, P value < 0.001). The Fulani showed lower anti-malarial IgG1 and IgG3 antibody levels as compared to the non-Fulani and higher levels of IgG2 antibodies. CONCLUSION: The FcgammaRIIa-H/H131 genotype and H131 allele is at higher frequency in the Fulani ethnic group. The H/H131 genotype was consistently associated with higher levels of anti-malarial IgG2 and IgG3 antibodies, while the R/R131 genotype was associated with higher levels of IgG1 antibodies.

  • 82. Nilsson, C.
    et al.
    Larsson Sigfrinius, A-K
    Montgomery, S M
    Sverremark-Ekström, Eva
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för immunologi.
    Linde, A
    Lilja, G
    Blomberg, Marita Troye
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för immunologi.
    Epstein-Barr virus and cytomegalovirus are differentially associated with numbers of cytokine-producing cells and early atopy2009Ingår i: Clinical and experimental allergy, ISSN 1365-2222, Vol. 39, nr 4, s. 509-17Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND: We have previously shown that Epstein-Barr virus (EBV) seropositivity, at 2 years of age, was inversely related to IgE-sensitization and that this effect was enhanced when EBV is combined with cytomegalovirus (CMV) seropositivity. We hypothesize that early exposure to EBV or CMV will affect the cytokine balance in the individual. OBJECTIVE: The aim of this study was to relate the cytokine profile in peripheral blood mononuclear cells (PBMC) to the EBV and CMV serostatus and IgE-sensitization in children at 2 years of age. METHODS: Seventy-five children were followed prospectively from birth until 2 years of age. Their EBV and CMV serostatus was correlated to the numbers of IFN-gamma, IL-4, IL-10 and IL-12-producing PBMC following PHA stimulation in vitro. Skin prick tests and allergen-specific IgE antibodies were used to assess IgE-sensitization. RESULTS: In the study cohort, there was an inverse association between EBV seropositivity and IgE-sensitization but not with CMV seropositivity. Following linear regression analysis, we did not detect any statistically significant associations between children with IgG antibodies against EBV at 2 years of age and the investigated cytokines. However, there was a non-significant tendency to a positive association between high numbers of all individual cytokine-producing cells and EBV seropositivity. Children who were CMV seropositive had significantly higher numbers of IFN-gamma and lower numbers of IL-4-producing cells compared with CMV negative children. There was a significant, positive association between the number of IL-4-producing cells and IgE-sensitization. CONCLUSION: Taken together our results indicate that infections with EBV and CMV in different ways will interact with the immune system and may protect children from developing early atopy.

  • 83. Nouatin, O. P.
    et al.
    Agbowai, C.
    Ibitokou, S.
    Ezinmegnon, S.
    Gbedande, K.
    Adeothy, A. -I
    Moutairou, K.
    Borgella, S.
    Varani, S.
    Massougbodji, A.
    Troye-Blomberg, Marita
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för immunologi.
    Luty, A. J. F.
    Deloron, Philippe
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för immunologi.
    Fievet, N.
    Consequence of malaria during pregnancy on immunological responses of the newborn: a study of regulatory t cells2011Ingår i: Tropical medicine & international health, ISSN 1360-2276, E-ISSN 1365-3156, Vol. 16, s. 86-87Artikel i tidskrift (Refereegranskat)
  • 84. Nouatin, Odilon
    et al.
    Gbedande, Komi
    Ibitokou, Samad
    Vianou, Bertin
    Houngbegnon, Parfait
    Ezinmegnon, Sem
    Borgella, Sophie
    Akplogan, Carine
    Cottrell, Gilles
    Varani, Stefania
    Massougbodji, Achille
    Moutairou, Kabirou
    Troye-Blomberg, Marita
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Deloron, Philippe
    Luty, Adrian J. F.
    Fievet, Nadine
    Infants' Peripheral Blood Lymphocyte Composition Reflects Both Maternal and Post-Natal Infection with Plasmodium falciparum2015Ingår i: PLOS ONE, E-ISSN 1932-6203, Vol. 10, nr 11, artikel-id e0139606Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Maternal parasitoses modulate fetal immune development, manifesting as altered cellular immunological activity in cord blood that may be linked to enhanced susceptibility to infections in early life. Plasmodium falciparum typifies such infections, with distinct placental infection-related changes in cord blood exemplified by expanded populations of parasite antigen-specific regulatory T cells. Here we addressed whether such early-onset cellular immunological alterations persist through infancy. Specifically, in order to assess the potential impacts of P. falciparum infections either during pregnancy or during infancy, we quantified lymphocyte subsets in cord blood and in infants' peripheral blood during the first year of life. The principal age-related changes observed, independent of infection status, concerned decreases in the frequencies of CD4(+), NKdim and NKT cells, whilst CD8(+), Treg and Teff cells' frequencies increased from birth to 12 months of age. P. falciparum infections present at delivery, but not those earlier in gestation, were associated with increased frequencies of Treg and CD8(+) T cells but fewer CD4(+) and NKT cells during infancy, thus accentuating the observed age-related patterns. Overall, P. falciparum infections arising during infancy were associated with a reversal of the trends associated with maternal infection i.e. with more CD4(+) cells, with fewer Treg and CD8(+) cells. We conclude that maternal P. falciparum infection at delivery has significant and, in some cases, year-long effects on the composition of infants' peripheral blood lymphocyte populations. Those effects are superimposed on separate and independent age-as well as infant infection-related alterations that, respectively, either match or run counter to them.

  • 85.
    Nyakeriga, Alice M.
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för immunologi. Texas Tech University, USA; Kilifi District Hospital, Kenya.
    Troye-Blomberg, Marita
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för immunologi.
    Haptoglobin phenotypes and iron status in children living in a malaria endemic area of Kenyan coast2013Ingår i: Acta Tropica, ISSN 0001-706X, E-ISSN 1873-6254, Vol. 126, nr 2, s. 127-131Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Malaria infection may be affected by host genetic factors as well as nutritional status. Iron status and the phenotype of haptoglobin, a heme-binding acute phase reactant may be determinants of malaria parasitemia. A combination of cross sectional studies and longitudinal follow-up were used to describe the association between iron status, C-reactive protein, malaria infections and host genetic factors including; haptoglobin (Hp) phenotypes, in children below 9 years in a malaria endemic area in Coastal Kenya. The prevalence of 0.45 and 0.41, respectively for Hp 1-1 and Hp 2-1 phenotypes was significantly higher than 0.14 for Hp 2-2 phenotype (n = 162). Children with Hp 2-2 phenotype showed significantly higher iron storage compared to those with Hp 1-1 and Hp 2-1 phenotypes when children with malaria parasites and high C-reactive protein (>9 mg/L) were excluded from the analysis. There were no significant differences in malaria parasite densities among Hp phenotypes but children with Hp 2-2 had lower number of clinical malaria episodes (P=0.045). Taken together, this study shows that the presence of malaria may complicate the interpretation of iron status in children based on their Hp-phenotypes. Further studies will be required to address possible interactions among the various genetic factors and iron status in a malaria endemic setting.

  • 86. Okafor, Christian M. F.
    et al.
    Anumudu, Chiaka I.
    Omosun, Yusuf O.
    Uthaipibull, Chairat
    Ayede, Idowu
    Awobode, Henrietta O.
    Odaibo, Alex B.
    Langhorne, Jean
    Holder, Anthony A.
    Nwuba, Roseangela I.
    Troye-Blomberg, Marita
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut.
    Cellular responses to modified Plasmodium falciparum MSP1(19) antigens in individuals previously exposed to natural malaria infection2009Ingår i: Malaria Journal, ISSN 1475-2875, E-ISSN 1475-2875, Vol. 8, s. 263-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: MSP1 processing-inhibitory antibodies bind to epitopes on the 19 kDa C-terminal region of the Plasmodium falciparum merozoite surface protein 1 (MSP1(19)), inhibiting erythrocyte invasion. Blocking antibodies also bind to this antigen but prevent inhibitory antibodies binding, allowing invasion to proceed. Recombinant MSP1(19) had been modified previously to allow inhibitory but not blocking antibodies to continue to bind. Immunization with these modified proteins, therefore, has the potential to induce more effective protective antibodies. However, it was unclear whether the modification of MSP1(19) would affect critical T-cell responses to epitopes in this antigen. Methods: The cellular responses to wild-type MSP1(19) and a panel of modified MSP1(19) antigens were measured using an in-vitro assay for two groups of individuals: the first were malaria-nave and the second had been naturally exposed to Plasmodium falciparum infection. The cellular responses to the modified proteins were examined using cells from malaria-exposed infants and adults. Results: Interestingly, stimulation indices (SI) for responses induced by some of the modified proteins were at least two-fold higher than those elicited by the wild-type MSP1(19). A protein with four amino acid substitutions (Glu27 -> Tyr, Leu31 -> Arg, Tyr34 -> Ser and Glu43 -> Leu) had the highest stimulation index (SI up to 360) and induced large responses in 64% of the samples that had significant cellular responses to the modified proteins. Conclusion: This study suggests that specific MSP1(19) variants that have been engineered to improve their antigenicity for inhibitory antibodies, retain T-cell epitopes and the ability to induce cellular responses. These proteins are candidates for the development of MSP1-based malaria vaccines.

  • 87. Olaniyan, Subulade A.
    et al.
    Amodu, Olukemi K.
    Bakare, Adekunle A.
    Troye-Blomberg, Marita
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Omotade, Olayemi O.
    Rockett, Kirk A.
    Tumour necrosis factor alpha promoter polymorphism, TNF-238 is associated with severe clinical outcome of falciparum malaria in Ibadan southwest Nigeria2016Ingår i: Acta Tropica, ISSN 0001-706X, E-ISSN 1873-6254, Vol. 161, s. 62-67Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Tumour necrosis factor (TNF) - alpha has been shown to play an important role in the pathogenesis of falciparum malaria. Two TNF promoter polymorphisms, TNF-308 and TNF-238 have been associated with differential activity and production of TNF. In order to investigate the association between TNF-308 and TNF-238 and the clinical outcome of malaria in a Nigerian population, the two TNF polymorphisms were analysed using Sequenom iPLEX Platform. A total of 782 children; 283 children with uncomplicated malaria, 255 children with severe malaria and 244 children with asymptomatic infection (controls) were studied. The distribution of TNF-308 and TNF-238 genotypes were consistent with the Hardy-Weinberg equilibrium. Distribution of both TNF polymorphisms differed significantly across all clinical groups (TNF-308: p = 0.007; TNF-238: p=0.001). Further tests for association with severe malaria using genotype models controlling for age, parasitaemia and HbAS showed a significant association of the TNF-238 polymorphism with susceptibility to severe malaria (95% CI = 1.43-6.02, OR= 2.94, p = 0.003237) The GG genotype of TNF-238 significantly increased the risk of developing cerebral malaria from asymptomatic malaria and uncomplicated malaria (95% CI = 1.99-18.17, OR= 6.02, p <0.001 and 95% CI= 1.78-8.23, OR= 3.84, p <0.001 respectively). No significant association was found between TNF-308 and malaria outcome. These results show thegenetic association of TNF-238 in the clinical outcome of malaria in Ibadan, southwest Nigeria. These findings add support to the role of TNF in the outcome of malaria infection. Further large scale studies across multiple malaria endemic populations will be required to determine the specific roles of TNF-308 and TNF-238 in the outcome of falciparum malaria infection.

  • 88.
    Perdijk, Olaf
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut. Wageningen University, Netherlands.
    Arama, Charles
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut. University of Bamako, Mali.
    Giusti, Pablo
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Maiga, Bakary
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut. University of Bamako, Mali.
    Troye-Blomberg, Marita
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Dolo, Amagana
    Doumbo, Ogobara
    Persson, Jan-Olov
    Stockholms universitet, Naturvetenskapliga fakulteten, Matematiska institutionen.
    Boström, Stephanie
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Haptoglobin phenotype prevalence and cytokine profiles during Plasmodium falciparum infection in Dogon and Fulani ethnic groups living in Mali2013Ingår i: Malaria Journal, ISSN 1475-2875, E-ISSN 1475-2875, Vol. 12, s. 432-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: The Fulani are known to have a lower parasitaemia and less clinical episodes of malaria as compared to the Dogon sympatric ethnic group, living in Mali. Higher circulating malaria-specific antibody titers and increased pro-inflammatory cytokine levels have been shown in Fulani individuals. Several studies have tried to link haptoglobin (Hp) phenotypes with susceptibility to malaria, but without consensus. This study investigated the role of Hp phenotypes and cytokine levels in Dogon and Fulani during asymptomatic Plasmodium falciparum infection. Methods: Two different cohorts were combined in this study: a 2008 cohort with 77 children aged between two and ten years and a 2001 cohort, with 82 children and adults, aged between 11 and 68 years. Hp phenotypes in plasma were measured by Western Blot. Circulating levels of sCD163, IL-6, IL-10, IFN-gamma and TNF were measured by ELISA. Multiple regression analysis was performed to associate Hp phenotypes with cytokine profiles. In addition, in vitro stimulation of peripheral blood mononuclear cells (PBMCs) with Hp:Hb complexes was performed and cytokine release in corresponding supernatants were measured using cytometric bead array. Results: The results revealed a higher Hp2-2 phenotype prevalence in the Fulani. The Hp2-2 phenotype was associated with a higher susceptibility to P. falciparum infection in Dogon, but not in Fulani. In concordance with previous studies, Fulani showed increased inflammatory mediators (IL-6, IFN-gamma) and additionally also increased sCD163 levels compared to Dogon, irrespective of infection. Furthermore, infected individuals showed elevated sCD163 levels compared to uninfected individuals, in both Fulani and Dogon. Multiple regression analysis revealed that the Hp1-1 phenotype was associated with higher levels of TNF and IFN-gamma, as compared to the Hp2-2 phenotype. In vitro stimulation of PBMCs with Hb:Hp1-1 complexes resulted in a pro-inflammatory cytokine profile, whilst stimulation with Hb: Hp2-2 complexes showed a more balanced profile. Conclusions: Ethnicity might be an important confounder on the Hp phenotype-dependent susceptibility to malaria and future studies could consider taking this into account when designing new immunological studies. Although, the relatively small sample size used in this study warrens for precautions in the interpretation of the data and these findings should ideally be validated in a bigger cohort.

  • 89. Portugal, Silvia
    et al.
    Doumtabe, Didier
    Traore, Boubacar
    Miller, Louis H.
    Troye-Blomberg, Marita
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för immunologi.
    Doumbo, Ogobara K.
    Dolo, Amagana
    Pierce, Susan K.
    Crompton, Peter D.
    B cell analysis of ethnic groups in Mali with differential susceptibility to malaria2012Ingår i: Malaria Journal, E-ISSN 1475-2875, Vol. 11, s. 162-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Several studies indicate that people of the Fulani ethnic group are less susceptible to malaria compared to those of other ethnic groups living sympatrically in Africa, including the Dogon ethnic group. Although the mechanisms of this protection remain unclear, the Fulani are known to have higher levels of Plasmodium falciparum-specific antibodies of all Ig classes as compared to the Dogon. However, the proportions of B cell subsets in the Fulani and Dogon that may account for differences in the levels of Ig have not been characterized. Methods: In this cross-sectional study, venous blood was collected from asymptomatic Fulani (n = 25) and Dogon (n = 25) adults in Mali during the malaria season, and from P. falciparum-naive adults in the U. S. (n = 8). At the time of the blood collection, P. falciparum infection was detected by blood-smear in 16% of the Fulani and 36% of the Dogon volunteers. Thawed lymphocytes were analysed by flow cytometry to quantify B cell subsets, including immature and naive B cells; plasma cells; and classical, activated, and atypical memory B cells (MBCs). Results: The overall distribution of B cell subsets was similar between Fulani and Dogon adults, although the percentage of activated MBCs was higher in the Fulani group (Fulani: 11.07% [95% CI: 9.317 - 12.82]; Dogon: 8.31% [95% CI: 6.378 - 10.23]; P = 0.016). The percentage of atypical MBCs was similar between Fulani and Dogon adults (Fulani: 28.3% [95% CI: 22.73 - 34.88]; Dogon: 29.3% [95% CI: 25.06 - 33.55], but higher than U. S. adults (U. S.: 3.0% [95% CI: -0.21 - 6.164]; P < 0.001). Plasmodium falciparum infection was associated with a higher percentage of plasma cells among Fulani (Fulani infected: 3.3% [95% CI: 1.788 - 4.744]; Fulani uninfected: 1.71% [95% CI: 1.33 - 2.08]; P = 0.011), but not Dogon adults. Conclusion: These data show that the malaria-resistant Fulani have a higher percentage of activated MBCs compared to the Dogon, and that P. falciparum infection is associated with a higher percentage of plasma cells in the Fulani compared to the Dogon, findings that may account for the higher levels of P. falciparum antibodies in the Fulani.

  • 90. Potup, Pachuen
    et al.
    Kumsiri, Ratchanok
    Kano, Shigeyuki
    Kalambaheti, Thareerat
    Looareesuwan, Sornchai
    Troye-Blomberg, Marita
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut.
    Maneerat, Yaowapa
    Blood stage plasmodium falciparum antigens induce immunoglobulin class switching in human enriched B cell culture2009Ingår i: Southeast Asian Journal of Tropical Medicine and Public Health, ISSN 0125-1562, Vol. 40, nr 4, s. 651-664Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    This study aimed to demonstrate class switch recombination (CSR) in heavy chain expressing immunoglobulin G (IgG) and IgE in human B cells after exposure to Plasmodium falciparum schizont lysate. Human B cells (CD20(+)CD27(-)) were Cultured with crude P, falciparum antigen (cPfAg) and anti-CD40. On Day 4 post-exposure, total RNA from B cells was prepared and the occurrence of CSR from IgM to IgG and/or IgE was investigated by reverse transcription-polymerase chain reaction. Molecular markers to detect active CSR included enzyme activation-induced cytidine deaminase mRNA, gamma and epsilon-germline transcripts (gamma, epsilon-GLT), circle transcript (CT) and mature transcript (gamma and epsilon-mRNA) expression. On Day 7 and Day 14 after exposure, levels of Igs in the culture supernatant were determined by enzyme-linked immunosorbent assay. Our findings showed that we could demonstrate cPfAg-stimulated B cells undergoing CSR by use of the expressed CSR markers and the increase in specific IgG and IgE indicating the potential of this approach in the study of CSR in P. falciparum-stimulated B cells.

  • 91.
    Quin, Jaclyn E.
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Bujila, Ioana
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Chérif, Mariama
    Sanou, Guillaume S.
    Qu, Ying
    Homann, Manijeh Vafa
    Rolicka, Anna
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Sirima, Sodiomon B.
    O'Connell, Mary A.
    Lennartsson, Andreas
    Troye-Blomberg, Marita
    Stockholms universitet, Naturvet