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  • 51.
    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.

  • 52.
    Giusti, Pablo
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Urban, Britta C
    Frascaroli, Giada
    Albrecht, Letusa
    Tinti, Anna
    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 chemokines.2011In: 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 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.

  • 53. Gryseels, Bruno
    et al.
    Zumla, Alimuddin
    Troye-Blomberg, Marita
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    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.2009In: The Lancet Infectious Diseases, ISSN 1474-4457, Vol. 9, no 6, p. 334-7Article in journal (Refereed)
  • 54.
    Holmlund, U.
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Amoudruz, P.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Johansson, M. A.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Haileselassie, Y.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Ongoiba, A.
    Kayentao, K.
    Traoré, B.
    Doumbo, S.
    Schollin, J.
    Doumbo, O.
    Montgomery, S. M.
    Sverremark-Ekström, E.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Maternal country of origin, breast milk characteristics and potential influences on immunity in offspring2010In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 162, no 3, p. 500-509Article in journal (Refereed)
    Abstract [en]

    Breast milk contains pro- and anti-inflammatory cytokines and chemokines with potential to influence immunological maturation in the child. We have shown previously that country of birth is associated with the cytokine/chemokine profile of breast milk. In this study we have investigated how these differences in breast milk affect the cellular response of cord blood mononuclear cells (CBMCs) and intestinal epithelial cells (IECs, cell line HT-29) to microbial challenge. Ninety-five women were included: 30 from Mali in West Africa, 32 Swedish immigrants and 33 native Swedish women. CBMCs or IECs were stimulated in vitro with breast milk, alone or in combination with lipopolysaccharide (LPS) or peptidoglycan (PGN). Breast milk in general abrogated the LPS-induced down-regulation of surface CD14 and Toll-like receptor (TLR)-4 expression on CB monocytes, while inhibiting the PGN-induced TLR-2 up-regulation. However, breast milk from immigrant women together with LPS induced a lower CBMC release of interleukin (IL)-6 (P = 0·034) and CXCL-8/IL-8 (P = 0·037) compared with breast milk from Swedish women, while breast milk from Swedish women and Mali women tended to increase the response. The same pattern of CXCL-8/IL-8 release could be seen after stimulation of IECs (HT-29). The lower CBMC and IEC (HT-29) responses to microbial compounds by breast milk from immigrant women could be explained by the fact that breast milk from the immigrant group showed a divergent pro- and anti-inflammatory content for CXCL-8/IL-8, transforming growth factor-β1 and soluble CD14, compared to the other two groups of women. This may have implications for maturation of their children's immune responses.

  • 55. Holtel, Andreas
    et al.
    Troye-Blomberg, Marita
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Penas-Jimenez, Inmaculada
    EU-funded malaria research under the 6th and 7th Framework Programmes for research and technological development.2011In: Malaria Journal, ISSN 1475-2875, E-ISSN 1475-2875, Vol. 10, p. 11-Article in journal (Refereed)
    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.

  • 56. Huang, Jenny
    et al.
    Ehrnfelt, Cecilia
    Paulie, Staffan
    Stockholm University, Faculty of Science, The Wenner-Gren Institute, Immunology. Mabtech AB, Sweden.
    Zuber, Bartek
    Ahlborg, Niklas
    Stockholm University, Faculty of Science, The Wenner-Gren Institute, Immunology. Mabtech AB, Sweden.
    ELISpot and ELISA analyses of human IL-21-secreting cells: Impact of blocking IL-21 interaction with cellular receptors2015In: JIM - Journal of Immunological Methods, ISSN 0022-1759, E-ISSN 1872-7905, Vol. 417, p. 60-66Article in journal (Refereed)
    Abstract [en]

    Interleukin (IL)-21 is crucial for the regulation of lymphocytes and is implicated in autoimmune and other diseases. The relevance of being able to measure human IL-21 prompted us to develop ELISA and ELISpot assays for analysis of IL-21 levels and IL-21-producing cells, respectively. Monoclonal antibodies (mAbs) to IL-21 were made and ELISA and ELISpot assays were developed. The selected detection mAb also neutralized IL-21-mediated activation of human cells. Peripheral blood mononuclear cells (PBMCs) from healthy donors (n = 24) were stimulated polyclonally (phytohemagglutinin; PHA) or with antigen (Candida albicans extract and tetanus toxoid). Using ELISpot, high numbers of IL-21-producing cells were detected after PHA activation; lower but positive responses to antigen were seen in approximately 50% of the donors. In contrast, the ELISA detected IL-21 in supernatants from PHA-activated cells but not from antigen-stimulated cells. When analyzing IL-17A in parallel, PHA and antigens induced detectable responses in ELISpot as well as in ELISA. Hypothesizing that the lack of detectable IL-21 levels after antigenic stimulation was due to a combination of low frequencies of IL-21-secreting cells and consumption of IL-21 by cellular receptors during cell culture, PBMCs (n = 18) were stimulated in the presence of the neutralizing detection mAb. When preventing IL-21 from interacting with its receptor, increased IL-21 levels were found by ELISA after PHA activation and IL-21 could also be measured after antigen stimulation. ELISpot results were unaffected by the addition of the neutralizing mAb. In conclusion, IL-21 secreted by low frequencies of antigen-specific ex vivo-stimulated PBMC can be difficult to detect by ELISA but prevention of IL-21 interaction with its receptor leads to detectable IL-21 levels. In ELISpot, where the cytokine is captured by mAbs on a solid phase immediately upon secretion, blocking the receptor interaction does not affect the detection of IL-21-secreting cells.

  • 57.
    Höidén, Ingmarie
    Stockholm University, Faculty of Science, The Wenner-Gren Institute, Immunology.
    Regulation of superantigen-induced cytokine production1995Doctoral thesis, comprehensive summary (Other academic)
  • 58.
    Iriemenam, Nnaemeka C
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Okafor, Christian M F
    Balogun, Halima A
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Ayede, Idowu
    Omosun, Yusuf
    Persson, Jan-Olov
    Hagstedt, Margareta
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Anumudu, Chiaka I
    Nwuba, Roseangela I
    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.
    Cytokine profiles and antibody responses to Plasmodium falciparum malaria infection in individuals living in Ibadan, southwest Nigeria.2009In: African Health Sciences, ISSN 1680-6905, E-ISSN 1729-0503, Vol. 9, no 2, p. 66-74Article in journal (Refereed)
    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.

  • 59.
    Israelsson, E.
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Balogun, Halima
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Vasconcelos, N.-M.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Beser, J.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Roussilhon, C
    Rogier, C
    Trape, J F
    Berzins, Klavs
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Antibody responses to a C-terminal fragment of the Plasmodium falciparum blood-stage antigen Pf332 in Senegalese individuals naturally primed to the parasite2008In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 152, no 1, p. 64-71Article in journal (Refereed)
    Abstract [en]

    Previous studies have shown that antibodies from humans exposed continuously to malaria recognize the Plasmodium falciparum asexual blood-stage antigen Pf332. Here we analysed the antibody responses to a C-terminal fragment of Pf332, designated C231, in individuals from Senegal, by measuring the serum levels of immunoglobulin M (IgM), IgG class and subclass and IgE antibodies. IgG antibody reactivity with crude P. falciparum antigen was detected in all the donors, while many of the children lacked or had low levels of such antibodies against C231. The antibody levels increased significantly with age for both crude P. falciparum antigen and C231, and in the older age groups most of the donors displayed antibodies to C231. This was also true for IgM, IgE and IgG subclass reactivity against C231. Moreover, the ratio of IgG1/IgG2 was considerably lower for C231 than for crude P. falciparum antigen, and in age groups 10–14 and 15–19 years the levels of IgG2 against C231 even exceeded that of IgG1. The IgG2/IgG3 ratios suggest that C231 gives similar levels of IgG2 and IgG3, except for children aged 4–9 years, where IgG3 was higher. Raw IgM, IgG class and subclass and IgE antibody levels to C231 tended to be higher in those who did not experience a malaria attack, but following linear multivariate analysis the trends were not significant.

  • 60.
    Israelsson, Elisabeth
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Ekström, Mattias
    Nasr, Amre
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Dolo, Amagana
    Kearsley, Susannah
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Arambepola, Gishanthi
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Homann, Manijeh V.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Maiga, Bakary
    Doumbo, Ogobara K.
    ElGhazali, Gehad
    Giha, Hayder A.
    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
    Marked differences in CRP genotype frequencies between the Fulani and sympatric ethnic groups in Africa2009In: Malaria Journal, ISSN 1475-2875, E-ISSN 1475-2875, Vol. 8, no 136Article in journal (Refereed)
    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.

  • 61.
    Israelsson, Elisabeth
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Maiga, Bakary
    Kearsley, Susannah
    Dolo, Amagana
    Homann, Manijeh Vafa
    Doumbo, Ogobara K
    Troye-Blomberg, Marita
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Tornvall, Per
    Berzins, Klavs
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Cytokine gene haplotypes with a potential effect on susceptibility to malaria in sympatric ethnic groups in Mali2011In: Infection, Genetics and Evolution, ISSN 1567-1348, E-ISSN 1567-7257, Vol. 11, no 7, p. 1608-1615Article in journal (Refereed)
    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.

  • 62. 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
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Williams, Thomas N
    Wilson, Michael
    Kwiatkowski, Dominic P
    Genome-wide and fine-resolution association analysis of malaria in West Africa.2009In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, p. 657-665Article in journal (Refereed)
    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.

  • 63. Johansson, Catharina
    et al.
    Ahlborg, Niklas
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Andersson, Anna
    Lundeberg, Lena
    Karlsson, Maria A.
    Scheynius, Annika
    Linder, Maria Tengvall
    Elevated Peripheral Allergen-Specific T Cell Response Is Crucial for a Positive Atopy Patch Test Reaction2009In: International Archives of Allergy and Immunology, ISSN 1018-2438, E-ISSN 1423-0097, Vol. 150, no 1, p. 51-58Article in journal (Refereed)
    Abstract [en]

    Background: Atopic eczema is a chronic inflammatory skin disease in which several subgroups of cases can be identified. Atopy patch testing (APT) reveals allergen sensitization also in atopic eczema patients devoid of detectable allergen-specific IgE, suggesting the importance of factors other than IgE in the reaction. Here we investigate the relationship between APT reactions and allergen-specific peripheral IgE and T cell reactivity in atopic eczema patients. Methods: Adult patients with atopic eczema (n = 64) and healthy controls (n = 24) were analyzed for reactivity to Malassezia sympodialis extract by APT, measurement of specific plasma IgE and in vitro determination of the frequency of allergen-reactive peripheral blood mononuclear cells producing interleukin-4 and interleukin-5 using the ELISpot method. Results: When combining the results of the APT, IgE measurements and the ELISpot analyses, reactivity to M. sympodialis was found in a majority of the atopic eczema patients (69%), whereas the healthy controls were negative throughout. T cell reactivity to M. sympodialis, manifested by production of both interleukins 4 and 5, was highly predictive for a positive APT reaction and displayed a strongly positive correlation with the APT score. In contrast, the allergen-specific IgE levels did not predict the APT outcome, and no correlation could be found between the IgE levels and the APT score. Conclusion: Peripheral allergen-specific T helper 2 cell-mediated reactivity appears to be required for a positive APT reaction to M. sympodialis. The diagnostic potential of measuring peripheral allergen-specific T cell responses should be considered in atopic eczema. 

  • 64.
    Johansson, Maria
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Early gut microbiota in relation to cytokine responses and allergic disease2011Licentiate thesis, comprehensive summary (Other academic)
  • 65.
    Johansson, Maria A
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute, Immunology.
    Saghafian-Hedengren, Shanie
    Stockholm University, Faculty of Science, The Wenner-Gren Institute, Immunology.
    Haileselassie, Yeneneh
    Stockholm University, Faculty of Science, The Wenner-Gren Institute, Immunology.
    Roos, Stefan
    Troye-Blomberg, Marita
    Stockholm University, Faculty of Science, The Wenner-Gren Institute, Immunology.
    Nilsson, Caroline
    Sverremark-Ekström, Eva
    Stockholm University, Faculty of Science, The Wenner-Gren Institute, Immunology.
    Early-Life Gut Bacteria Associate with IL-4-, IL-10- and IFN-γ Production at Two Years of Age2012In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 11, p. e49315-(9 pp)Article in journal (Refereed)
    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.

  • 66.
    Johansson, Maria A.
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute, Immunology.
    Sjögren, Ylva M.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute, Immunology.
    Persson, Jan-Olov
    Stockholm University, Faculty of Science, Department of Mathematics.
    Nilsson, Caroline
    Sverremark-Ekström, Eva
    Stockholm University, Faculty of Science, The Wenner-Gren Institute, Immunology.
    Early colonization with a group of Lactobacilli decreases the risk for allergy at five years of age despite allergic heredity.2011In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 6, no 8, p. e23031-Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Microbial deprivation early in life can potentially influence immune mediated disease development such as allergy. The aims of this study were to investigate the influence of parental allergy on the infant gut colonization and associations between infant gut microbiota and allergic disease at five years of age.

    METHODS AND FINDINGS: Fecal samples were collected from 58 infants, with allergic or non-allergic parents respectively, at one and two weeks as well as at one, two and twelve months of life. DNA was extracted from the fecal samples and Real time PCR, using species-specific primers, was used for detection of Bifidobacterium (B.) adolescentis, B. breve, B. bifidum, Clostridium (C.) difficile, a group of Lactobacilli (Lactobacillus (L.) casei, L. paracasei and L. rhamnosus) as well as Staphylococcus (S.) aureus. Infants with non-allergic parents were more frequently colonized by Lactobacilli compared to infants with allergic parents (p = 0.014). However, non-allergic five-year olds acquired Lactobacilli more frequently during their first weeks of life, than their allergic counterparts, irrespectively of parental allergy (p = 0.009, p = 0.028). Further the non-allergic children were colonized with Lactobacilli on more occasions during the first two months of life (p = 0.038). Also, significantly more non-allergic children were colonized with B. bifidum at one week of age than the children allergic at five years (p = 0.048).

    CONCLUSION: In this study we show that heredity for allergy has an impact on the gut microbiota in infants but also that early Lactobacilli (L. casei, L. paracasei, L. rhamnosus) colonization seems to decrease the risk for allergy at five years of age despite allergic heredity.

  • 67.
    Kaneko, Akira
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    A community-directed strategy for sustainable malaria elimination on islands: Short-term MDA integrated with ITNs and robust surveillance2010In: Acta Tropica, ISSN 0001-706X, E-ISSN 1873-6254, Vol. 114, no 3, p. 177-183Article in journal (Refereed)
    Abstract [en]

    In the Asia Pacific sites with low and unstable transmission, elimination should be feasible with existing tools. On Aneityum island, Vanuatu both Plasmodium falciparum and Plasmodium vivax malaria were eliminated in 1991 after implementation of a combined intervention package, including mass drug administration (MDA) and insecticide-treated bed nets (ITNs), with high degree of community involvement. Subsequently, community-based surveillance and vector control measures have kept. By reviewing the experiences of the Aneityum project, I intended to examine the roles of community in malaria elimination. To be successful, the program should transfer major intervention components from the external donor-directed initiative to the community-directed approach. Scaling up of community involvement from simple participation to social participation, where communities involve in health planning functions is necessary from malaria control to malaria elimination.

  • 68. Lokki, A Inkeri
    et al.
    Järvelä, Irma
    Israelsson, Elisabeth
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Maiga, Bakary
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Troye-Blomberg, Marita
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Dolo, Amagana
    Doumbo, Ogobara K
    Meri, Seppo
    Holmberg, Ville
    Lactase persistence genotypes and malaria susceptibility in Fulani of Mali.2011In: Malaria Journal, ISSN 1475-2875, E-ISSN 1475-2875, Vol. 10, p. 9-Article in journal (Refereed)
    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.

  • 69. Lundberg, Mathias
    et al.
    Curbo, Sophie
    Reiser, Kathrin
    Masterman, Thomas
    Braesch-Andersen, Sten
    Areström, Irene
    Ahlborg, Niklas
    Stockholm University, Faculty of Science, The Wenner-Gren Institute, Immunology. Mabtech, Nacka, Sweden.
    Methodological Aspects of ELISA Analysis of Thioredoxin 1 in Human Plasma and Cerebrospinal Fluid2014In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 7, p. e103554-Article in journal (Refereed)
    Abstract [en]

    Thioredoxin-1 (Trx1) is a protein antioxidant involved in major cellular processes. Increased plasma levels of Trx1 have been associated with human diseases suggesting that Trx1 is a marker for oxidative stress with putative clinical use. However, the reported mean levels of Trx1 in the control cohorts vary a hundred-fold between studies (0.8-87 ng/ml), possibly due to methodological differences between the capture ELISA used in the different studies. The aim of this study was to investigate methodological aspects related to the ELISA measurement of Trx1. ELISAs utilizing different capture and detection combinations of antibodies to Trx1 and as well as recombinant human (rh) Trx1 standards from two sources were characterized. The different ELISAs were subsequently used to measure Trx1 in human plasma and cerebrospinal fluid samples (CSF) from healthy donors and from patients with various neurological diagnoses. The Trx1 standards differed in their content of monomeric and oligomeric Trx1, which affected the ELISAs composed of different antibody combinations. Thus, the levels of Trx1 determined in human plasma and CSF samples varied depending on the antibody used in the ELISAs and on the rhTrx1 standard. Furthermore, the relevance of preventing interference by heterophilic antibodies (HA) in human plasma and CSF was investigated. The addition of a HA blocking buffer to human samples drastically reduced the ELISA signals in many samples showing that HA are likely to cause false positive results unless they are blocked. In conclusion, the study shows that the design of a Trx1 ELISA in regards to antibodies and standards used has an impact on the measured Trx1 levels. Importantly, analyses of human plasma and CSF without preventing HA interference may obscure the obtained data. Overall, the results of this study are crucial for the improvement of future studies on the association of Trx1 levels with various diseases.

  • 70. Lyke, Kirsten E.
    et al.
    Dabo, Abdoulaye
    Arama, Charles
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Daou, Modibo
    Diarra, Issa
    Wang, Amy
    Plowe, Christopher V.
    Doumbo, Ogobara K.
    Sztein, Marcelo B.
    Reduced T Regulatory Cell Response during Acute Plasmodium falciparum Infection in Malian Children Co-Infected with Schistosoma haematobium2012In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 2, p. e31647-Article in journal (Refereed)
    Abstract [en]

    Background: Regulatory T cells (Tregs) suppress host immune responses and participate in immune homeostasis. In co-infection, secondary parasite infections may disrupt the immunologic responses induced by a pre-existing parasitic infection. We previously demonstrated that schistosomiasis-positive (SP) Malian children, aged 4-8 years, are protected against the acquisition of malaria compared to matched schistosomiasis-negative (SN) children. Methods and Findings: To determine if Tregs contribute to this protection, we performed immunologic and Treg depletion in vitro studies using PBMC acquired from children with and without S. haematobium infection followed longitudinally for the acquisition of malaria. Levels of Tregs were lower in children with dual infections compared to children with malaria alone (0.49 versus 1.37%, respectively, P = 0.004) but were similar months later, during a period with negligible malaria transmission. The increased levels of Tregs in SN subjects were associated with suppressed serum Th1 cytokine levels, as well as elevated parasitemia compared to co-infected counterparts. Conclusions: These results suggest that lower levels of Tregs in helminth-infected children correlate with altered circulating cytokine and parasitologic results which may play a partial role in mediating protection against falciparum malaria.

  • 71. Lyke, Kirsten E.
    et al.
    Wang, Amy
    Dabo, Abdoulaye
    Arama, Charles
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Daou, Modibo
    Diarra, Issa
    Plowe, Christopher V.
    Doumbo, Ogobara K.
    Sztein, Marcelo B.
    Antigen-Specific B Memory Cell Responses to Plasmodium falciparum Malaria Antigens and Schistosoma haematobium Antigens in Co-Infected Malian Children2012In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 6, p. e37868-Article in journal (Refereed)
    Abstract [en]

    Polyparasitism is common in the developing world. We have previously demonstrated that schistosomiasis-positive (SP) Malian children have age-dependent protection from malaria compared to matched schistosomiasis-negative (SN) children. Evidence of durable immunologic memory to malaria antigens is conflicting, particularly in young children and the effect of concomitant schistomiasis upon acquisition of memory is unknown. We examined antigen-specific B memory cell (MBC) frequencies (expressed as percentage of total number of IgG-secreting cells) in 84 Malian children aged 4-14 to malaria blood-stage antigens, apical membrane antigen 1 (AMA-1) and merozoite surface protein 1 (MSP-1) and to schistosomal antigens, Soluble Worm Antigenic Preparation (SWAP) and Schistosoma Egg Antigen (SEA), at a time point during the malaria transmission season and a follow-up dry season visit. We demonstrate, for the first time, MBC responses to S. haematobium antigens in Malian children with urinary egg excretion and provide evidence of seasonal acquisition of immunologic memory, age-associated differences in MBC acquisition, and correlation with circulating S. haematobium antibody. Moreover, the presence of a parasitic co-infection resulted in older children, aged 9-14 years, with underlying S. haematobium infection having significantly more MBC response to malaria antigens (AMA1 and MSP1) than their age-matched SN counterparts. We conclude that detectable MBC response can be measured against both malaria and schistosomal antigens and that the presence of S. haematobium may be associated with enhanced MBC induction in an age-specific manner.

  • 72.
    Masjedi, K.
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Bruze, M.
    Hindsen, M.
    Minang, J.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Ahlborg, N.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Is the variability of nickel patch test reactivity over time associated with fluctuations in the systemic T-cell reactivity to nickel?2009In: British Journal of Dermatology, ISSN 0007-0963, E-ISSN 1365-2133, Vol. 161, no 1, p. 102-109Article in journal (Refereed)
    Abstract [en]

    Background Patch test reactivity to nickel varies over time. To what extent this variation is associated with fluctuations in the T-cell reactivity to nickel is not known. Objectives Our aim was to investigate the relationship between variation over time in the patch test and the systemic T-cell reactivity to nickel. Methods Patients (n = 15) with a history of contact allergy to nickel were subjected to three consecutive patch tests at 3-month intervals, utilizing NiSO4 at 10 concentrations ranging from 0.0032% to 12.5%. Prior to each patch test, blood mononuclear cells were analysed for T-cell reactivity to nickel by interleukin (IL)-4 and IL-13 enzyme-linked immunospot assay. Results Eleven patients reacted positively in all three patch tests, two patients reacted in one or two tests and two remained negative. All 13 positive patients displayed variability over time, in terms of the lowest dose of nickel to which they responded. Also the cytokine response to nickel varied over time but the patients' mean cytokine response was positively correlated with their mean patch test reactivity (r(s) = 0.70, P < 0.01 for IL-4; r(s) = 0.78, P < 0.001 for IL-13). However, although the changes over time in patch test reactivity and the cytokine responses to nickel displayed a similar pattern in many patients, there was no significant correlation between the individuals' variation over time in vivo and in vitro. Conclusions The overall magnitude of the T-cell reactivity to nickel and the patch test reactivity are closely associated but fluctuations in the systemic T-cell reactivity cannot be singled out as the major cause of longitudinal variability in nickel patch test reactivity.

  • 73. 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
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    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 populations.2010In: European Cytokine Network, ISSN 1148-5493, E-ISSN 1952-4005, Vol. 21, no 2, p. 77-83Article in journal (Refereed)
    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-gamma 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.

  • 74. 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
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Bousema, J Teun
    van der Meer, Jos W
    van der Ven, André J A M
    Troye-Blomberg, Marita
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    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.2010In: Journal of Infectious Diseases, ISSN 0022-1899, E-ISSN 1537-6613, Vol. 201, no 1, p. 142-52Article in journal (Refereed)
    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.

  • 75.
    Minang, Jacob T.
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Arestrom, Irene
    Ahlborg, Niklas
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    ELIspot displays a better detection over ELISA of T helper (Th) 2-type cytokine-production by ex vivo-stimulated antigen-specific T cells from human peripheral blood2008In: Immunological Investigations, ISSN 0882-0139, E-ISSN 1532-4311, Vol. 37, no 4, p. 279-291Article in journal (Refereed)
    Abstract [en]

    Detection of cytokines secreted by ex vivo antigen-stimulated peripheral blood mononuclear cells (PBMC) by ELISA is hampered by low frequencies of specific T cells and cellular receptor consumption. We investigated if ELISpot, measuring cytokine production at the single cell level, facilitated a better detection of the Th2 cytokines IL-4 and IL-5. PBMC from nickel-allergic (n = 31) and non-allergic subjects (n = 10) were stimulated with nickel or tetanus toxoid (TT) and cytokine production assessed by ELISpot and ELISA. By IL-4 ELISpot, 74% of the allergic and 0% control subjects responded to nickel and 56% of all subjects to TT. ELISA detected IL-4 after nickel stimulation only in 13% of the allergic subjects. Also detection of TT-induced IL-5 was improved by ELISpot with 54% subjects responding versus 24% in ELISA. In contrast, detection of nickel-induced IL-5 was more comparable between methods, most likely due to the 7-fold higher IL-5 production per cell in response to nickel versus IT. The low IL-5 response to TT was associated with a higher induction of the down-regulatory cytokine IL-10 by TT as compared to nickel (p < 0.001). Overall, ELISpot displayed a better detection of IL-4 as well as low intensity IL-5 responses thus emphasizing the importance of selecting suitable methods for the measurement of cytokine production ex vivo.

  • 76. Minja, Daniel T. R.
    et al.
    Schmiegelow, Christentze
    Oesterholt, Mayke
    Magistrado, Pamela A.
    Boström, Stephanie
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    John, Davis
    Pehrson, Caroline
    Andersen, Daniel
    Deloron, Philippe
    Salanti, Ali
    Lemnge, Martha
    Luty, Adrian J. F.
    Alifrangis, Michael
    Theander, Thor
    Lusingu, John P. A.
    Reliability of rapid diagnostic tests in diagnosing pregnancy associated malaria in North Eastern Tanzania2012In: Malaria Journal, ISSN 1475-2875, E-ISSN 1475-2875, Vol. 11, p. 211-Article in journal (Refereed)
    Abstract [en]

    Background: Accurate diagnosis and prompt treatment of pregnancy-associated malaria (PAM) are key aspects in averting adverse pregnancy outcomes. Microscopy is the gold standard in malaria diagnosis, but it has limited detection and availability. When used appropriately, rapid diagnostic tests (RDTs) could be an ideal diagnostic complement to microscopy, due to their ease of use and adequate sensitivity in detecting even sub-microscopic infections. Polymerase chain reaction (PCR) is even more sensitive, but it is mainly used for research purposes. The accuracy and reliability of RDTs in diagnosing PAM was evaluated using microscopy and PCR. Methods: A cohort of pregnant women in north-eastern Tanzania was followed throughout pregnancy for detection of plasmodial infection using venous and placental blood samples evaluated by histidine rich protein 2 (HRP-2) and parasite lactate dehydrogenase (pLDH) based RDTs (Parascreen (TM)) or HRP-2 only (Paracheck Pf (R) and ParaHIT (R) f), microscopy and nested Plasmodium species diagnostic PCR. Results: From a cohort of 924 pregnant women who completed the follow up, complete RDT and microscopy data was available for 5,555 blood samples and of these 442 samples were analysed by PCR. Of the 5,555 blood samples, 49 ((proportion and 95% confidence interval) 0.9% [0.7 - 1.1]) samples were positive by microscopy and 91 (1.6% [1.3-2.0]) by RDT. Forty-six (50.5% [40.5 - 60.6]) and 45 (49.5% [39.4 - 59.5]) of the RDT positive samples were positive and negative by microscopy, respectively, whereas nineteen (42.2% [29.0 - 56.7]) of the microscopy negative, but RDT positive, samples were positive by PCR. Three (0.05% [0.02 - 0.2]) samples were positive by microscopy but negative by RDT. 351 of the 5,461 samples negative by both RDT and microscopy were tested by PCR and found negative. There was no statistically significant difference between the performances of the different RDTs. Conclusions: Microscopy underestimated the real burden of malaria during pregnancy and RDTs performed better than microscopy in diagnosing PAM. In areas where intermittent preventive treatment during pregnancy may be abandoned due to low and decreasing malaria risk and instead replaced with active case management, screening with RDT is likely to identify most infections in pregnant women and out-performs microscopy as a diagnostic tool.

  • 77. Muss, Claus
    et al.
    Stejskal, Vera
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Titel, Ekkehard
    The effectiveness of choline citrate infusions monitored by lymphocyte transformation test (LTT) in multiple sclerosis. A new approach to the diagnosis and treatment of the disease2009In: Neuro - endocrinology letters, ISSN 0172-780X, Vol. 30, no 3, p. 331-334Article in journal (Refereed)
    Abstract [en]

    The efficacy of intravenous choline citrate infusions was investigated in 34 patients with multiple sclerosis (MS) by clinical evaluation and by monitoring of lymphocyte proliferation in vitro against fragments of myelin basic protein (MOG-35-55, MBP15-31, PLP 39-15) over a period of 12 weeks. Patients have been diagnosed with MS at least one year before entering the study and suffered from mild relapsing/remitting course to long-term chronic progressive disease. Twenty one patients exhibited positive lymphocyte proliferation to myelin fragments prior to treatment and were therefore selected for further studies. Choline citrate was administered with a dosage of 1200mg/ 2x week for a period of 3 months. This treatment resulted in a significant decrease of lymphocyte proliferation to neural fragments (MOG- 35-55, MBP15-31) in lymphocyte transformation test (LTT). There was no significant SI change of PLP Peptide (PLP 39-15) LTT found after treatment with choline citrate. During the 3 mo observation period, patients remained stable and no side-effects of the treatment were observed. In addition, some patients reported long-lasting improvement (less paresthesia and increase of muscle strength in lower extremities) which was demonstrated up to 3 years later. In one spectacular case a commercial pilot was able to return to duty again after treatment. This pilot was allowed back in to his position as a commercial flying cockpit member and is on duty for more than 4 yrs now.

  • 78. Nasr, A.
    et al.
    Iriemenam, N. C.
    Troye-Blomberg, Marita
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Arnot, D.
    Theander, T. G.
    Berzins, Klavs
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    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, Sudan2011In: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 74, no 4, p. 390-396Article in journal (Refereed)
    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.

  • 79. Nilsson, C.
    et al.
    Larsson Sigfrinius, A-K
    Montgomery, S M
    Sverremark-Ekström, Eva
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Linde, A
    Lilja, G
    Blomberg, Marita Troye
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Epstein-Barr virus and cytomegalovirus are differentially associated with numbers of cytokine-producing cells and early atopy2009In: Clinical and experimental allergy, ISSN 1365-2222, Vol. 39, no 4, p. 509-17Article in journal (Refereed)
    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.

  • 80. 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
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Luty, A. J. F.
    Deloron, Philippe
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Fievet, N.
    Consequence of malaria during pregnancy on immunological responses of the newborn: a study of regulatory t cells2011In: Tropical medicine & international health, ISSN 1360-2276, E-ISSN 1365-3156, Vol. 16, p. 86-87Article in journal (Refereed)
  • 81.
    Nyakeriga, Alice M.
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute, Immunology. Texas Tech University, USA; Kilifi District Hospital, Kenya.
    Troye-Blomberg, Marita
    Stockholm University, Faculty of Science, The Wenner-Gren Institute, Immunology.
    Haptoglobin phenotypes and iron status in children living in a malaria endemic area of Kenyan coast2013In: Acta Tropica, ISSN 0001-706X, E-ISSN 1873-6254, Vol. 126, no 2, p. 127-131Article in journal (Refereed)
    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.

  • 82. Palma, Carla
    et al.
    Schiavoni, Giovanna
    Abalsamo, Laura
    Mattei, Fabrizio
    Piccaro, Giovanni
    Sanchez, Massimo
    Fernandez, Carmen
    Stockholm University, Faculty of Science, The Wenner-Gren Institute, Immunology.
    Singh, Mahavir
    Gabriele, Lucia
    Mycobacterium tuberculosis PstS1 amplifies IFN-gamma and induces IL-17/IL-22 responses by unrelated memory CD4(+) T cells via dendritic cell activation2013In: European Journal of Immunology, ISSN 0014-2980, E-ISSN 1521-4141, Vol. 43, no 9, p. 2386-2397Article in journal (Refereed)
    Abstract [en]

    The immunological mechanisms that modulate protection during Mycobacterium tuberculosis (Mtb) infection or vaccination are not fully understood. Secretion of IFN- and, to a lesser extent, of IL-17 by CD4(+) T cells plays a major role both in protection and immunopathology. Few MtbAgs interacting with DCs affect priming, activation, and regulation of Ag-unrelated CD4(+) T-cell responses. Here we demonstrate that PstS1, a 38 kDa-lipoprotein of Mtb, promotes Ag-independent activation of memory T lymphocytes specific for Ag85B or Ag85A, two immunodominant protective Ags of Mtb. PstS1 expands CD4(+) and CD8(+) memory T cells, amplifies secretion of IFN- and IL-22 and induces IL-17 production by effector memory cells in an Ag-unrelated manner in vitro and in vivo. These effects were mediated through the stimulation of DCs, particularly of the CD8(-) subtype, which respond to PstS1 by undergoing phenotypic maturation and by secreting IL-6, IL-1 and, to a lower extent, IL-23. IL-6 secretion by PstS1-stimulated DCs was required for IFN-, and to a lesser extent for IL-22 responses by Ag85B-specific memory T cells. These results may open new perspectives for immunotherapeutic strategies to control Th1/Th17 immune responses in Mtb infections and in vaccinations against tuberculosis.

  • 83. Portugal, Silvia
    et al.
    Doumtabe, Didier
    Traore, Boubacar
    Miller, Louis H.
    Troye-Blomberg, Marita
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Doumbo, Ogobara K.
    Dolo, Amagana
    Pierce, Susan K.
    Crompton, Peter D.
    B cell analysis of ethnic groups in Mali with differential susceptibility to malaria2012In: Malaria Journal, ISSN 1475-2875, E-ISSN 1475-2875, Vol. 11, p. 162-Article in journal (Refereed)
    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.

  • 84.
    Rahman, Muhammad J
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Chuquimia, Olga D
    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.
    Singh, Mahavir
    Fernández, Carmen
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Impact of Toll-like receptor 2 deficiency on immune responses to mycobacterial antigens2011In: Infection and Immunity, ISSN 0019-9567, E-ISSN 1098-5522, Vol. 79, no 11, p. 4649-4656Article in journal (Refereed)
    Abstract [en]

    In the present study, we addressed the question of whether Toll-like receptor 2 (TLR2)-mediated innate immunity can contribute to the development of acquired immune responses. We immunized TLR2(-/-) and wild-type (WT) mice three times subcutaneously with the mycobacterial antigen (Ag19kDa) (a TLR2 ligand) or Ag85A (not a TLR2 ligand). One week after the last immunization, sera and spleens were collected. To evaluate cellular responses, we measured gamma interferon (IFN-γ) after in vitro restimulation of spleen cells with antigen alone or antigen-pulsed bone marrow-derived macrophages (BMM(Ag)) or pulmonary macrophages (PuM(Ag)). Antibody responses were comparable in the two mouse strains, but we observed differences in the cellular responses. Recall responses to Ag85A were similar in the two strains, but responses to Ag19kDa given alone or presented by BMM or PuM were lower in TLR2(-/-) than in WT mice. The largest differences in cellular responses were observed when Ag19kDa was presented by PuM. To understand this, we analyzed phenotypic and functional differences between BMM and PuM upon stimulation with various ligands. Generally, PuM had a lower response to the TLR2 ligand Pam(3)Cys-Ser-(Lys)(4) trihydrochloride and to anti-CD40 than BMM, as measured by cytokine secretion and upregulation of costimulatory molecules. This might provide a partial explanation for the lower capacity of PuM when pulsed with Ag19kDa, also a TLR2 ligand. Altogether, our results revealed weaknesses in the T cell and antigen-presenting cell (APC) compartments of the Ag19kDa-immunized TLR2(-/-) mice but indicated that specific immune responses could be generated in the absence of TLR2 regardless of the characteristics of the antigen used.

  • 85.
    Rahman, Muhammad Jubayer
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Department of Immunology.
    Immunization with mycobacterial antigens: a role for innate immunity in antigen presentationManuscript (preprint) (Other (popular science, discussion, etc.))
    Abstract [en]

    We have found that toll-like receptor (TLR) 2 was important in the control of mycobacterial infection in the lungs. However, it is unclear how the TLR2-mediated innate immunity contributes to the development of acquired immune responses upon immunization with mycobacterial antigens. In the present study, we addressed this issue by immunizing TLR2 knockout (TLR2-/-) and wild-type (WT) mice with mycobacterial 19kDa (TLR2 ligand) or Ag85A (non-TLR2 ligand) antigens. We compared both humoral and cellular immune responses in the two mouse strains. Interferon gamma (IFN-g) responses were measured in the culture supernatants after in vitro restimulation of spleen cells with antigen alone, antigen-pulsed bone marrow derived macrophages (BMMAg) or BCG-infected BMM (BMMBCG). We found that the magnitude of antigen-specific antibody responses in serum was comparable in the two mouse strains. With regard to the two antigens, immunization with 19kDa induces more Th1 type immune responses compared to the immunization with Ag85A. We observed differences in the response of the two strains upon restimulation with antigen alone or with BMMAg regarding 19kDa. Recall IFN-g responses to 19kDa were significantly lower in the TLR2-/- mice compared to the WT mice. Interestingly, IFN-g responses to BMMBCG were similar in both strains probably due to the fact that BCG targets other cell surface molecules. The expression of CD86 in the BMMBCG was found to be TLR2-independent whereas in the BMMAg it was TLR2-dependent.

    Altogether, results from this study indicate that specific immune responses could be generated in the absence of TLR2 regardless of the characteristics of the antigens (TLR2 dependent or independent) used for immunization. We discuss the relevance of innate immunity for the induction of acquired immune responses.

  • 86.
    Rahman, Muhammad Jubayer
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Department of Immunology.
    Chuquimia, Olga D
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Department of Immunology.
    Singh, Mahavir
    Fernández, Carmen
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Department of Immunology.
    Immunization with mycobacterial antigens: a role for innate immunity in antigen presentationManuscript (preprint) (Other academic)
    Abstract [en]

    We have found that toll-like receptor (TLR) 2 was important in the control of mycobacterial infection in the lungs. However, it is unclear how the TLR2-mediated innate immunity contributes to the development of acquired immune responses upon immunization with mycobacterial antigens. In the present study, we addressed this issue by immunizing TLR2 knockout (TLR2-/-) and wild-type (WT) mice with mycobacterial 19kDa (TLR2 ligand) or Ag85A (non-TLR2 ligand) antigens. We compared both humoral and cellular immune responses in the two mouse strains. Interferon gamma (IFN-g) responses were measured in the culture supernatants after in vitro restimulation of spleen cells with antigen alone, antigen-pulsed bone marrow derived macrophages (BMMAg) or BCG-infected BMM (BMMBCG). We found that the magnitude of antigen-specific antibody responses in serum was comparable in the two mouse strains. With regard to the two antigens, immunization with 19kDa induces more Th1 type immune responses compared to the immunization with Ag85A. We observed differences in the response of the two strains upon restimulation with antigen alone or with BMMAg regarding 19kDa. Recall IFN-g responses to 19kDa were significantly lower in the TLR2-/- mice compared to the WT mice. Interestingly, IFN-g responses to BMMBCG were similar in both strains probably due to the fact that BCG targets other cell surface molecules. The expression of CD86 in the BMMBCG was found to be TLR2-independent whereas in the BMMAg it was TLR2-dependent.

    Altogether, results from this study indicate that specific immune responses could be generated in the absence of TLR2 regardless of the characteristics of the antigens (TLR2 dependent or independent) used for immunization. We discuss the relevance of innate immunity for the induction of acquired immune responses.

  • 87.
    Rahman, Muhammad Jubayer
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Dégano, Irene Roman
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Singh, Mahavir
    Fernández, Carmen
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Influence of maternal gestational treatment with mycobacterial antigens on postnatal immunity in an experimental murine model2010In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 5, no 3, p. e9699-Article in journal (Refereed)
    Abstract [en]

    It has been proposed that the immune system could be primed as early as during the fetal life and this might have an impact on postnatal vaccination. Therefore, we addressed in murine models whether gestational treatment with mycobacterial antigens could induce better immune responses in the postnatal life. METHODS/FINDINGS: BALB/c mice were treated subcutaneously (s.c.) at the second week of gestation with antigen (Ag)85A or heparin-binding hemagglutinin (HBHA) in the absence of adjuvant. Following birth, offspring mice were immunized intranasally (i.n.) with the same antigens formulated with the adjuvant cholera toxin (CT) at week 1 and week 4. One week after the last immunization, we assessed antigen-specific recall interferon gamma (IFN-gamma) responses by in vitro restimulation of lung-derived lymphocytes. Protection against infection was assessed by challenge with high dose Mycobacterium bovis Bacille Calmette-Guérin (BCG) given i.n. We found that recall IFN-gamma responses were higher in the offspring born to the treated mother compared to the untreated-mother. More importantly, we observed that the offspring born to the treated mother controlled infection better than the offspring born to the untreated mother. Since the gestational treatment was done in absence of adjuvant, essentially there was no antibody production observed in the pregnant mice and therefore no influence of maternal antibodies was expected. We hypothesized that the effect of maternal treatment with antigen on the offspring occurred due to antigen transportation through placenta. To trace the antigens, we conjugated fluorescent nanocrystals with Ag85A (Qdot-ITK-Ag85A). After inoculation in the pregnant mice, Qdot-ITK-Ag85A conjugates were detected in the liver, spleen of pregnant females and in all the fetuses and placentas examined. CONCLUSION: The fetal immune system could be primed in utero by mycobacterial antigens transported through the placenta.

  • 88.
    Rahman, Muhammad Jubayer
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Department of Immunology.
    Fernández, Carmen
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Department of Immunology.
    Neonatal vaccination with Mycobacterium bovis BCG: potential effects as a priming agent shown in a heterologous prime-boost immunization protocol2009In: Vaccine, ISSN 0264-410X, E-ISSN 1873-2518, Vol. 27, no 30, p. 4038-4046Article in journal (Refereed)
    Abstract [en]

    In general prime-boost immunization including Mycobacterium bovis bacille Calmette-Guérin (BCG) as a priming agent has been a recent successful strategy in animal models. However, the effects of BCG as a priming vaccine have not been investigated systematically. Thus, we modelled a heterologous prime-boost immunization in mice with BCG administered at the neonatal period and mycobacterial heparin-binding hemagglutinin (HBHA) at adult ages. Mice were challenged with a high dose of BCG (10(7) colony forming units) via intranasal (i.n.) route. We addressed whether the route of administration and addition of adjuvants could be of importance in HBHA-immunizations while animals were primed with BCG. Our results showed that prime-boost immunization induced significantly higher levels of protection in animals compared to the group vaccinated with BCG alone. Most importantly, the levels of protection were comparable between the i.n. and subcutaneous (s.c.) boostings with native (n) HBHA and the coadministration of adjuvant was not necessary. Moreover, priming with BCG improved also the protection promoted by the recombinant form of HBHA, even if to a lower degree to that observed after nHBHA boosting. In general, vaccination with BCG prior to the HBHA administration was found to contribute in two ways: it primed the immune system and provided adjuvant effect. We discuss the several outcomes following neonatal BCG priming and HBHA boosting for better protection against tuberculosis

  • 89. Rasul, Abu E.
    et al.
    Nagy, Noemi
    Sohlberg, Ebba
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Adori, Monika
    Claesson, Hans-Erik
    Klein, George
    Klein, Eva
    Simultaneous detection of the two main proliferation driving EBV encoded proteins, EBNA-2 and LMP-1 in single B cells2012In: JIM - Journal of Immunological Methods, ISSN 0022-1759, E-ISSN 1872-7905, Vol. 385, no 1-2, p. 60-70Article in journal (Refereed)
    Abstract [en]

    Epstein Barr virus (EBV) is carried by almost all adults, mostly without clinical manifestations. Latent virus infection of B lymphocytes induces activation and proliferation that can be demonstrated in vitro. In healthy individuals, generation of EBV induced malignant proliferation is avoided by continuous immunological surveillance. The proliferation inducing set of the virally encoded genes is expressed exclusively in B cells in a defined differentiation window. It comprises nine EBV encoded nuclear proteins, EBNA 1-6, and three cell membrane associated proteins, LMP-1,2A and 2B, designated as latency Type III. Outside this window the expression of the viral genes is limited. Healthy carriers harbor a low number of B lymphocytes in which the viral genome is either silent or expresses one virally encoded protein, EBNA-1, latency Type I. In addition, EBV genome carrying B cells can lack either EBNA-2 or LMP-1, latency Type IIa or Type IIb respectively. These cells have no inherent proliferation capacity. Detection of both EBNA-2 and LMP-1 can identify B cells with growth potential. We devised therefore a method for their simultaneous detection in cytospin deposited cell populations. Simultaneous detection of EBNA-2 and LMP-1 was reported earlier in tissues derived from infectious mononucleosis (IM), postransplantation lymphoproliferative disorders (PTLD) and from humanized mice infected with EBV. We show for the first time the occurrence of Type IIa and Type IIb cells in cord blood lymphocyte populations infected with EBV in vitro. Further, we confirm the variation of EBNA-2 and LMP-1 expression in several Type III lines and that they vary independently in individual cells. We visualize that in Type III LCL, induced for plasmacytoid differentiation by IL-21 treatment, EBV protein expression changes to Type ha (EBNA-2 negative LMP-1 positive). We also show that when the proliferation of EBV infected cord blood lymphocyte culture is inhibited by the immunomodulator, PSK the majority of the cells express latency Type IIa pattern. These results show that by modifying the differentiation state, the proliferating EBV positive B cells can be curbed. Type IIa expression is a characteristic for EBV positive Reed-Sternberg (R/S) cells in EBV positive Hodgkin's lymphomas. For survival and proliferation, the R/S cells require the contribution of the in vivo microenvironment Consequently, Type IIa lines could not be established from Hodgkin's lymphoma in vitro. We propose that these experimental cultures can be exploited for study of the Type IIa cells.

  • 90. Rizzo, Roberta
    et al.
    Stignani, Marina
    Amoudruz, Petra
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Nilsson, Caroline
    Melchiorri, Loredana
    Baricordi, Olavio
    Sverremark-Ekström, Eva
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Allergic women have reduced sHLA-G plasma levels at delivery.2009In: American Journal of Reproductive Immunology and Microbiology, ISSN 8755-8920, Vol. 61, no 5, p. 368-76Article in journal (Refereed)
    Abstract [en]

    PROBLEM: HLA-G antigen maintains a tolerogenic condition at the foeto-maternal interface, counteracts inflammation in autoimmune diseases and soluble HLA-G (sHLA-G) levels decrease in allergic-asthmatics. Taking into consideration these findings, we analyzed if sHLA-G and interleukin-10 (IL-10) could be influenced by pregnancy and labour in allergic and non-allergic women. METHOD OF STUDY: sHLA-G isoforms and IL-10 levels were determined in the plasma samples of 43 women (15 non-allergic, 28 allergic) during third trimester, at delivery and 2 years after pregnancy by immunoenzymatic assays. RESULTS: A significant increase in sHLA-G and IL-10 levels was documented at delivery in both allergic and non-allergic women. Allergic women showed lower sHLA-G concentrations. sHLA-G1 was evidenced as the predominant plasma isoform. CONCLUSION: The data showed increased sHLA-G and IL-10 concentrations at delivery, regardless of the allergic status. The sHLA-G1 isoform is mainly responsible for the increased sHLA-G levels at delivery.

  • 91.
    Saghafian-Hedengren, Shanie
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute, Immunology.
    Sundström, Yvonne
    Stockholm University, Faculty of Science, The Wenner-Gren Institute, Immunology.
    Sohlberg, Ebba
    Stockholm University, Faculty of Science, The Wenner-Gren Institute, Immunology.
    Nilsson, Caroline
    Linde, Annika
    Troye-Blomberg, Marita
    Stockholm University, Faculty of Science, The Wenner-Gren Institute, Immunology.
    Berg, Louise
    Sverremark-Ekström, Eva
    Stockholm University, Faculty of Science, The Wenner-Gren Institute, Immunology.
    Herpesvirus seropositivity in childhood associates with decreased monocyte-induced NK-cell IFN-γ production2009In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 182, no 4, p. 2511-2517Article in journal (Refereed)
    Abstract [en]

    EBV infection is inversely associated with IgE sensitization in children, and this association is further enhanced by CMV coinfection. In mice, herpesvirus latency causes systemic innate activation and protection from bacterial coinfection, implying the importance of herpesviruses in skewing immune responses during latent infection. Early control of viral infections depends on IFN- release by NK cells, which generally requires the presence of accessory cells. We investigated IFN- production by NK cells in PBMCs from children seropositive (SP) for EBV alone, for both EBV and CMV, or seronegative for both viruses. The ability of classical (CD14++CD16–) and proinflammatory (CD14+CD16+) monocytes to induce autologous NK cell IFN- was studied by coculture experiments with enriched CD3–CD56+ cells. Transwell experiments were used to evaluate how monocytes interact with NK cells to induce IFN- synthesis. SP children had a significantly reduced proportion of IFN-+ NK cells and cognate intracellular IFN- levels, which was more pronounced in CMV-coinfected subjects. Also, resting PBMCs of SP children displayed lower proportions of proinflammatory monocytes. IFN- production by NK cells was dependent on interactions with monocytes, with the proinflammatory subset inducing the highest IFN-. Finally, SP children had markedly lower levels of plasma IFN-, concurrent with in vitro findings. Herpesvirus infections could be one contributing factor for maturation toward balanced Th1-Th2 responses. Our data indicate that early infection by herpesviruses may affect NK cell and monocyte interactions and thereby also influence the development of allergies.

  • 92.
    Saghafian-Hedengren, Shanie
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Sverremark-Ekström, Eva
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Linde, Annika
    Department of Epidemiology, Swedish Institute for Infectious Disease Control, Solna, Sweden.
    Lilja, Gunnar
    Department of Clinical Science and Education, Sodersjukhuset, Karolinska Institutet and Sachs' Children's Hospital, Stockholm, Sweden.
    Nilsson, Caroline
    Department of Clinical Science and Education, Sodersjukhuset, Karolinska Institutet and Sachs' Children's Hospital, Stockholm, Sweden.
    Early-life EBV infection protects against persistent IgE sensitization.2010In: The Journal of allergy and clinical immunology, ISSN 1097-6825, Vol. 125, no 2, p. 433-8Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Infection with EBV has previously been implicated in influencing allergic disorders, but its precise role remains contradictory. The timing of primary infection may contribute to the discrepancies. OBJECTIVE: This study aimed at investigating whether the time-point of primary EBV infection during childhood could be of importance in modulating the risk of developing IgE sensitization. METHODS: A total of 219 Swedish infants were followed prospectively to 5 years of age with clinical examinations, skin prick testing, specific IgE analyses, and determination of serostatus against EBV. RESULTS: After analysis of the children's EBV serostatus, we found that 5-year-olds who were infected with EBV before the age of 2 years were at a significantly lower risk of being persistently IgE-sensitized-that is, sensitized at both 2 and 5 years of age (adjusted odds ratio, 0.34; 95% CI, 0.12-0.94). In contrast, contraction of EBV after 2 years of age was highly associated with late-onset IgE sensitization (adjusted odds ratio, 4.64; 95% CI, 1.57-13.69). Persistently sensitized 5-year-olds had higher specific-IgE levels than children with late-onset IgE sensitization (P < .01). CONCLUSION: Our data support the value of early-life microbial exposure for protection against the development of IgE sensitization and underscore the proximate postnatal years as an important period during which EBV could contribute to an allergo-protective immune profile.

  • 93. Schmiegelow, Christentze
    et al.
    Minja, Daniel
    Oesterholt, Mayke
    Pehrson, Caroline
    Suhrs, Hannah Elena
    Boström, Stephanie
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Lemnge, Martha
    Magistrado, Pamela
    Rasch, Vibeke
    Lusingu, John
    Theander, Thor G.
    Nielsen, Birgitte Bruun
    Factors associated with and causes of perinatal mortality in northeastern Tanzania2012In: Acta Obstetricia et Gynecologica Scandinavica, ISSN 0001-6349, E-ISSN 1600-0412, Vol. 91, no 9, p. 1061-1068Article in journal (Refereed)
    Abstract [en]

    Objective. To identify factors associated with perinatal mortality in northeastern Tanzania. Design. Prospective cohort study. Setting. Northeastern Tanzania. Population. 872 mothers and their newborns. Methods. Pregnant women were screened for factors possibly associated with perinatal mortality, including preeclampsia, small-for-gestational age, preterm delivery, anemia, and health-seeking behavior. Fetal growth was monitored using ultrasound. Finally, the specific causes of the perinatal deaths were evaluated. Main outcome measure. Perinatal mortality. Results. Forty-six deaths occurred. Key factors associated with perinatal mortality were preterm delivery (adjusted odds ratio (OR) 14.47, 95% confidence interval (CI) 3.2364.86, p < 0.001), small-for-gestational age (adjusted OR 3.54, 95%CI 1.1810.61, p = 0.02), and maternal anemia (adjusted OR 10.34, 95%CI 1.8956.52, p = 0.007). Adherence to the antenatal care program (adjusted OR 0.027, 95%CI 0.0030.26, p = 0.002) protected against perinatal mortality. The cause of death in 43% of cases was attributed to complications related to labor and specifically to intrapartum asphyxia (30%) and neonatal infection (13%). Among the remaining deaths, 27% (7/26) were attributed to preeclampsia and 23% (6/26) to small-for-gestational age. Of these, 54% (14/26) were preterm. Conclusions. Preeclampsia, small-for-gestational age and preterm delivery were key risk factors and causes of perinatal mortality in this area of Tanzania. Maternal anemia was also strongly associated with perinatal mortality. Furthermore, asphyxia accounted for a large proportion of the perinatal deaths. Interventions should target the prevention and handling of these conditions in order to reduce perinatal mortality.

  • 94. Simon, KC
    et al.
    Saghafian Hedengren, Shanie
    Stockholm University, Faculty of Science, The Wenner-Gren Institute, Immunology.
    Sverremark-Ekström, Eva
    Stockholm University, Faculty of Science, The Wenner-Gren Institute, Immunology.
    Nilsson, C
    Stockholm University, Faculty of Science, The Wenner-Gren Institute.
    Aschero, A
    Age at Epstein-Barr virus infection and Epstein-Barr virus nuclear antigen-1 antibodies in Swedish children2012In: Elsevier, ISSN 2211-0348, Vol. 1, no 3, p. 136-138Article in journal (Refereed)
    Abstract [en]

    There is strong evidence supporting a role for Epstein-Barr virus (EBV) in the etiopathogenesis of multiple sclerosis (MS). Because of the strong association between antibody (Ab) titer against EBV nuclear antigen 1 (EBNA1) and late age at EBV infection, manifested as infectious mononucleosis (IM), and MS risk, we sought to determine whether age at primary EBV infection was associated with subsequent anti-EBNA1 Ab titer in a longitudinal study of Swedish children with EBV seropositivity and anti-EBNA1 Ab titers measured at ages 2, 5, and 10.

  • 95.
    Simone, Olivia
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Bejarano, Maria Teresa
    Pierce, Susan K
    Antonaci, Salvatore
    Wahlgren, Mats
    Troye-Blomberg, Marita
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Donati, Daria
    TLRs innate immunereceptors and Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) CIDR1α-driven human polyclonal B-cell activation.2011In: Acta Tropica, ISSN 0001-706X, E-ISSN 1873-6254, Vol. 119, no 2-3, p. 144-150Article in journal (Refereed)
    Abstract [en]

    Chronic malaria severely affects the immune system and causes polyclonal B-cell activation, as evidenced by the presence of hypergammaglobulinemia, elevated levels of autoantibodies, loss of B-cell memory and the frequent occurrence of Burkitt's lymphomas (BL) in children living in malaria endemic areas. Previous studies have shown that the cysteine-rich interdomain region 1α (CIDR1α) of the Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) of the FCR3S1.2 strain, subsequently named CIDR1α, interacts with B cells partially through the binding to the B-cell receptor (BCR). This interaction leads to an activated phenotype, increased survival, and a low degree of proliferation. CIDR1α preferentially activates the memory B-cell compartment, therefore PfEMP1 is considered to act as a polyclonal B-cell activator and its role in memory maintenance has been suggested. In this report, we extend the analysis of the PfEMP1-CIDR1α B-cell interaction and demonstrate that PfEMP1-CIDR1α increases the expression of TLR7 and TLR10 mRNA transcripts and sensitizes B cells to TLR9 signalling via the MyD88 adaptor molecule. Furthermore, despite its ability to bind to surface Igs, PfEMP1-CIDR1α-induced B-cell activation does not seem to proceed through the BCR, since it does not induce Lyn and/or phospho-tyrosine mediated signalling pathways. Rather PfEMP1-CIDR1α induces the phosphorylation of downstream kinases, such as ERK1/2, p38 and IKBα, in human B cells. These findings indicate that PfEMP1-CIDR1α induces a persistent activation of B cells, which in turn can contribute to the exhaustion and impairment of B-cell functions during chronic malaria infection.

  • 96.
    Sjöberg, Katarina
    Stockholm University, Faculty of Science, The Wenner-Gren Institute, Immunology.
    Parasite specific immune responses in humans exposed to Plasmodium falciparum malaria1991Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Malaria is one of the most serious diseases worldwide with regard to mortality and morbidity and the most severe form in humans is caused by Plasmodium falciparum. The development of a vaccine against this disease is an important goal in malaria research and extensive efforts are made to identify antigens suitable for inclusion in such vaccines. The selected antigens must have the capacity to induce protective immune responses in the vaccinated population. Thus, knowledge of the mechanisms and antigens involved in eliciting protective immunity in donors naturally exposed and immune to P.falciparum is required. In this thesis P.falciparum malaria induced human immune responses have been studied in two ways.

    First, by immortalizing B-cells from malaria exposed and immune donors, in vitro cell lines continuously producing human monoclonal antibodies (HuMAbs) were established to obtain reagents for studying antigens relevant for induction of protective immunity. The asexual erythrocytic stages of the parasite cycle are the cause of the clinical manifestations seen in malaria and the studies were focused on antigens expressed during these stages. Two different antigens detected by HuMAbs are described in more detail. Both are present on all erythrocytic parasite stages and also associated with the membrane of the infected host cell, but at different maturation stages of the parasite. Chemical analysis revealed that one of the HuMAbs (33G2) recognized a family of cross reactive protein antigens, while the other (A52A6) detected a lipid antigen with a complex structure. Results from immunofluorescence microscopy suggested an involvement of this latter antigen in the parasite invasion into the host eryhrocytic cell and both antibodies were efficient inhibitors of this process in in vitro cultures of P.falciparum.

    Taken together, the properties of these HuMAbs obtained from a naturally exposed and immune donor, suggest that they may be important in vivo and thus should be useful tools for understanding the mechanisms of parasite host cell invasion as well as reagents for antigenic epitopes of potential interest for inclusion in a malaria vaccine.

    Secondly, it was of importance to establish whether a human population will differ in their individual immune responses to malaria antigens, due to their genetic background. Therefore, B- and T-cell immune responses against defined epitopes of Pfl55/RESA, an antigen generally considered to be a good vaccine candidate, were investigated in P.falciparum exposed related donors (i.e. monozygotic twinpairs, dizygotic twin pairs and siblings) and unrelated controls. The results revealed a clear genetic regulation of these responses.

    The measured immune responses are dependent on the activation of T-cells of the "helper" subtype, which must recognize antigen in the context of MHC class II molecules. Thus, MHC class II molecules function as restriction elements and it was of importance to investigate if the individual immune responses were restricted by certain class MHC class II haplotypes. However, no such correlations were found, neither when unrelated nor when related donors were studied.

    It was concluded that although the immune responses against Pfl55/RESA were genetically regulated, it was not possible to correlate them to any MHC class II products, suggesting that other non-MHC linked genetic factors were involved.

  • 97.
    Sjögren, Y M
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Jenmalm, M C
    Böttcher, M F
    Björkstén, B
    Sverremark-Ekström, Eva
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Altered early infant gut microbiota in children developing allergy up to 5 years of age.2009In: Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology, ISSN 1365-2222, Vol. 39, no 4, p. 518-526Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Early colonization with bifidobacteria and lactobacilli is postulated to protect children from allergy, while Clostridium (C.) difficile colonization might be associated with allergic disease. Previous studies of infant gut microbiota in relation to subsequent allergy development have mostly employed culture-dependent techniques, studied genera of bacteria and the follow-up period was limited to 2 years. OBJECTIVE: To relate gut microbiota in early infancy, notably bifidobacteria and lactobacilli at species level, to allergy development during the first 5 years of life and study if environmental factors influence the early infant gut microbiota. METHODS: Fecal samples were collected at 1 week, 1 month and 2 months after birth from 47 Swedish infants, followed prospectively to 5 years of age. Bacterial DNA was analysed with real-time PCR and related to allergy development, family size as well as endotoxin and Fel d 1 levels in house dust samples. Primers binding to C. difficile, four species of bifidobacteria, two lactobacilli groups and Bacteroides fragilis were used. Children regarded as allergic manifested allergic symptoms and were skin prick test positive during their first 5 years while non-allergic children were neither. RESULTS: Children who developed allergy were significantly less often colonized with lactobacilli group I (Lactobacillus (L.) rhamnosus, L. casei, L. paracasei), Bifidobacterium adolescentis and C. difficile during their first 2 months. Infants colonized with several Bifidobacterium species had been exposed to higher amounts of endotoxin and grew up in larger families than infants harbouring few species. CONCLUSION: A more diverse gut microbiota early in life might prevent allergy development and may be related to the previously suggested inverse relationship between allergy, family size and endotoxin exposure.

  • 98.
    Sjölander, Anders
    Stockholm University, Faculty of Science, The Wenner-Gren Institute, Immunology.
    Design, production and characterization of synthetic immunogens: application on Plasmodium falciparum malaria antigens1991Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The development of synthetic subunit vaccines is presently one of the major strategies to construct vaccines against infectious diseases. Such vaccines are based on isolated and characterized immunogens and should include appropriate B- and T-cell epitopes. The construction of synthetic vaccines is dependent on the accessibility of techniques for efficient production of the immunogens and the possibility to combine several immunogens and safe and potent adjuvant/ delivery systems in the same vaccine formulation. The present thesis describes methods for the design, production and immunological characterization of immunogens based on the Plasmodium falciparum malaria blood stage antigens Pf 155/RES A and Clustered-Asparagine- Rich-Protein (CARP).

    Genetic fusion systems based on the IgG-binding domains of staphylococcal protein A and the serum albumin binding region of streptococcal protein G were developed for the polymerization, assembly and expression of genes encoding epitope-carrying peptides and the subsequent affinity purification of the produced fusion proteins by a one-step procedure. Immunogens produced in this way were immunogenic in various animal models after administration in Freund's adjuvant and induced antibodies which reacted with the malaria sequence used for immunization as well as with the corresponding intact protein. Furthermore, these antibodies were efficient inhibitors of merozoite invasion of erythrocytes in vitro. The antibody responses were sustained over long time periods, could be efficiently boosted and were specific for Pfl55/RESA as well as the sequence used for immunization.

    Since Freund's adjuvant is not suitable for use in humans, the immunopotentiating capacity of several other adjuvant/delivery systems was investigated. Of these, only immunostimulating complexes (ISCOMs) induced antibody levels comparable to those obtained with Freund's adjuvant. ISCOMs are spherical particles composed by the glycoside adjuvant Quil A, cholesterol and phospholipids in which antigens are presented in a multimeric form. ISCOM-based immunogens were prepared by direct incorporation or by conjugation of fusion proteins to pre-formed influenza vims ISCOMs. Immunization with ISCOMs prepared in this way resulted in strong antibody responses to all polypeptide components of the particles and these antibodies recognized the corresponding intact proteins. The antibody responses induced by the ISCOMs were efficiently boosted, indicating the induction of immunological memory including memory specific for the malariaderived sequences. The efficient boosting of the antibody responses to the malaria sequences suggests that possible competitive or suppressive effects of the additional components of the ISCOM preparations in general were weak or absent. Taken together, these results imply that incorporation or conjugation of fusion proteins to ISCOMs may form a suitable basis for the construction of multivalent synthetic subunit vaccines.

    The immunogenicity in inbred mice of synthetic immunogens has been shown to be influenced by genetic restriction. Strong B- and T-cell responses in mice to fusion proteins containing large numbers of Pf 155/RES A repeat sequences were linked to expression of the MHC class II I-Ak allele. While a certain cross-reactivity between the different Pf 155/RES A repeat sequences was demonstrated for the T-cells that were stimulated by the fusion proteins, the corresponding antibody responses were specific for the repeat sequences used for immunization. These results indicate that the T-cells which were induced by immunization with the different fusion proteins and the corresponding B-cells had separate major specificities.

  • 99.
    Sohlberg, Ebba
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Innate immune responses in cord blood,and the influence of pathological pregnancy2011Licentiate thesis, comprehensive summary (Other academic)
  • 100.
    Sohlberg, Ebba
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute, Immunology.
    Saghafian-Hedengren, Shanie
    Stockholm University, Faculty of Science, The Wenner-Gren Institute, Immunology.
    Bremme, Katarina
    Sverremark-Ekström, Eva
    Stockholm University, Faculty of Science, The Wenner-Gren Institute, Immunology.
    Cord blood monocyte subsets are similar to adult and show potent peptidoglycan-stimulated cytokine responses2011In: Immunology, ISSN 0019-2805, E-ISSN 1365-2567, Vol. 133, no 1, p. 41-50Article in journal (Refereed)
    Abstract [en]

    P>Human monocytes can be divided into two major subpopulations, CD14++ CD16- and CD14+ CD16+ cells, which are suggested to play different roles in antimicrobial responses. In neonates, characteristics and functional responses of monocyte subsets have not previously been explored, and might contribute to the qualitative difference between neonatal and adult cytokine profiles. We report that at baseline, monocyte subsets in cord blood and adult peripheral blood are present in similar frequencies, and show similar expression of CD11c, CD80/CD86, CD163 and HLA-DR. In response to the bacterial ligand peptidoglycan, cord blood monocytes had high inherent capacity for production of the early-response cytokines with levels of tumour necrosis factor and interleukin-12p70 exceeding adult levels, and also a higher phosphorylation of p38-mitogen-activated protein kinase. The CD14+ CD16+ cells expressed more interleukin-12p70 than CD14++ CD16- cells and were present in a higher frequency in peptidoglycan-stimulated cord blood mononuclear cell cultures. Together, the behaviour of cord blood CD14+ CD16+ cells following peptidoglycan stimulation might indicate a qualitative difference between the neonatal antimicrobial response and that of the adult. In addition we found that serum factors in cord blood and adult sera affected cytokine production similarly, with the exception of tumour necrosis factor, regardless of the source of serum or cells. Overall, our data provide new insights into monocyte heterogeneity in cord blood and monocyte subset responses to a bacterial ligand at birth.

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