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  • 1.
    Abu Bakar, Siddique
    Stockholm University.
    Immunological and functional properties of a non-repeat region in Plasmodium falciparum antigen Pf155/RESA1998Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Plasmodium falciparum malaria is one of the most prevalent of all the great insect-borne diseases causing high morbidity and mortality in humans. As conventional anti-malarial treatment is becoming increasingly inefficient, alternative approaches to combat the parasite, like vaccine development, are of high priority. Among other antigens, Pf155/RESA has been taken into consideration for inclusion in a vaccine against the asexual blood stages of P. falciparum. Repeat sequences of this antigen induce neutralizing antibodies and are potentially involved in protective immune responses. However, the genetic restriction in the immune responses to these epitopes has made it of importance to define additional regions in this antigen which may be suitable for inclusion in a vaccine. The present studies were aimed at investigating potential immunodominant B- and T-cell epitopes in the non-repeat regions of Pf155/RESA suitable for inclusion in subunit vaccine immunogens.

    In order to define immunodominant B- and T-cell epitopes, short overlapping peptides were synthesized, corresponding to three different non-repeat sequences of Pf155/RESA. Sera collected from malaria endemic countries recognized pepetides representing N-terminal sequences of the antigen. Based on high antibody reactivity in ELISA, two peptides were selected for affinity purification of antibodies from Liberian sera. The purified antibodies were shown to be efficient in parasite growth inhibition in vitro. Furthermore, the peptides had the ability to stimulate peripheral blood mononuclear cells from P. falciparum-immune donors to proliferate and to secrete IL-4 and/or IFN-g. Although the frequency of responders was high, the magnitude of the responses was generally low.

    Antibodies were raised in rabbits against synthetic peptides corresponding to different non-repeat sequences in Pf155/RESA. Although all antisera reacted strongly with the corresponding peptide, they reacted only weakly with full-length Pf155/RESA. Antibodies to some of the non-repeat sequences inhibited merozoite invasion in vitro, notably, also the invasion of parasites deficient in Pf155/RESA, indicating the presence of an antigen highly homologous to Pf155/RESA.

    Upon infection with P. falciparum, erythrocytes expose cryptic determinants in band 3, which are thought to mediate cytoadherence to endothelial cells. The N-terminal non-repeat region of Pf155/RESA contains a hexapeptide motif which is highly homologous to the cytoadherence related sequences of erythrocyte band 3. Synthetic peptides containing this hexapeptide motif inhibited the binding of P. falciparum-infected erythrocytes to melanoma cells in vitro. Antibodies raised against the largely overlapping sequences displayed highly different specificity patterns. Antibodies to the cytoadherence related motif of Pf155/RESA as well as antibodies raised against the peptides corresponding to the band 3 motif inhibited cytoadherence but not parasite growth. In contrast antibodies to sequences adjacent to the Pf155/RESA cytoadherence motif inhibited parasite growth in vitro but had no effect on cytoadherence.

    In summary, although the target antigens for the anti-parasitic activities displayed by the antibodies in these studies are unclear, sequences in non-repeat regions of Pf155/RESA may induce antibodies with capacity to inhibit parasite growth in vitro or to block the cytoadherence of P. falciparum infected erythrocytes to endothelial cells. The combination of non-repeat sequences with repeat sequences of Pf155/RESA in a subunit vaccine may provide immunogens with an improved capacity to induce parasite neutralizing antibody responses.

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

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

  • 3.
    Ahlborg, Niklas
    Stockholm University, Faculty of Science, The Wenner-Gren Institute, Immunology.
    Immune responses to repeat sequences of the Plasmodium falciparum malaria antigen Pf3321995Doctoral thesis, comprehensive summary (Other academic)
  • 4. Albrecht, Daniel S.
    et al.
    Forsberg, Anton
    Sandstrom, Angelica
    Bergan, Courtney
    Kadetoff, Diana
    Protsenko, Ekaterina
    Lampa, Jon
    Lee, Yvonne C.
    Hoglund, Caroline Olgart
    Catana, Ciprian
    Cervenka, Simon
    Akeju, Oluwaseun
    Lekander, Mats
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska Institutet, Sweden; Karolinska University Hospital, Sweden.
    Cohen, George
    Halldin, Christer
    Taylor, Norman
    Kim, Minhae
    Hooker, Jacob M.
    Edwards, Robert R.
    Napadow, Vitaly
    Kosek, Eva
    Loggia, Marco L.
    Brain glial activation in fibromyalgia - A multi-site positron emission tomography investigation2019In: Brain, behavior, and immunity, ISSN 0889-1591, E-ISSN 1090-2139, Vol. 75, p. 72-83Article in journal (Refereed)
    Abstract [en]

    Fibromyalgia (FM) is a poorly understood chronic condition characterized by widespread musculoskeletal pain, fatigue, and cognitive difficulties. While mounting evidence suggests a role for neuroinflammation, no study has directly provided evidence of brain glial activation in FM. In this study, we conducted a Positron Emission Tomography (PET) study using [C-11]PBR28, which binds to the translocator protein (TSPO), a protein upregulated in activated microglia and astrocytes. To enhance statistical power and generalizability, we combined datasets collected independently at two separate institutions (Massachusetts General Hospital [MGH] and Karolinska Institutet [KI]). In an attempt to disentangle the contributions of different glial cell types to FM, a smaller sample was scanned at KI with [C-11]-L-deprenyl-D2 PET, thought to primarily reflect astrocytic (but not microglial) signal. Thirty-one FM patients and 27 healthy controls (HC) were examined using [C-11]PBR28 PET. 11 FM patients and 11 HC were scanned using [C-11]-L-deprenyl-D2 PET. Standardized uptake values normalized by occipital cortex signal (SUVR) and distribution volume (V-T) were computed from the [C-11]PBR28 data. [C-11]-L-deprenyl-D2 was quantified using lambda k(3). PET imaging metrics were compared across groups, and when differing across groups, against clinical variables. Compared to HC, FM patients demonstrated widespread cortical elevations, and no decreases, in [C-11]PBR28 ITT and SUVR, most pronounced in the medial and lateral walls of the frontal and parietal lobes. No regions showed significant group differences in [C-11]-L-deprenyl-Ds signal, including those demonstrating elevated [C-11] PBR28 signal in patients (p's >= 0.53, uncorrected). The elevations in [C-11]PBR28 V-T and SUVR were correlated both spatially (i.e., were observed in overlapping regions) and, in several areas, also in terms of magnitude. In exploratory, uncorrected analyses, higher subjective ratings of fatigue in FM patients were associated with higher [C-11] PBR28 SUVR in the anterior and posterior middle cingulate cortices (p's < 0.03). SUVR was not significantly associated with any other clinical variable. Our work provides the first in vivo evidence supporting a role for glial activation in FM pathophysiology. Given that the elevations in [C-11]PBR28 signal were not also accompanied by increased [C-11]-deprenyl-D2 signal, our data suggests that microglia, but not astrocytes, may be driving the TSPO elevation in these regions. Although [C-11]-L-deprenyl-D2 signal was not found to be increased in FM patients, larger studies are needed to further assess the role of possible astrocytic contributions in FM. Overall, our data support glial modulation as a potential therapeutic strategy for FM.

  • 5.
    Ali, Magdi Mahmoud
    Stockholm University, Faculty of Science, Wenner-Gren Institute for Experimental Biology.
    Immunologic aspects of the pathogenesis of human onchocerciasis2006Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Onchocerciasis, or river blindness, is a parasitic disease that affects more than 20 million people globally. The induction of pathology is directly related to the presence and destruction of the microfilarial stages (mf) of this filarial nematode. The disease presents clinically with a wide spectrum of dermal and ocular manifestations, the basis of the variation is believed to involve the immune system. The clinical presentations of infected hosts relate to the intensity of the reactions against the parasite. Anti-microfilarial drugs are also thought to somehow involve the immune system in their pharmacological action. In this study we have investigated some of the factors that might contribute to the pathogenesis, with the aim of gaining a better understanding of the role of immune response in these host inflammatory reactions to Onchocerca volvulus parasite. In the first study we have highlighted the clinically most severe form of dermal onchocerciasis, known as reactive onchocercal dermatitis (ROD), one that is often ignored and has not been properly identified. This form has special characteristics and important biological information that could greatly assist the general understanding of the disease as a whole. Amongst the three major foci of the disease in the study country, Sudan, the prevalence of ROD was found to be associated with different environmental and epidemiological characteristics; strikingly higher in the hypo-endemic areas. Including ROD cases in the prevalence will upgrade the level of endemicity of a locality, and often bring patients much in need of treatment into mass treatment programs that currently only treat localities with medium to high levels of endemicity. In the following research studies, we tried to address the immunological characteristics of the clinically different onchocerciasis patients. Then we also investigated the role of genetic polymorphism in the gene encoding receptor that links innate and adaptive immunity, namely, FcγRIIa.

    Patients with either of two major forms of the clinical spectrum-mild and severe dermatopathology were studied by assaying the antigen-driven proliferation of peripheral blood mononuclear cells and the ability of patients’ serum antibodies to promote cytoadherence activity to mf in vitro. Immune responses of those with severe skin disease were found to be stronger compared with the mild dermatopathology group. Mectizan® treatment was followed by an increase in immune responsiveness in those with initially poor responses. Thus the degree of dermatopathology is related to the host’s immune response against mf and immunocompetence may be necessary for Mectizan® to clear the infection efficiently.

    The infection has also been associated with increased levels of circulating immune complexes (CIC) containing parasite antigens and a cytokine response that involves both pro-and anti-inflammatory cytokines. Our fourth paper investigated the effect of IC from the O. volvulus infected patients on the production of pro-and anti-inflammatory cytokines. CIC were increased in all patients studied. The precipitate from plasma treated with polyethylene glycol (PEG) were added to peripheral blood mononuclear cell (PBMC) cultures, and the levels of IL-10, tumor necrosis factor TNF-α, IL-1β and their endogenous antagonists soluble TNF-Rp75 and IL-1-receptor antagonist (IL-1ra) were measured. A significant induction of all cytokines measured occurred in the onchocerciasis patients compared to healthy controls. However, the IL-1ra level was suppressed. The suppression of the production of IL-1ra suggests that the IC containing antigens may have a selectively suppressive effect on the production of this anti-inflammatory cytokine; thus implicating its possible role in counteracting inflammatory responses associated with the disease, and suggesting a potential therapeutic significance.

    FcgRIIa receptors are involved in many important biological responses, and considered as important mediators of inflammation. A polymorphism in the gene encoding this receptor, that is either arginine (R) or histidine (H) at position 131, affects the binding to the different IgG subclasses. We therefore hypothesized that this polymorphism might be one of the underlying mechanisms to the varied clinical presentations seen in this disease. FcgRIIa genotyping was carried out by gene specific polymerase chain reaction (PCR) and allele-specific restriction enzyme digestion of DNA from clinically characterized patients. The genotype R/R frequencies were found to be significantly higher among patients with the severe form of the disease (including ROD), and it was particularly associated with one tribe (Masaleet) compared to Fulani. Moreover, the H allele was found to be associated with lower risk of developing the severe form. As no significant difference was seen between onchocerciasis cases and controls, the study also implies that this polymorphism influences protection from developing the severe form rather than being related to protection from the infection.

  • 6.
    Amoudruz, Petra
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Maternal immune characteristics and innate immune responses in the child in relation to allergic disease2008Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The mechanistic factors responsible for the increase in allergic diseases are still not fully understood, but a reduced microbial stimulation seems to be one of the key issues. Research is now aiming at investigating the relationship between the innate immune system, involving the toll-like receptors, and allergy development. Further, the maternal influence on the child, possibly through in utero effects, but also through the breast milk, has shown to be of great importance. This thesis aimed at understanding how the maternal immune system is influenced by early exposures and allergic disease, but also to investigate the consequences of the maternal phenotype on the innate immune system of the developing child.

    The Th1/Th2 cytokine pattern in allergic diseases has been extensively studied. Here we were interested in comparing the innate cytokines in allergic and non-allergic women, and to see if the allergic status was influencing the effect of pregnancy differently. We demonstrate that IL-1β, IL-6, IL-10 and IL-12 production in cells from adult women are not influenced by allergic status, neither during pregnancy nor 2 years after. However, pregnancy had an apparent effect on cytokine levels, regardless of allergic status. Also, total IgE levels in allergic women were significantly lower 2 years after pregnancy in comparison with the levels during pregnancy, pointing to the fact that pregnancy indeed has an immunomodulatory role.

    We further wanted to investigate the immune system of mothers who had migrated to Sweden in comparison with indigenous mothers. The reason for our interest here was that children born from immigrated mothers have shown to have an increased risk of developing diseases such as allergy and Crohn’s disease. The results showed that immigrants from a developing country had significantly higher levels of breast milk IL-6, IL-8 and TGF-β1. Further, regardless of maternal country of birth, a larger number of previous pregnancies was associated with down-regulation of several substances, statistically significant for soluble CD14 and IL-8. The results suggest that maternal country of birth may indeed influence adult immune characteristics, potentially relevant to disease risk in offspring.

    The influence of allergic status of the mother on the expression of CD14, TLR2 and TLR4 was further investigated in monocytes from mothers and their newborn babies upon microbial stimulation. We could not find any differences in monocytic TLR levels between the groups. No significant differences regarding cytokine levels between allergic and non-allergic mothers in response to stimuli were found either. However, the cytokine and chemokine release triggered by TLR2 stimulation in CB revealed that CBMC from children with maternal allergic disease released significantly less IL-6, and a trend towards less IL-8.

    As we could not find differences in TLR levels attributed to maternal allergy, but an impaired IL-6 response, we turned our focus on an intracellular event taking place after TLR ligation. The results confirmed our results of decreased IL-6 levels in CB from children to allergic mothers. At 2 years of age, the children of allergic mothers still displayed a diminished IL-6 response. Additionally, they also had a decreased activity of p38 MAPK. p38 has an important role in driving Th1 responses, suggesting that the p38 pathway could be one of the responsible mechanisms behind the impaired responses correlated to allergic heredity found in CB as well as at 2 years of age.

    Infancy is a crucial time period for the developing immune system. Further, the relative composition of the two major monocytic subsets CD14++CD16- and CD14+CD16+ is altered in some allergic diseases. TLR levels are different in the two subsets, proposing a possible link to the reduced responding capacity of monocytes from children with allergic heredity. We followed up our earlier studies of children at birth and at 2 years of age by looking at 5 year old children. There were no differences regarding monocytic subsets, nor in TLR levels in unstimulated cells. However, when stimulating the cells with PGN, both monocytic subsets in allergic subjects were less capable of upregulating TLR2 compared to the age-matched controls.

    Taken together, the work in this thesis suggests that the maternal immune system is affected by the process of pregnancy and childhood exposures. It further suggests that maternal allergy affects the young child, in terms of impaired responses to microbial stimuli, which later in infancy correlates with allergic disease in the child. These impaired innate responses could lead to a diminished Th1 response, or alternatively to a deficiency in regulatory mechanisms, and thereby cause allergic disease.

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

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

  • 8. Anchang-Kimbi, Judith K.
    et al.
    Achidi, Eric Akum
    Nkegoum, Blaise
    Mendimi, Joseph-Marie N.
    Sverremark-Ekström, Eva
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Troye-Blomberg, Marita
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    IgG isotypic antibodies to crude Plasmodium falciparum blood-stage antigen associated with placental malaria infection in parturient Cameroonian women2016In: African Health Sciences, ISSN 1680-6905, E-ISSN 1729-0503, Vol. 16, no 4, p. 1007-1017Article in journal (Refereed)
    Abstract [en]

    Background: Few studies have reported an association between placental malaria (PM) infection and levels of isotypic antibodies against non-pregnancy associated antigens. Objective: To determine and evaluate IgG isotypic antibody levels to crude P. falciparum blood stage in women with and without PM infection. Methods: Levels of IgG (IgG1-IgG4) and IgM to crude P. falciparum blood stage antigen were measured by ELISA in 271 parturient women. Placental malaria infection was determined by placental blood microscopy and placental histology. Age, parity and intermittent preventive treatment during pregnancy with sulphadoxine-pyrimethamine (IPTp-SP) usage were considered during analysis. Results: P. falciparum-specific IgG1 (96.5%) and IgG3 (96.7%) antibodies were predominant compared with IgG2 (64.6%) and IgG4 (49.1%). Active PM infection was associated with significant increased levels of IgG1, IgG4 and IgM while lower levels of these antibodies were associated with uptake of two or more IPTp-SP doses. PM infection was the only independent factor associated with IgG4 levels. Mean IgG1 + IgG3/IgG2 + IgG4 and IgG1 + IgG2 + IgG3/IgG4 ratios were higher among the PM-uninfected group while IgG4/IgG2 ratio prevailed in the infected group. Conclusion: PM infection and IPTp-SP dosage influenced P. falciparum-specific isotypic antibody responses to blood stage antigens. An increase in IgG4 levels in response to PM infection is of particular interest.

  • 9.
    Andersson, Gudrun
    Stockholm University, Faculty of Science, The Wenner-Gren Institute, Immunology.
    Monoclonal antibodies to human interferon-α and interferon-γ: Characterization and application with focus on interferon-γ as a T cell cytokine1992Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The major functions of the immune system are to combat infections and to control that normal auto-immunity does not turn into auto-aggression. Antibodies, together with T cell receptors and MHC molecules, dictates the immunological specificity. However, soluble factors (like cytokines and enzymes) and interactions between leucocytes and endothelium (via adhesion molecules) are decisive for the qualitative and quantitative nature of the immune response to a provocation.

    The aims of this study were to establish and characterize mouse monoclonal antibodies (mAbs) to the human cytokines interferon alpha (IFNa) and interferon gamma (IFNy), to develop and evaluate the applicability of immunoassays based on these mAbs, and to study T cell secretion of IFNy in response to antigen and in extracellular matrix interactions in vitro.

    Reactivity of the established mAbs with their respective natural antigen was ascertained and mAbs binding to distinct epitopes identified. We found individual binding patterns of the mAbs to IFNa variants. These varied if the IFNa subtypes were in solution or bound to different solid supports, underlining the importance of thorough characterization of mAbs. The applicability of the anti-IFNa mAbs in ELISAs and their use for characterization of natural IFNa mixtures was demonstrated.

    Of the mAbs established to IFNy two had suitable characteristics for a sensitive sandwich ELISA, which was also adapted for determinations of IFNy in body fluids as evaluated with serum and plasma. This ELISA combination was also applied in an ELISPOT assay for determination of IFNy secretion on the single cell level. Using the ELISA we could show that IFNy is a quantitative but also qualitative marker for cellular immunity in vitro as evaluated with Francisella tnlarensis as a model antigen (IFNy is required for clearance of this infection). Furthermore, appropriate culture conditions for future studies of IFNy as a marker for immunological memory in short term cultures were defined.

    Using purified human T cells suboptimally activated through the TcR/CD3 complex with immobilized OKT3 we found that co-immobilized fibronectin (Fn) could potentiate their secretion of IFNy as measured in ELISA and on the single cell level with the ELISPOT. This potentiation was inhibited with antibodies to the integrin VLA-5. IFNy has been shown to be an important factor in lymphocyte migration and Fn is an extracellular matrix component and abundant in most tissues.The finding that Fn can augment IFNy secretion may thus provide new insights into the migration dependent effector functions of T cells.

  • 10.
    Arama, Charles
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Novel immunization strategies and interethnic differences in response to malaria infection2012Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    A better understanding of the role of antigen-presenting cells (APCs) in host resistance to malaria is essential to unravel the complex interactions between the host and the parasite. This would improve the design of malaria vaccines.

    Mycobacterium bovis Bacillus Calmette-Guérin (BCG) has been utilized as a vector to deliver vaccine candidate antigens. We assessed the immunogenicity of a recombinant BCG-expressing (BCG-CS) circumsporozoite protein (CSp) as a malaria vaccine candidate. Immunization of BALB/c mice with BCG-CS augmented the numbers of dendritic cells (DCs) in draining lymph nodes and in the spleen. The activation markers MHC-class-II, CD40, CD80, and CD86 on DCs were significantly upregulated by BCG-CS as compared to wild-type BCG (wt-BCG). In vitro stimulation of bone marrow-derived DCs and macrophages with BCG-CS induced IL-12 and TNF-α production. BCG-CS induced higher phagocytic activity in macrophages as compared to wt-BCG. Finally, BCG-CS induced CSp-specific antibodies and IFN-γ-producing memory cells. Taken together, we found that BCG-CS is highly efficient in activating innate immune responses and could effectively prime the adaptive immune system.

    Heterologous prime–boost approaches using vectors are optimal strategies to improve a broad and prolonged immunogenicity of malaria vaccines. We have demonstrated in BALB/c mice that priming with a replication-defective human adenovirus serotype 35 (Ad35) vector encoding CSp (Ad35-CS), followed by boosting with BCG-CS, maintained antibody responses and significantly increased levels of long-lived plasma cells (LLPC) and IFN-g-producing cells in response to CSp peptides. The increased number of IFN-g-producing cells induced by the combination of Ad35-CS/BCG-CS and the sustained type 1 antibody profile, together with high levels of LLPCs, may be essential for the development of long-term protective immunity against liver-stage parasites.

    Fulani and Dogon, two sympatric ethnic groups living in northeastern Mali, are characterized by a marked difference in the susceptibility to P. falciparum malaria. We investigated whether APCs obtained from Fulani and Dogon children exhibited differences in terms of activation status and toll-like receptor (TLR) responses during malaria infection. We observed decreased activation of APCs and markedly suppressed TLR responses in Dogon children as compared to Fulani. These findings suggest that APCs and TLR signaling may be of importance for the protective immunity against malaria observed in the Fulani.

    In conclusion, this thesis provides new insights that could facilitate a rational design of novel vaccines against malaria. Furthermore, the results elicit some immunological bases of the APC activation underlying the differences in host susceptibility to malaria infections.

  • 11.
    Arama, Charles
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Assefaw-Redda, Yohannes
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Rodriguez, Ariane
    Fernández, Carmen
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Corradin, Giampietro
    Kaufmann, Stefan H. E.
    Reece, Stephen T.
    Troye-Blomberg, Marita
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Heterologous prime-boost regimen adenovector 35-circumsporozoite protein vaccine/recombinant Bacillus Calmette-Guerin expressing the Plasmodium falciparum circumsporozoite induces enhanced long-term memory immunity in BALB/c mice2012In: Vaccine, ISSN 0264-410X, E-ISSN 1873-2518, Vol. 30, no 27, p. 4040-4045Article in journal (Refereed)
    Abstract [en]

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

  • 12.
    Arama, Charles
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute, Immunology.
    Waseem, Shahid
    Stockholm University, Faculty of Science, The Wenner-Gren Institute, Immunology.
    Fernández, Carmen
    Stockholm University, Faculty of Science, The Wenner-Gren Institute, Immunology.
    Assefaw-Redda, Yohannes
    Stockholm University, Faculty of Science, The Wenner-Gren Institute, Immunology.
    You, Liya
    Stockholm University, Faculty of Science, The Wenner-Gren Institute, Immunology.
    Rodriguez, Ariane
    Radošević, Katarina
    Goudsmit, Jaap
    Kaufmann, Stefan H E
    Reece, Stephen T
    Troye-Blomberg, Marita
    Stockholm University, Faculty of Science, The Wenner-Gren Institute, Immunology.
    A recombinant Bacille Calmette-Guerin construct expressing the Plasmodium falciparum circumsporozoite protein enhances dendritic cell activation and primes for circumsporozoite-specific memory cells in BALB/c mice2012In: Vaccine, ISSN 0264-410X, E-ISSN 1873-2518, Vol. 30, no 37, p. 5578-5584Article in journal (Refereed)
    Abstract [en]

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

  • 13.
    Arefin, Badrul
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Kucerova, Lucie
    Dobes, Pavel
    Márkus, Róbert
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Strnad, Hynek
    Wang, Zhi
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Hyrsl, Pavel
    Zurovec, Michal
    Theopold, Ulrich
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Genome-Wide Transcriptional Analysis of Drosophila Larvae Infected by Entomopathogenic Nematodes Shows Involvement of Complement, Recognition and Extracellular Matrix Proteins2014In: Journal of Innate Immunity, ISSN 1662-811X, E-ISSN 1662-8128, Vol. 6, no 2, p. 192-204Article in journal (Refereed)
    Abstract [en]

    Heterorhabditis bacteriophora is an entomopathogenic nematode (EPN) which infects its host by accessing the hemolymph where it releases endosymbiotic bacteria of the species Photorhabdus luminescens. We performed a genome-wide transcriptional analysis of the Drosophila response to EPN infection at the time point at which the nematodes reached the hemolymph either via the cuticle or the gut and the bacteria had started to multiply. Many of the most strongly induced genes have been implicated in immune responses in other infection models. Mapping of the complete set of differentially regulated genes showed the hallmarks of a wound response, but also identified a large fraction of EPN-specific transcripts. Several genes identified by transcriptome profiling or their homologues play protective roles during nematode infections. Genes that positively contribute to controlling nematobacterial infections encode: a homolog of thioester-containing complement protein 3, a basement membrane component (glutactin), a recognition protein (GNBP-like 3) and possibly several small peptides. Of note is that several of these genes have not previously been implicated in immune responses.

  • 14.
    Arefin, Md. Badrul
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. Stockholm University.
    Molecular characterization of the Drosophila responses towards nematodes2016Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    A sophisticated evolutionary conserved innate immune system has evolved in insects to fight pathogens and to restrict damage in harmful (danger) situations including cancer. A significant amount of knowledge about different infection models in Drosophila has been generated in past decades, which revealed functional resemblances and implications for vertebrate systems. However, how Drosophila responds towards multicellular parasitic nematodes and in danger situations is still little understood. Therefore, the aim of the thesis was to characterize multiple aspects of the host defense in the two important contexts mentioned above.

    We analyzed the transcriptome profiles of nematode-infected Drosophila larvae with uninfected samples. For this we employed the entomopathogenic nematode Heterorhabditis bacteriophora with its symbiont Photorhabdus luminescence to infect Drosophila larvae. We found 642 genes were differentially regulated upon infection. Among them a significant portion belonged to immune categories. Further functional analysis identified a thioester containing protein TEP3, a recognition protein GNBP-like 3, the basement membrane component protein Glutactin and several other small peptides. Upon loss or reduced expression of these genes hosts showed mortality during nematode infections. This study uncovers a novel function for several of the genes in immunity.

    Furthermore, we investigated the cellular response towards nematodes. When we eliminated hemocytes genetically (referred to as hml-apo) in Drosophila, we found hml-apo larvae are resistant to nematodes. Subsequent characterization of hml-apo larvae showed massive lamellocyte differentiation (another blood cell type which is rare in naïve larvae), emergence of melanotic masses, up- and down-regulation of Toll and Imd signaling respectively suggesting a pro-inflammatory response. Moreover, a striking defective leg phenotype in adult escapers from pupal lethality was observed. We identified nitric oxide (NO) as a key regulator of these processes. We also showed that imaginal disc growth factors 3 (IDGF3): (a) protects hosts against nematodes, (b) is a clotting component and (c) negatively regulates Wnt and JAK/STAT signaling. To follow larval behavior in the presence or absence of nematodes we monitored Drosophila larval locomotion behaviors using FIMtrack (a recently devised automated method) to elucidate evasive strategies of hosts. Finally, we characterized host defenses in three Drosophila leukemia models with and without nematode infection. Taken together, these studies shed light on host responses in two crucial circumstances, nematode infections and danger situations.

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

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

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

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

  • 17.
    Arko-Mensah, John
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Rahman, Muhammad J
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Dégano, Irene R
    Chuquimia, Olga D
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Fotio, Agathe L
    Garcia, Irene
    Fernández, Carmen
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Resistance to mycobacterial infection: a pattern of early immune responses leads to a better control of pulmonary infection in C57BL/6 compared with BALB/c mice.2009In: Vaccine, ISSN 0264-410X, E-ISSN 1873-2518, Vol. 27, no 52, p. 7418-27Article in journal (Refereed)
    Abstract [en]

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

  • 18.
    Awah, Nancy
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Malarial anaemia: the potential involvement of Plasmodium falciparum rhoptry proteins2009Licentiate thesis, comprehensive summary (Other academic)
    Abstract [en]

    Malaria remains a challenging health problem in malaria endemic regions. Infection with malaria invariably leads to anaemia. The groups at risk of developing malarial anaemia include children below the age of five years and pregnant women, especially primigravidae. Several factors have been suggested to be responsible for its aetiology, including increased destruction of infected and normal red blood cells together with bone marrow suppression. However, until recently, the molecular mechanisms involved have remained elusive. The aim of the work presented herein was to investigate the mechanisms responsible for the destruction of normal red blood cells in anaemia, and more specifically to define the role of the ring surface protein (RSP/RAP) -2 and other members of the low molecular weight rhoptry associated protein (RAP) complex, RAP-1 and -3.

    In the first study we showed that antibodies to the RAP complex could mediate the destruction of RSP-2 tagged erythroid cells by phagocytosis or by complement activation and then lysis. In addition, antibodies to RAP-1 and RAP-2 could induce the death of RSP-2/RAP-2 tagged erythroblasts. We further investigated the frequency and functionality of naturally occurring RSP-2/RAP-2 antibodies in the sera of anaemic and non-anaemic Cameroonian children. We found that all sera investigated contained RSP-2/RAP-2 reactive antibodies by both immunoflorescence and flow cytometry. The anaemic group of children had significantly higher levels of antibodies of the IgG isotype than the non-anaemic individuals, while the levels of IgM were similar in both groups. With respect to IgG subclasses, low levels of IgG1 and -3 antibodies were detected. Higher levels of IgG3 were seen in the non-anaemic individuals as compared to anaemic subjects. With regards to antibody functionality, the non-anaemic individuals recognised a greater proportion of RSP-2/RAP-2 tagged erythrocytes and activated complement to a greater extent than the anaemic individuals.

    From our findings, we can conclude that antibodies to the RAP complex are potentially involved in erythroid cell destruction during malaria which may result in anaemia, and that high levels of such antibodies may be detrimental to the host.

  • 19.
    Awah, Nancy W.
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Troye-Blomberg, Marita
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Berzins, Klavs
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Gysin, Jürg
    Unité de Parasitologie Expérimentale, URA Institut Pasteur/Univ-Med.
    Mechanisms of malarial anaemia: potential involvement of the Plasmodium falciparum low molecular weight rhoptry-associated proteins.2009In: Acta Tropica, ISSN 0001-706X, E-ISSN 1873-6254, Vol. 112, no 3, p. 295-302Article in journal (Refereed)
    Abstract [en]

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

  • 20.
    Bachmayer, Nora
    Stockholm University, Faculty of Science, Wenner-Gren Institute for Experimental Biology.
    The role of natural killer cells and inflammatory mediators in preeclamptic pregnancies2008Doctoral thesis, monograph (Other academic)
    Abstract [en]

    The maternal immune system must be able to adjust during pregnancy and accept the foetus that expresses paternal antigens. These changes are found both in placenta and circulation, including a mild inflammatory response. NK cells are abundant during the early part of pregnancy in placenta and are thought to be important for placental development. During preeclampsia the placenta is poorly developed, together with an escalated pro-inflammatory profile noticed in both placenta and circulation. We wanted to study NK cells in placenta and circulation from preeclamptic cases as well as levels of cytokines. HMGB1, an alarmin involved in inflammation, was also measured in preeclamptic placentae.

    When studying preeclamptic placentae in third trimester we found higher numbers of NK cells as well as a higher expression of CD94+ NK cells. We also found slightly elevated levels of HMGB1 together with significantly lower expression of IL-12 in preeclamptic placentae. Further, the NK cell activating cytokines IL-12/IL-23p40 and IL-15 in sera from preeclamptic women were increased compared to healthy pregnancies. The elevated levels of NK cell activating IL-12/IL-23p40 and IL-15 found in preeclamptic sera, made us investigate the circulating NK cells in preeclampsia. However, no differences were seen between healthy and preeclamptic pregnancies.

    The main immunological alterations in third trimester preeclamptic pregnancies with regard to NK cells were found in placenta. Altered maternal cytokine levels in placenta could influence decidual NK cells in preeclampsia, noticed by their higher numbers and altered receptor expression. If these alterations also exist during early pregnancy it could result in a poorly developed and dysfunctional placenta.

  • 21.
    Balogun, Halima A.
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Vasconcelos, N.-M.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Lindberg, R.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Haeggström, M.
    Moll, K.
    Chen, Q.
    Wahlgren, M.
    Berzins, Klavs
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Immunogenicity and antigenic properties of Pf332-C231, a fragment of a non-repeat region of the Plasmodium falciparum antigen Pf332 2009In: Vaccine, ISSN 0264-410X, E-ISSN 1873-2518, Vol. 28, no 1, p. 90-97Article in journal (Refereed)
    Abstract [en]

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

  • 22.
    Balogun, Halima Aramide
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Immunological characteristics of a C-terminal fragment of the Plasmodium falciparum blood-stage antigen Pf3322006Licentiate thesis, monograph (Other academic)
    Abstract [en]

    Till date, there are no effective control strategies against the deadly disease of malaria, and millions of children across Africa, Oceania, Asia, and Latin America are at the mercy of this long term enemy of man every second that passes by. Other control measures combined with vaccination might help improve control strategy against malaria, but the development of vaccines face various challenges as well, due to the complexity of the parasites’ life cycle and other host factors. The asexual blood stage antigen Pf332 of Plasmodium falciparum, is expressed during the trophozoite stage, and transported from the parasitophorous membrane to the outer erythrocyte membrane during schizogony.

    Previous studies have suggested this antigen as a potential vaccine candidate, because Pf332-reactive human monoclonal antibody (mAb 33G2) inhibits parasite growth and cytoadherence in vitro. Elucidating and understanding the immunological capabilities of antigen Pf332, as a vaccine candidate was the aim of the studies presented in this thesis.

    In our first study we identified and characterized the immunogenicity of a non-repeat fragment of antigen Pf332, termed Pf332-C231, a 231 amino acids long fragment corresponding to 13 percent of the total protein. Various analyses carried out with this fragment reveal that recombinant C231 was immunogenic in rabbits. In addition, anti- C231 antibodies have in vitro inhibitory capabilities. In immunoflourescence and immunoblot assays, rabbit anti-C231 antibodies were able to recognize the native protein.

    In the other study, we examined the distribution of antibodies regarding recombinant C231 and crude P. falciparum extract in a malaria endemic area of Senegal. IgG antibody reactivity with crude P. falciparum antigen was detected in the sera of all the  donors while many of the children lacked or had low levels of such antibodies against C231. The distribution of the anti-C231 antibodies in the different IgG subclasses differed from that shown by crude P. falciparum antigen. The crude P. falciparum antigen gives a higher IgG3 response than IgG2 for all age-groups, while C231 gave similar levels of IgG2 and IgG3. Correlation studies showed that the levels of anti-C231antibodies were associated with protection from clinical malaria, but this only reached significance with IgE. These findings further emphasize the inclusion of antigen Pf332 as a subunit vaccine candidate against P. falciparum malaria.

  • 23.
    Balogun, Halima
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Awah, Nancy
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Farouk, S.
    Berzins, Klavs
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Pf332-C231- reactive antibodies affect growth and development of intraerythrocytic Plasmodium falciparum parasitesArticle in journal (Refereed)
  • 24.
    Balogun, Halima
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Awah, Nancy
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Nilsson, S.
    Rousillhon, C.
    Rogier, C.
    Trape, J. F.
    Chen, Q.
    Berzins, Klavs
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Pattern of antibodies to the Duffy binding-like domain of Plasmodium falciparum antigen Pf332 in Senegalese individualsManuscript (preprint) (Other academic)
  • 25.
    Bayard, Cecilia
    Stockholm University.
    Purification, characterization and immunological studies of rat urinary proteins causing allergy in humans1999Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Rats are among the most frequently used laboratory animals and allergy to them constitutes a common occupational problem. Approximately 20-30% of the persons engaged in work with laboratory animals acquire symptoms of allergy. These include rhinitis, conjunctivitis, urticaria and sometimes asthma, symptoms which usually develop during the first three years of exposure. The allergic reaction arises from direct contact with rat urine, or from airborne dusts originating from dried animal urine. Rat urine contains a complex mixture of proteins some of which are known to be allergenic, for example a2u-globulin. In urine from fertile male rats a2u-globulin is one of the most abundant proteins.

    The primary aim of this thesis was to purify and identify the most potent allergens in rat urine. Optimization of various methods for evaluation of the allergenicity of the identified allergens was the second aim. The third aim was to examine in some detail the IgE binding regions of the major allergen, Rat n 1.02, a2u-globulin.

    Rat urinary proteins were separated and purified by ultrafiltration and high resolution chromatographic methods. The two dominating proteins were identified in this study as different forms of the same parent protein, i.e. a2u-globulin. It was also proved that the urinary protein previously named pre-albumin had no amino acid sequence resemblance to prealbumin (transthyretin) present in rat serum.

    Rat urinary proteins separated by SDS-PAGE were used as antigens when IgE antibodies in sera from allergic patients were studied with immunoblotting. A detection system utilizing chemiluminescence and a luminometer apparatus gave scanning curves of the IgE-binding reactivities and allowed arbitrary measurement of the amount of IgE bound to certain urine proteins. Specific immunoblotting patterns of IgE binding to the electrophoretically separated proteins were shown for each individual. Differences were seen in regard of the distribution among the recognized antigens and the amount of IgE bound. All rat allergic subjects studied had IgE antibodies binding to the major urinary protein, a2u-globulin. However, this protein was not always the most dominating allergen.

    Overlapping octapeptides corresponding to the amino acid sequence of the major allergen Rat n 1.02 were synthesized on solid support and screened in parallel to pinpoint the IgE binding regions of the protein using a modified ELISA procedure. Our results indicate the existence of linear IgE-binding epitopes, mainly located towards the N-terminal and C-terminal parts of the protein, as recognized by IgE antibodies in the studied sera. The role of these short amino acid sequences in the allergic reaction and their appropriateness for immunotherapy calls for further investigation.

    In conclusion, this thesis has contributed to the isolation, identification and characterization of the allergens involved in a major occupational disease among people who work with laboratory animals, namely rat allergy.

  • 26. Bemark, Mats
    et al.
    Friskopp, Linda
    Saghafian-Hedengren, Shanie
    Stockholm University, Faculty of Science, The Wenner-Gren Institute, Immunology.
    Koethe, Susanne
    Fasth, Anders
    Abrahamsson, Jonas
    Sverremark-Ekström, Eva
    Stockholm University, Faculty of Science, The Wenner-Gren Institute, Immunology.
    Andersson, Bengt A.
    Mellgren, Karin
    A glycosylation-dependent CD45RB epitope defines previously unacknowledged CD27(-)IgM(high) B cell subpopulations enriched in young children and after hematopoietic stem cell transplantation2013In: Clinical Immunology, ISSN 1521-6616, E-ISSN 1521-7035, Vol. 149, no 3, p. 421-431Article in journal (Refereed)
    Abstract [en]

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

  • 27.
    Björkander, Sofia
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Heidari-Hamedani, Ghazal
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Bremme, K.
    Gunnarsson, I.
    Holmlund, Ulrika
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Peripheral Monocyte Expression of the Chemokine Receptors CCR2, CCR5 and CXCR3 is Altered at Parturition in Healthy Women and in Women with Systemic Lupus Erythematosus2013In: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 77, no 3, p. 200-212Article in journal (Refereed)
    Abstract [en]

    Monocytes are precursors of macrophages and recruited to the uterus throughout pregnancy to perform important immunological functions. In this study, we hypothesized that pregnant women have reduced peripheral monocyte expression of chemokine receptors and alterations in PBMC responses to microbial stimuli as an adaption to pregnancy and that these changes are less pronounced in women with autoimmunity. We therefore investigated the chemokine receptor expression, migratory behaviour and responses to microbial stimulation of peripheral monocytes from pregnant women at parturition (n=13) and from non-pregnant women (n=9). In addition, we compared healthy pregnant women with women suffering from SLE (n=5), a condition with pronounced systemic inflammation increasing the risk for pregnancy complications. We demonstrate that peripheral monocytes are affected by pregnancy with reduced percentages of CCR2+, CCR5+ and CXCR3+ monocytes of both classical (CD16) and inflammatory (CD16+) subsets and that the trophoblast-secreted chemokine CCL2/MCP-1 recruited monocytes of both subsets in vitro. Further, PBMCs from pregnant women had a divergent response to microbial stimulation with lower CCL5/RANTES and higher CCL2/MCP-1 secretion compared with non-pregnant women. In addition, pregnant women had lower basal PBMC-secretion of CCL5/RANTES and higher basal secretion of IL-10 and CCL2/MCP-1. Interestingly, the women with SLE responded similar to pregnancy as did healthy women with lower percentages of CCR2+, CCR5+ and CXCR3+ monocytes. However, they had increased expression of CCR5 on CD16+ monocytes and heightened PBMC-secretion of CCL5/RANTES. In conclusion, our data indicate that monocyte chemokine receptor expression and the chemokine milieu during pregnancy are tightly regulated to support pregnancy.

  • 28. Björkander, Sophia
    Allergy development during the first 10 years of life in a Swedish prospective birth cohort is preceded by a lack of early lactobacilli-colonization and a skewed plasma chemokine-profileManuscript (preprint) (Other academic)
  • 29.
    Björkander, Sophia
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Immune maturation and lymphocyte characteristics in relation to early gut bacteria exposure2016Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    At birth, the immune system is immature and the gut microbiota influences immune maturation. Staphylococcus aureus (S. aureus) and lactobacilli are part of the neonatal gut microbiota and have seemingly opposite effects on the immune system. S. aureus is a potent immune activator and early-life colonization associates with higher immune responsiveness later in life. Lactobacilli-colonization associates with reduced allergy-risk and lower immune responsiveness. Further, lactobacilli modulate immune-activation and have probiotic features.

    Here, we investigated S. aureus-induced activation of human lymphocytes, including T regulatory cells (Tregs), conventional T-cells (CD4+ and CD8+), unconventional T-cells (γδ T-cells and MAIT-cells) and NK-cells from children and adults, together with the modulatory effect of lactobacilli on immune-activation. Further, early-life colonization with these bacteria was related to lymphocyte-maturation, plasma cytokine- and chemokine-levels and allergy. 

    S. aureus cell free supernatant (CFS) and staphylococcal enterotoxin (SE) A induced an increased percentage of FOXP3+ Tregs and of CD161+, IL-10+, IFN-γ+ and IL-17A+ Tregs (Paper I). The same pattern was observed in children with a lower degree of activation, possibly due to lower CD161-expression and poor activation of naive T-cells (Paper II). S. aureus-CFS induced IFN-γ-expression, proliferation and cytotoxic capacity in conventional and unconventional T-cells, and NK-cells. SEA, but not SEH, induced activation of unconventional T-cells and NK-cells by unknown mechanism(s) (Paper III, extended data). Lactobacilli-CFS reduced S. aureus-induced lymphocyte activation without the involvement of IL-10, Tregs or monocytes, but possibly involving lactate (Paper III). Early-life colonization with S. aureus associated with increased percentages of CD161+ and IL-10+ Tregs while lactobacilli-colonization negatively correlated with the percentage of IL-10+ Tregs later in life (Paper II). Allergic disease in childhood associated with double allergic heredity, being born wintertime and with higher plasma levels of TH2-, TH17- and TFH-related chemokines early in life. Lactobacilli-colonization associated with lower prevalence of allergy, reduced chemokine-levels and increased levels of IFN-γ in plasma (Paper IV).   

    This thesis provides novel insights into S. aureus- and SE-mediated activation of Tregs, unconventional T-cells and NK-cells and suggests an overall impairment of immune-responsiveness towards this bacterium in children. Further, S. aureus-colonization may influence the maturation of peripheral Tregs. Our data show that lactobacilli potently dampen lymphocyte-activation in vitro and that colonization associates with Treg-responsiveness, altered plasma cytokine- and chemokine-levels and with remaining non-allergic, thereby supporting the idea of lactobacilli as important immune-modulators.

  • 30.
    Björkander, Sophia
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Johansson, Maria A.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Hell, Lena
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Lasaviciute, Gintare
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Nilsson, Caroline
    Holmlund, Ulrika
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Sverremark-Ekström, Eva
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    FOXP3+ CD4 T-cell maturity and responses to microbial stimulation alter with age and associate with early-life gut colonization2016In: Journal of Allergy and Clinical Immunology, ISSN 0091-6749, E-ISSN 1097-6825, Vol. 138, no 3, p. 905-908Article in journal (Refereed)
  • 31.
    Bolad, A K
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Nebie, I
    Esposito, F
    Berzins, Klavs
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    The use of impregnated curtains does not affect antibody responses against Plasmodium falciparum and complexity of infecting parasite populations in children from Burkina Faso2004In: Acta Tropica, ISSN 0001-706X, E-ISSN 1873-6254, Vol. 90, no 3, p. 237-247Article in journal (Refereed)
    Abstract [en]

    In Burkina Faso, where malaria is hyper-endemic and transmission intensity is very high, the majority of malaria-related morbidity and mortality occurs in children less than 5 years of age. A control measure such as the use of insecticide-treated curtains (ITC) significantly reduces transmission of malaria infection. Concerns remain whether reduced transmission intensity may lead to a delay in the development of immunity in younger children and even to a partial loss of already acquired immunity. In this study, the levels of P. falciparum-specific IgG subclasses, the number of infecting parasite clones determined by PCR-based genotyping of the msp2 gene and the parasite density were analysed in 154 asymptomatic children (3–6 years) living in 16 villages (8 with and 8 without ITC) in the vicinity of Ouagadougou, the capital of Burkina Faso. In addition, the parasite inhibitory effects of Ig fractions, prepared from selected children, in co-operation with normal human monocytes were studied. Blood samples from asymptomatic ITC-users showed a significant decrease in P. falciparum prevalence as well as in parasite density. However, no significant difference was observed in P. falciparum-specific antibodies or in parasite multiplicity of infection between the two groups. Furthermore, Ig fractions from children of both groups showed similar levels of inhibitory activity against autologous parasite growth both on their own and in co-operation with monocytes.

  • 32.
    Boström, Stephanie
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute.
    Giusti, Pablo
    Stockholm University, Faculty of Science, The Wenner-Gren Institute.
    Arama, Charles
    Stockholm University, Faculty of Science, The Wenner-Gren Institute. University of Bamako, Mali.
    Persson, Jan-Olov
    Stockholm University, Faculty of Science, Department of Mathematics.
    Dara, Victor
    Traore, Boubacar
    Dolo, Amagana
    Doumbo, Ogobara
    Troye-Blomberg, Marita
    Stockholm University, Faculty of Science, The Wenner-Gren Institute.
    Changes in the levels of cytokines, chemokines and malaria specific antibodies in response to Plasmodium falciparum infection in children living in sympatry in Mali2012In: Malaria Journal, ISSN 1475-2875, E-ISSN 1475-2875, Vol. 11, p. 109-Article in journal (Refereed)
    Abstract [en]

    Background: The Fulani are known to be less susceptible to Plasmodium falciparum malaria as reflected by lower parasitaemia and fewer clinical symptoms than other sympatric ethnic groups. So far most studies in these groups have been performed on adults, which is why little is known about these responses in children. This study was designed to provide more information on this gap. Methods: Circulating inflammatory factors and antibody levels in children from the Fulani and Dogon ethnic groups were measured. The inflammatory cytokines; interleukin (IL)-1beta, IL-6, IL-8, IL-10, IL-12p70, tumor necrosis factor (TNF) and the chemokines; regulated on activation normal T cell expressed and secreted (RANTES), monokine-induced by IFN-gamma (MIG), monocyte chemotactic protein (MCP)-1 and IFN-gamma-inducible protein (IP)-10 were measured by cytometric bead arrays. The levels of interferon (IFN)-alpha, IFN-gamma and malaria-specific antibodies; immunoglobulin (Ig) G, IgM and IgG subclasses (IgG1-IgG4) were measured by ELISA. Results: The results revealed that the Fulani children had higher levels of all tested cytokines compared to the Dogon, in particular IFN-gamma, a cytokine known to be involved in parasite clearance. Out of all the tested chemokines, only MCP-1 was increased in the Fulani compared to the Dogon. When dividing the children into infected and uninfected individuals, infected Dogon had significantly lower levels of RANTES compared to their uninfected peers, and significantly higher levels of MIG and IP-10 as well as MCP-1, although the latter did not reach statistical significance. In contrast, such patterns were not seen in the infected Fulani children and their chemokine levels remained unchanged upon infection compared to uninfected counterparts. Furthermore, the Fulani also had higher titres of malaria-specific IgG and IgM as well as IgG1-3 subclasses compared to the Dogon. Conclusions: Taken together, this study demonstrates, in accordance with previous work, that Fulani children mount a stronger inflammatory and antibody response against P. falciparum parasites compared to the Dogon and that these differences are evident already at an early age. The inflammatory responses in the Fulani were not influenced by an active infection which could explain why less clinical symptoms are seen in this group.

  • 33.
    Boström, Stéphanie
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Inflammatory responses due to Plasmodium falciparum infection during pregnancy and childhood2012Licentiate thesis, comprehensive summary (Other academic)
  • 34.
    Boström, Stéphanie
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Malaria during pregnancy and childhood: A focus on soluble mediators and neutrophils2014Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    In areas where malaria is endemic, pregnant women and children bear the main burden of severe and life-threatening malarial disease. The aim of this work was to study the impact of Plasmodium falciparum infection on inflammatory responses in pregnant women and children residing in African countries. In paper I we investigated peripheral blood samples from pregnant women, living in Tanzania, for potential biomarkers of P. falciparum infection during pregnancy. We found that IL-10 and IP-10 were potential candidates, which increased upon infection, irrespective of gestational age. In addition, increased IL-10 and IP-10 and decreased RANTES levels were predictive of an infection. In paper II we investigated frequencies of peripheral blood-cell types and biomarkers upon infection, in pregnant women living in Benin, and assessed the predictive values of variables measured at inclusion for pregnancy outcomes at delivery. Higher IL-10 levels distinguished quantitative PCR-detectable, sub-microscopic infections, at inclusion, but not at delivery. Maternal anaemia at delivery was associated with increased numbers of circulating monocytes, Treg cells and IL-10 levels measured at inclusion. In paper III we investigated neutrophil functions in the context of pregnancy malaria in vivo and in vitro. Numbers of circulating neutrophils and IL-8 levels were reduced in the infected women, whilst increased levels of IL-8 were found in placental blood of those infected. In vitro assays suggested migration of neutrophils to infected placentas, which also was supported by histological examinations showing the presence of neutrophils containing hemozoin (Hz), in the infected placenta. Stimulation of neutrophils with various Hz preparations revealed distinct patterns of neutrophil activation. In paper IV we investigated cytokines and malaria-specific antibody titres in children belonging to two African ethnic groups, living in Mali, with known different susceptibility to malaria. The Fulani showed increased cytokines (IL-6, IL-8, IL-12, IFN-α, IFN-γ) and higher titres of malaria-specific antibody subclasses (IgG, IgM and IgG1-IgG3), compared to the Dogon. Taken together, this thesis shows that host biomarkers in peripheral blood may represent useful diagnostic markers for malaria during pregnancy. The neutrophil population was shown to be highly affected by the presence of P. falciparum parasites, suggesting a role for neutrophils during malaria infections. The Fulani, showed increased pro-inflammatory and antibody responses against P. falciparum parasites, as compared to Dogon, and these differences are established already at an early age.  

  • 35.
    Boström, Stéphanie
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Amulic, Borko
    Schmiegelow, Christentze
    Abed, Ulrike
    Minja, Daniel
    Lusingu, John
    Brinkmann, Volker
    Luty, Adrian
    Schwarzer, Evelin
    Troye-Blomberg, Marita
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Neutrophil migration during placental malaria in vivo and in vitro and distinct neutrophil patterns induced by hemozoinManuscript (preprint) (Other academic)
  • 36.
    Boström, Stéphanie
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute.
    Ibitokou, Samad
    Oesterholt, Mayke
    Schmiegelow, Christentze
    Persson, Jan-Olov
    Stockholm University, Faculty of Science, Department of Mathematics.
    Minja, Daniel
    Lusingu, John
    Lemnge, Martha
    Fievet, Nadine
    Deloron, Philippe
    Luty, Adrian J. F.
    Troye-Blomberg, Marita
    Stockholm University, Faculty of Science, The Wenner-Gren Institute.
    Biomarkers of Plasmodium falciparum infection during pregnancy in women living in Northeastern Tanzania2012In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 11, p. e48763-Article in journal (Refereed)
    Abstract [en]

    In pregnant women, Plasmodium falciparum infections are an important cause of maternal morbidity as well as fetal and neonatal mortality. Erythrocytes infected by these malaria-causing parasites accumulate through adhesive interactions in placental intervillous spaces, thus evading detection in peripheral blood smears. Sequestered infected erythrocytes induce inflammation, offering the possibility of detecting inflammatory mediators in peripheral blood that could act as biomarkers of placental infection. In a longitudinal, prospective study in Tanzania, we quantified a range of different cytokines, chemokines and angiogenic factors in peripheral plasma samples, taken on multiple sequential occasions during pregnancy up to and including delivery, from P. falciparum-infected women and matched uninfected controls. The results show that during healthy, uninfected pregnancies the levels of most of the panel of molecules we measured were largely unchanged except at delivery. In women with P. falciparum, however, both comparative and longitudinal assessments consistently showed that the levels of IL-10 and IP-10 increased significantly whilst that of RANTES decreased significantly, regardless of gestational age at the time the infection was detected. ROC curve analysis indicated that a combination of increased IL-10 and IP-10 levels and decreased RANTES levels might be predictive of P. falciparum infections. In conclusion, our data suggest that host biomarkers in peripheral blood may represent useful diagnostic markers of P. falciparum infection during pregnancy, but placental histology results would need to be included to verify these findings.

  • 37.
    Brenden, Nina
    Stockholm University.
    MHCI-E mediated protection from IDDM on NOD mice: The role of regulatory T cells1998Doctoral thesis, comprehensive summary (Other academic)
  • 38. Bråbäck, Lennart
    et al.
    Ekéus, Cecilia
    Lowe, Adrian J
    Hjern, Anders
    Stockholm University, Faculty of Social Sciences, Centre for Health Equity Studies (CHESS).
    Confounding with familial determinants affects the association between mode of delivery and childhood asthma medication - a national cohort study2013In: Allergy, Asthma & Clinical Immunology, ISSN 1710-1484, E-ISSN 1710-1492, Vol. 9, no 14Article in journal (Refereed)
    Abstract [en]

    Background: Mode of delivery may affect the risk of asthma but the findings have not been consistent and factors shared by siblings may confound the associations in previous studies.

    Methods: The association between mode of delivery and dispensed inhaled corticosteroid (ICS) (a marker of asthma) was examined in a register based national cohort (n=199 837). A cohort analysis of all first born children aged 2-5 and 6-9 years was performed. An age-matched sibling-pair analysis was also performed to account for shared genetic and environmental risk factors.

    Results: Analyses of first-borns demonstrated that elective caesarean section was associated with an increased risk of dispensed ICS in both 2-5 (adjusted odds ratio (aOR)=1.19, 95% confidence interval (CI) 1.09-1.29) and 6-9 (aOR=1.21, 1.09-1.34) age groups. In the sibling-pair analysis, the increased risk associated with elective caesarean section was confirmed in 2-5 year olds (aOR=1.22, 1.05-1.43) but not in 6-9 year olds (aOR=1.06, 0.78-1.44). Emergency caesarean section and vacuum extraction had some association with dispensed ICS in the analyses of first-borns but these associations were not confirmed in the sibling-pair analyses.

    Conclusions: Confounding by familial factors affects the association between mode of delivery and dispensed ICS. Despite this confounding, there was some evidence that elective caesarean section contributed to a modestly increased risk of dispensed ICS but only up to five years of age.

  • 39.
    Bujila, Ioana
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Chérif, Mariama
    Sanou, Guillaume S.
    Vafa, Manijeh
    O'Connell, Mary A.
    Ouédraogo, Issa N.
    Lennartsson, Andreas
    Troye-Blomberg, Marita
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Östlund Farrants, Ann-Kristin
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Transcriptome and DNA methylome analysis of two sympatric ethic groups with differential susceptibility to Plasmodium falciparum infection living in Burkina FasoManuscript (preprint) (Other academic)
  • 40.
    Bujila, Ioana
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Rolicka, Anna
    Schwarzer, Evelin
    Skorokhod, Oleksii
    Troye-Blomberg, Marita
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Östlund Farrants, Ann-Kristin
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Exposure to Plasmodium falciparum-derived hemozoin leads to impairment of transcriptional activation upon dendritic cell maturationManuscript (preprint) (Other academic)
  • 41.
    Bujila, Ioana
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Schwarzer, Evelin
    Skorokhod, Oleksii
    Weidner, Jessica M.
    Troye-Blomberg, Marita
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Östlund Farrants, Ann-Kristin
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Malaria-derived hemozoin exerts early modulatory effects on the phenotype and maturation of human dendritic cells2016In: Cellular Microbiology, ISSN 1462-5814, E-ISSN 1462-5822, Vol. 18, no 3, p. 413-423Article in journal (Refereed)
    Abstract [en]

    Plasmodium falciparum (P. falciparum)-induced effects on the phenotype of human dendritic cells (DC) could contribute to poor induction of long-lasting protective immunity against malaria. DC ability to present antigens to naïve T cells, thus initiating adaptive immune responses depends on complex switches in chemokine receptors, production of soluble mediators and expression of molecules enabling antigen-presentation and maturation. To examine the cellular basis of these processes in the context of malaria, we performed detailed analysis of early events following exposure of human monocyte-derived DC to natural hemozoin (nHZ) and the synthetic analog of its heme core, β-hematin. DC exposed to either molecule produced high levels of the inflammatory chemokine MCP-1, showed continuous high expression of the inflammatory chemokine receptor CCR5, no upregulation of the lymphoid homing receptor CCR7 and no cytoskeletal actin redistribution with loss of podosomes. DC partially matured as indicated by increased expression of major histocompatibility complex (MHC) class II and CD86 following nHZ and β-hematin exposure, however there was a lack in expression of the maturation marker CD83 following nHZ but not β-hematin exposure. Overall our data demonstrate that exposure to nHZ partially impairs the capacity of DC to mature, an effect in part differential to β-hematin.

  • 42.
    Calla-Magarinos, Jacqueline
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute, Immunology. National University Hospital of Iceland.
    Fernandez, Carmen
    Stockholm University, Faculty of Science, The Wenner-Gren Institute, Immunology.
    Troye-Blomberg, Marita
    Stockholm University, Faculty of Science, The Wenner-Gren Institute, Immunology.
    Freysdottir, Jona
    Alkaloids from Galipea longiflora Krause modify the maturation of human dendritic cells and their ability to stimulate allogeneic CD4(+) T cells2013In: International Immunopharmacology, ISSN 1567-5769, E-ISSN 1878-1705, Vol. 16, no 1, p. 79-84Article in journal (Refereed)
    Abstract [en]

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

  • 43.
    Calla-Magariños, Jacqueline
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute.
    Quispe, T.
    Giménez, A.
    Freysdottir, J.
    Troye-Blomberg, Marita
    Stockholm University, Faculty of Science, The Wenner-Gren Institute.
    Fernández, Carmen
    Stockholm University, Faculty of Science, The Wenner-Gren Institute.
    Quinolinic Alkaloids from Galipea longiflora Krause Suppress Production of Proinflammatory Cytokines in vitro and Control Inflammation in vivo upon Leishmania Infection in Mice2013In: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 77, no 1, p. 30-38Article in journal (Refereed)
    Abstract [en]

    An antileishmanial activity of quinolinic alkaloids from Galipea longiflora Krause, known as Evanta, has been demonstrated. We have previously shown that, apart from its leishmanicidal effect, in vitro pretreatment of spleen cells with an alkaloid extract of Evanta (AEE) interfered with the proliferation and interferon-γ production in lymphocytes polyclonally activated either with concanavalin A or anti-CD3. In the present study, we investigated if AEE could interfere with antigen-specific lymphocyte activation. We found that in vitro and in vivo treatment reduced recall lymphocyte responses, as measured by IFN-γ production (55% and 63% reduction compared to untreated cells, respectively). Apart from IFN-γ, the production of IL-12 and TNF was also suppressed. No effects were observed for meglumine antimoniate (SbV), the conventional drug used to treat leishmaniasis. When mice infected with Leishmania braziliensis promastigotes in the hind footpad were treated with AEE, the dynamics of the infection changed and the footpath thickness was efficiently controlled. The parasite load was also reduced but to a lesser extent than upon treatment with SbV. Combined treatment efficiently controlled both the thickness and parasite load as smaller lesions during the entire course of the infection were seen in the mice treated with AEE plus SbV compared with AEE or SbV alone. We discuss the benefits of combined administration of AEE plus SbV.

  • 44.
    Cantera, Rafael
    et al.
    Stockholm University, Faculty of Science, Department of Zoology. Developmental Neurobiology, IIBCE, Montevideo, Uruguay.
    Barrio, Rosa
    Do the Genes of the Innate Immune Response Contribute to Neuroprotection in Drosophila?2015In: Journal of Innate Immunity, ISSN 1662-811X, E-ISSN 1662-8128, Vol. 7, no 1, p. 3-10Article, review/survey (Refereed)
    Abstract [en]

    A profound debate exists on the relationship between neurodegeneration and the innate immune response in humans. Although it is clear that such a relation exists, the causes and consequences of this complex association remain to be determined in detail. Drosophila is being used to investigate the mechanisms involved in neurodegeneration, and all genomic studies on this issue have generated gene catalogues enriched in genes of the innate immune response. We review the data reported in these publications and propose that the abundance of immune genes in studies of neurodegeneration reflects at least two phenomena: (i) some proteins have functions in both immune and nervous systems, and (ii) immune genes might also be of neuroprotective value in Drosophila. This review opens this debate in Drosophila, which could thus be used as an instrumental model to elucidate this question.

  • 45.
    Cardell, Susanna
    Stockholm University, Faculty of Science, The Wenner-Gren Institute, Immunology.
    T lymphocyte subsets: a study on heterogeneity based on lymphokine production1992Doctoral thesis, comprehensive summary (Other academic)
  • 46. Cherif, M. K.
    et al.
    Sanou, G. S.
    Maiga, B.
    Israelsson, E.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Ouedraogo, A. L.
    Bougouma, E. C.
    Diarra, A.
    Ouedraogo, A.
    Ouattara, A. S.
    Troye-Blomberg, Marita
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Dolo, A.
    Cavanagh, D. R.
    Theisen, M.
    Modiano, D.
    Sirima, S. B.
    Nebie, I.
    Fc gamma RIIa Polymorphism and Anti-Malaria-Specific IgG and IgG Subclass Responses in Populations Differing in Susceptibility to Malaria in Burkina Faso2012In: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 75, no 6, p. 606-613Article in journal (Refereed)
    Abstract [en]

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

  • 47.
    Chuquimia Flores, Olga Daniela
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Innate and adaptive immune responses in the lungs. Contribution to protection against mycobacterial infections2011Licentiate thesis, monograph (Other academic)
    Abstract [en]

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

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

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

  • 48.
    Chuquimia Flores, Olga Daniela
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Role of alveolar epithelial cells in macrophage responses against mycobacterial infections2013Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    This thesis aimed to investigate the role of alveolar epithelial cells (AEC) on immune responses against mycobacterial infections, specifically, the role of AEC in modulating macrophage functions through the secretion of broad variety of factors.

    In paper I, we compared murine AEC with interstitial macrophages (PuM) in their ability to take up and control mycobacterial growth and their capacity as antigen-presenting cells. We found that AEC were able to internalize and control bacterial growth and present antigens to T cells from immunized mice. In addition, both AEC and PuM exhibited distinct patterns of secreted factors, and a more comprehensive profile of AEC responses revealed that AEC were able to secrete different factors important to generate various effects in other cells. Paper II: Since AEC secrete a broad variety of factors, we hypothesized that being in the interface; AEC may play an important role in transmitting signals from the external to the internal compartment and in modulating the activity of PuM. Thus, we prepared AEC-derived media and tested their effect on bacteria and a number of macrophage functions a) migration, b) phagocytosis and control of intracellular bacterial growth, and c) alteration in cell morphology and expression of surface markers. We found that AEC-secreted factors had a dual effect, in one hand controlling bacterial growth and on the other hand increasing macrophage activity. In paper III, we first investigated the responsible mechanisms of intracellular bacterial growth control mediated by AEC-derived media. We found that infected macrophages upon AEC-secreted factors increased the control of intracellular bacterial growth by iNOS-independent pathways. Compared with other macrophage types, PuM, did not control the intracellular bacterial growth upon the well-known potent macrophage activator, IFN-γ. We found that SOCS1 was involved in the un-responsiveness to IFN-γ by PuM to control the intracellular bacterial growth. We suggested that PuM are restricted in their inflammatory responses perhaps for avoiding tissue damage.

    Overall, the current findings highlight the importance of AEC in the defense against bacterial infection in the lungs by secreting factors involved in activation and differentiation of immune cells such as macrophages.

  • 49.
    Chuquimia Flores, Olga Daniela
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Soluble factors from alveolar epithelial cells increase intracellular killing of BCG by macrophages through nitric oxide independent mechanismsManuscript (preprint) (Other academic)
  • 50.
    Chuquimia, Olga D.
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute, Immunology.
    Petursdottir, Dagbjort H.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute, Immunology.
    Periolo, Natalia
    Stockholm University, Faculty of Science, The Wenner-Gren Institute, Immunology.
    Fernandéz, Carmen
    Stockholm University, Faculty of Science, The Wenner-Gren Institute, Immunology.
    Alveolar epithelial cells are critical in protection of the respiratory tract by secretion of factors able to modulate the activity of pulmonary macrophages and directly control bacterial growth2013In: Infection and Immunity, ISSN 0019-9567, E-ISSN 1098-5522, Vol. 81, no 1, p. 381-389Article in journal (Refereed)
    Abstract [en]

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

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