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  • 1. Abedi-Valugerdi, Manuchehr
    et al.
    Hansson, Monika
    Stockholm University, Faculty of Science, Wenner-Gren Institute for Experimental Biology.
    Möller, Göran
    Genetic control of resistance to mercury-induced immune/autoimmune activation2001In: Scandinavian Journal of Immunology, Vol. 54, no Jul-Aug, 190-197 p.Article in journal (Refereed)
  • 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, 103-118 p.Article 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.
    Adler, J
    et al.
    Stockholm University, Faculty of Science, Wenner-Gren Institute for Experimental Biology.
    Pagakis, S N
    Parmryd, I
    Stockholm University, Faculty of Science, Wenner-Gren Institute for Experimental Biology.
    Replicate-based noise corrected correlation for accurate measurements of colocalization.2008In: J Microsc, ISSN 1365-2818, Vol. 230, no Pt 1, 121-33 p.Article in journal (Refereed)
  • 4.
    Adler, Jeremy
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    The unitary scale bar: human and machine readable2008In: Journal of Microscopy, ISSN 0022-2720, E-ISSN 1365-2818, Vol. 230, no 1, 163-166 p.Article in journal (Refereed)
    Abstract [en]

    A format is described for a scale bar that encodes the length represented within the structure of the bar itself, thereby removing the need for any supporting text. Although the 'unitary' scale bar has a conventional appearance it is also machine readable and therefore retains information about the scale even when the file format is changed. The format is based on the metre and is suitable for all terrestrial applications.

  • 5.
    Adler, Jeremy
    et al.
    Stockholm University, Faculty of Science, Wenner-Gren Institute for Experimental Biology.
    Pagakis,, S
    Parmryd, Ingela
    Stockholm University, Faculty of Science, Wenner-Gren Institute for Experimental Biology.
    Replicate based noise corrected correlation (RBNCC) for accurate measurements of colocalisation.2007Conference paper (Other (popular science, discussion, etc.))
    Abstract [en]

    Adler. J., Pagakis, S. and Parmryd, I. Replicate based noise corrected correlation (RBNCC) for accurate measurements of colocalisation. The Nordic confocal and advanced microscopy meeting. Fiskebäckskil, Sweden, March 2007

  • 6.
    Adler, Jeremy
    et al.
    Stockholm University, Faculty of Science, Wenner-Gren Institute for Experimental Biology.
    Pagakis,, S
    Parmryd, Ingela
    Stockholm University, Faculty of Science, Wenner-Gren Institute for Experimental Biology.
    Replicate Based Noise Corrected Correlation (RBNCC) for accurate measurements of colocalization2007Conference paper (Other (popular science, discussion, etc.))
    Abstract [en]

    Adler, J., Pagakis, S. and Parmryd, I. Replicate Based Noise Corrected Correlation (RBNCC) for accurate measurements of colocalization. The 7th International ELMI Meeting on Advanced Light Microscopy, York, UK, April 2007

  • 7.
    Adler, Jeremy
    et al.
    Stockholm University, Faculty of Science, Wenner-Gren Institute for Experimental Biology.
    Parmryd, Ingela
    Stockholm University, Faculty of Science, Wenner-Gren Institute for Experimental Biology.
    In support of the Pearson correlation coefficient.2007In: J Microsc, ISSN 0022-2720, Vol. 227, no Pt 1, 83; author reply 84-5 p.Article in journal (Refereed)
  • 8.
    Adler, Jeremy
    et al.
    Stockholm University, Faculty of Science, Wenner-Gren Institute for Experimental Biology.
    Parmryd, Ingela
    Stockholm University, Faculty of Science, Wenner-Gren Institute for Experimental Biology.
    Making accurate measurement of colocalization by correcting for image noise.2007Conference paper (Other (popular science, discussion, etc.))
    Abstract [en]

    Making accurate measurement of colocalization by correcting for image noise. The 51st Biophysical Society Annual Meeting in Baltimore, USA, March 2007

  • 9.
    Adler, Jeremy
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Cell Biology.
    Parmryd, Ingela
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Cell Biology.
    Plasma membrane topology and membrane models2009Conference paper (Other academic)
  • 10.
    Adler, Jeremy
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Parmryd, Ingela
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Quantifying Colocalization by Correlation: The Pearson Correlation Coefficient is Superior to the Mander's Overlap Coefficient2010In: CYTOMETRY PART A, ISSN 1552-4922, Vol. 77A, no 8, 733-742 p.Article in journal (Refereed)
    Abstract [en]

    The Pearson correlation coefficient (PCC) and the Mander's overlap coefficient (MOC) are used to quantify the degree of colocalization between fluorophores. The MOC was introduced to overcome perceived problems with the PCC. The two coefficients are mathematically similar, differing in the use of either the absolute intensities (MOC) or of the deviation from the mean (PCC). A range of correlated datasets, which extend to the limits of the PCC, only evoked a limited response from the MOC. The PCC is unaffected by changes to the offset while the MOC increases when the offset is positive. Both coefficients are independent of gain. The MOC is a confusing hybrid measurement, that combines correlation with a heavily weighted form of co-occurrence, favors high intensity combinations, downplays combinations in which either or both intensities are low and ignores blank pixels. The PCC only measures correlation. A surprising finding was that the addition of a second uncorrelated population can substantially increase the measured correlation, demonstrating the importance of excluding background pixels. Overall, since the MOC is unresponsive to substantial changes in the data and is hard to interpret, it is neither an alternative to nor a useful substitute for the PCC. The MOC is not suitable for making measurements of colocalization either by correlation or co-occurrence.

  • 11.
    Adler, Jeremy
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute, Cell Biology.
    Shevchuk, A
    Novak, P
    Korchev, Y
    Parmryd, I
    Stockholm University, Faculty of Science, The Wenner-Gren Institute, Cell Biology.
    Single Particle Tracking in 2D Produces Gibberish: A Solution2009Conference paper (Other academic)
  • 12. A-Elgadir, Thoraya M E
    et al.
    Elbashir, Mustafa I
    Berzins, Klavs
    Stockholm University, Faculty of Science, Wenner-Gren Institute for Experimental Biology.
    Masuadi, Emad M
    A-Elbasit, Ishraga E
    ElGhazali, Gehad
    Giha, Hayder A
    The profile of IgG-antibody response against merozoite surface proteins 1 and 2 in severe Plasmodium falciparum malaria in Eastern Sudan.2008In: Parasitol Res, ISSN 0932-0113, Vol. 102, no 3, 401-9 p.Article in journal (Refereed)
  • 13. Ali, Magdi M M
    et al.
    Elghazali, Gehad
    Montgomery, Scott M
    Farouk, Salah E
    Nasr, Amre
    Noori, Suzan I A
    Shamad, Mahdi M
    Fadlelseed, Omar E
    Berzins, Klavs
    Stockholm University, Faculty of Science, Wenner-Gren Institute for Experimental Biology.
    Fc{gamma}RIIa (CD32) Polymorphism and Onchocercal Skin Disease: Implications for the Development of Severe Reactive Onchodermatitis (ROD).2007In: Am J Trop Med Hyg, ISSN 0002-9637, Vol. 77, no 6, 1074-1078 p.Article in journal (Refereed)
  • 14.
    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.

  • 15.
    Ali, Magdi Mahmoud
    et al.
    Stockholm University, Faculty of Science, Wenner-Gren Institute for Experimental Biology.
    Baraka, Omer Z.
    AbdelRahman, Suzan I.
    Sulaiman, Suad M.
    Williams, Jeffery F.
    Homeida, Mamoun M.
    Mackenzie, Charles D.
    Immune responses directed against microfilariae correlate with severity of clinical onchodermatitis and treatment history2003In: Journal of Infectious Diseases, Vol. 187, no 4, 714-717 p.Article in journal (Refereed)
  • 16.
    Ali, Magdi Mahmoud
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Montgomery, Scott M.
    Farouk, Salah E.
    Noori, Suzan I. A.
    Shamad, Mahdi M.
    Tayeb, Omer
    ElGhazali, Gehad
    Berzins, Klavs
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    FcγRIIa (CD32) polymorphism and onchocercal skin disease: implications for the development of severe reactive onchodermatitis (ROD)2007In: American Journal of Tropical Medicine and Hygiene, ISSN 0002-9637, E-ISSN 1476-1645, Vol. 77, no 6, 1074-1078 p.Article in journal (Refereed)
    Abstract [en]

    The pathologic manifestations of Onchocerca volvulus infection depend on the interplay between the host and the parasite. A genetic single nucleotide polymorphism in the FcγRIIa gene, resulting in arginine (R) or histidine (H) at position 131, affects the binding to the different IgG subclasses and may influence the clinical variations seen in onchocerciasis. This study investigated the relationship between this polymorphism and disease outcome. FcγRIIa genotyping was performed on clinically characterized onchocerciasis patients (N = 100) and healthy controls (N = 74). FcγRIIa genotype R/R131 frequencies were significantly higher among patients with severe dermatopathology (P < 0.001). Increased risk of developing this form was mostly associated with one tribe (Masalit) (OR = 3.2, 95% CI 1-9.9, P = 0.042). The H131 allele was found to be significantly associated with a reduced risk of having the severe form of the disease (adjusted OR = 0.26, 95% CI = 0.13-0.46, P < 0.001). Our findings suggest that the polymorphism influences the clinical outcome of onchocerciasis.

  • 17.
    Ali, Magdi Mahmoud
    et al.
    Stockholm University, Faculty of Science, Wenner-Gren Institute for Experimental Biology.
    Mukhtar, Moawia M.
    Baraka, Omer Z.
    Homeida, Mamoun M.
    Kheir, Musa M.
    Mackenzie, Charles D.
    Immunocompetence may be important in the effectiveness of Mectizan® (ivermectin) in the treatment of human onchocerciasis2002In: Acta Tropica, Vol. 84, no 1, 49-53 p.Article in journal (Refereed)
  • 18.
    Ali, Magdi Mahmoud
    et al.
    Stockholm University, Faculty of Science, Wenner-Gren Institute for Experimental Biology.
    Shamad, Mahdi M.
    Homeida, Mamoun M.
    ElGhazali, Gehad
    Berzins, Klavs
    Mackenzie, Charles D.
    Reactive onchocercal dermatitis (Sowda) in Sudan: definition and prevalence2005In: Acta Trop.Article in journal (Refereed)
  • 19.
    Ali, Magdi Mahmoud
    et al.
    Stockholm University, Faculty of Science, Wenner-Gren Institute for Experimental Biology.
    Åhlin, Erik
    Mathsson, Linda
    Mackenzie, Charles D.
    Noori, Suzan I. A.
    Berzins, Klavs
    ElGhazali, Gehad
    Rönnelid, Johan
    Stimulation of TNF-a, IL-1ß and IL-10 production, but suppression of production of IL-1ra by high molecular weight immune complexes from Onchocerca volvulus-infected Sudanese patients: implications for disease pathogenesis and therapy2005Article in journal (Refereed)
  • 20.
    Alkemar, Gunnar
    Stockholm University, Faculty of Science, Wenner-Gren Institute for Experimental Biology.
    Ribosome and ribosomal RNA Structure: An experimental and computational analysis of expansion segments in eukaryotic ribosomal RNA2008Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Ribosomes are large ribonucleoprotein complexes which incorporate amino acids into peptide chains during translational process in all types of living cells. The eukaryotic ribosome is larger compared to its prokaryotic counterpart. The size differences are due to a larger protein part and that the rRNA contains eukaryote specific expansion segments (ES). Cryo-EM reconstruction has visualized many ES on the ribosomal surface which have given clues about function and structural features. However, the secondary structures of most ES are unknown or ill defined. In this thesis, the secondary and also to a certain extent the tertiary structures of several ES are determined by using computational methods and biochemical experimental techniques. The juxtaposition of ES6 close to ES3 in the Cryo-EM image of the yeast ribosome suggested that ES3 and ES6 might interact. A computational analysis of more than 2900 sequences shows that a complementary helical region of seven to nine contiguous base pairs can form between ES3 and ES6 in almost all analyzed sequences. Biochemical in situ experiments support the proposed interaction. Secondary structure models are presented for ES3 and ES6 in 18S rRNA and ES39 in 28S rRNA, where homologous structural elements could be modeled in the experimentally analyzed ribosomes from fungi, plants and mammals. The structure models were further supported by computational methods where the ES6 structure and the ES39 structure could be formed in more than 6000 and 900 sequences respectively. A tertiary structure model of ES3 and ES6 including the helical interaction is presented. An in vitro transcribed and folded ES6 sequence differed from that observed in situ, suggesting that chaperones, ribosomal proteins, and/or the tertiary rRNA interaction could be involved in the in vivo folding of ES6. An analysis of the similarities between ES39 structures suggests that it might be under selective constraint to preserve its secondary structure.

  • 21.
    Alkemar, Gunnar
    et al.
    Stockholm University, Faculty of Science, Wenner-Gren Institute for Experimental Biology.
    Nygård, Odd
    A possible tertiary rRNA interaction between expansion segments ES3 and ES6 in eukaryotic 40S ribosomal subunits.2003In: RNA, Vol. 9, no 1, 20-24 p.Article in journal (Refereed)
  • 22.
    Alkemar, Gunnar
    et al.
    Stockholm University, Faculty of Science, Wenner-Gren Institute for Experimental Biology.
    Nygård, Odd
    A possible tertiary rRNA interaction between expansion segments ES3 and ES6 in eukaryotic 40S ribosomal subunits.2003In: RNA, Vol. 9, no 1, 20-24 p.Article in journal (Refereed)
  • 23.
    Alkemar, Gunnar
    et al.
    Stockholm University, Faculty of Science, Wenner-Gren Institute for Experimental Biology.
    Nygård, Odd
    Comparative analysis of rRNA sequences from the large ribosomal subunit of more than 900 eukaryotic species reveals structural similarities in expansion segment ES39.Manuscript (Other academic)
  • 24.
    Alkemar, Gunnar
    et al.
    Stockholm University, Faculty of Science, Wenner-Gren Institute for Experimental Biology.
    Nygård, Odd
    Comparative analysis of rRNA sequences from the large ribosomal subunit of more than 900 eukaryotic species reveals structural similarities in expansion segment ES39.Manuscript (Other academic)
  • 25.
    Alkemar, Gunnar
    et al.
    Stockholm University, Faculty of Science, Wenner-Gren Institute for Experimental Biology.
    Nygård, Odd
    Probing the secondary structure of expansion segment ES6 in 18S ribosomal RNA.2006In: Biochemistry, Vol. 45, no 26, 8067-8078 p.Article in journal (Refereed)
  • 26.
    Alkemar, Gunnar
    et al.
    Stockholm University, Faculty of Science, Wenner-Gren Institute for Experimental Biology.
    Nygård, Odd
    Probing the secondary structure of expansion segment ES6 in 18S ribosomal RNA.2006In: Biochemistry, Vol. 45, no 26, 8067-8078 p.Article in journal (Refereed)
  • 27.
    Alkemar, Gunnar
    et al.
    Stockholm University, Faculty of Science, Wenner-Gren Institute for Experimental Biology.
    Nygård, Odd
    Secondary structure of two regions in expansion segments ES3 and ES6 with the potential of forming a tertiary interaction in eukaryotic 40S ribosomal subunits.2004In: RNA, Vol. 10, no 3, 403-411 p.Article in journal (Refereed)
  • 28.
    Alkemar, Gunnar
    et al.
    Stockholm University, Faculty of Science, Wenner-Gren Institute for Experimental Biology.
    Nygård, Odd
    Secondary structure of two regions in expansion segments ES3 and ES6 with the potential of forming a tertiary interaction in eukaryotic 40S ribosomal subunits.2004In: RNA, Vol. 10, no 3, 403-411 p.Article in journal (Refereed)
  • 29. Amodu, O. K.
    et al.
    Olaniyan, S. A.
    Adeyemo, A. A.
    Troye-Blomberg, Marita
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Olumese, P. E.
    Omotade, O. O.
    Association of the sickle cell trait and the ABO blood group with clinical severity of malaria in southwest Nigeria2012In: Acta Tropica, ISSN 0001-706X, E-ISSN 1873-6254, Vol. 123, no 2, 72-77 p.Article in journal (Refereed)
    Abstract [en]

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

  • 30.
    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.

  • 31.
    Amoudruz, Petra
    et al.
    Stockholm University, Faculty of Science, Wenner-Gren Institute for Experimental Biology.
    Holmlund, Ulrika
    Malmström, Vivianne
    Trollmo, Christina
    Bremme, Katarina
    Scheynius, Annika
    Sverremark-Ekström, Eva
    Neonatal immune responses to microbial stimuli - is there an influence of maternal allergy?2005In: Journal of Allergy and Clinical Immunology, ISSN 0091-6749, Vol. 115, no 6, 1304-1310 p.Article in journal (Refereed)
  • 32.
    Amoudruz, Petra
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Holmlund, Ulrika
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Saghafian-Hedengren, Shanie
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Nilsson, Caroline
    Sverremark-Ekström, Eva
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Impaired Toll-like receptor 2 signaling in monocytes from 5-year-old allergic children2009In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 155, no 3, 387-394 p.Article in journal (Refereed)
    Abstract [en]

    The relative composition of the two major monocytic subsets CD14+CD16− and CD14+CD16+ is altered in some allergic diseases. These two subsets display different patterns of Toll-like receptor levels, which could have implications for activation of innate immunity leading to reduced immunoglobulin E-specific adaptive immune responses. This study aimed to investigate if allergic status at the age of 5 years is linked to differences in monocytic subset composition and their Toll-like receptor levels, and further, to determine if Toll-like receptor regulation and cytokine production upon microbial stimuli is influenced by the allergic phenotype. Peripheral blood mononuclear cells from 5-year-old allergic and non-allergic children were stimulated in vitro with lipopolysaccharide and peptidoglycan. Cells were analysed with flow cytometry for expression of CD14, Toll-like receptors 2 and 4 and p38-mitogen-activated protein kinase (MAPK). The release of cytokines and chemokines [tumour necrosis factor, interleukin (IL)-1β, IL-6, IL-8, IL-10, IL-12p70] into culture supernatants was measured with cytometric bead array. For unstimulated cells there were no differences in frequency of the monocytic subsets or their Toll-like receptor levels between allergic and non-allergic children. However, monocytes from allergic children had a significantly lower up-regulation of Toll-like receptor 2 upon peptidoglycan stimulation. Further, monocytes from allergic children had a higher spontaneous production of IL-6, but there were no differences between the two groups regarding p38-MAPK activity or cytokine and chemokine production upon stimulation. The allergic subjects in this study have a monocytic population that seems to display a hyporesponsive state as implicated by impaired regulation of Toll-like receptor 2 upon peptidoglycan stimulation.

  • 33.
    Amoudruz, Petra
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Holmlund, Ulrika
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Schollin, Jens
    Sverremark-Ekström, Eva
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Montgomery, Scott M
    Stockholm University, Faculty of Social Sciences, Department of Psychology.
    Maternal country of birth and previous pregnancies are associated with breast milk characteristics2009In: Pediatric Allergy and Immunology, ISSN 0905-6157, E-ISSN 1399-3038, Vol. 20, no 1, 19-29 p.Article in journal (Refereed)
    Abstract [en]

    Populations in high infectious exposure countries are at low risk of some immune-mediated diseases such as Crohn’s disease and allergy. This low risk is maintained upon immigration to an industrialized country, but the offspring of such immigrants have a higher immune-mediated disease risk than the indigenous population. We hypothesize that early life exposures in a developing country shape the maternal immune system, which could have implications for the offspring born in a developed country with a low infectious load. The aim of this study was to investigate if exposures in childhood (indicated by country of origin) and subsequent exposures influence immunologic characteristics relevant to stimulation of offspring. Breast milk components among 64 mothers resident in Sweden, 32 of whom immigrated from a developing country, were examined using the ELISA and Cytometric Bead Array methods. Immigrants from a developing country had statistically significantly higher levels of breast milk interleukin-6 (IL-6), IL-8 and transforming growth factor-β1. A larger number of previous pregnancies were associated with down-regulation of several substances, statistically significant for soluble CD14 and IL-8. The results suggest that maternal country of birth may influence adult immune characteristics, potentially relevant to disease risk in offspring. Such a mechanism may explain the higher immune-mediated disease risk among children of migrants from a developing to developed country. Older siblings may influence disease risk through the action of previous pregnancies on maternal immune characteristics.

  • 34.
    Amoudruz, Petra
    et al.
    Stockholm University, Faculty of Science, Wenner-Gren Institute for Experimental Biology.
    Minang, Jacob T
    Sundström, Yvonne
    Nilsson, Caroline
    Lilja, Gunnar
    Troye-Blomberg, Marita
    Sverremark-Ekström, Eva
    Pregnancy, but not the allergic status, influences spontaneous and induced IL-1beta, IL-6, IL-10 and IL-12 responses2006In: Immunology, ISSN 0019-2805, Vol. 119, no 1, 18-26 p.Article in journal (Refereed)
  • 35. 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, 126- p.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.

  • 36. Andersson, C.
    et al.
    Vasconcelos, N.-M.
    Stockholm University, Faculty of Science, Wenner-Gren Institute for Experimental Biology.
    Sievertzon, M.
    Haddad, D.
    Liljeqvist, S.
    Berglund, P.
    Liljeström, P.
    Ahlborg, N.
    Ståhl, S.
    Berzins, K.
    Comparative immunization study using RNA and DNA constructs encoding a part of the Plasmodium falciparum antigen Pf3322001In: Scandinavian Journal of Immunology, ISSN 0300-9475, Vol. 54, no 1-2, 117-24 p.Article in journal (Refereed)
  • 37.
    Andersson, Ulf
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Physiology.
    On the biosynthesis of ATP synthase1998Doctoral thesis, comprehensive summary (Other academic)
  • 38.
    Andréasson, Claes
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Cell Biology.
    Rampelt, Heike
    Fiaux, Jocelyne
    Druffel-Augustin, Silke
    Bukau, Bernd
    The endoplasmic reticulum Grp170 acts as a nucleotide exchange factor of Hsp70 via a mechanism similar to that of the cytosolic Hsp112010In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 285, no 16, 12445-53 p.Article in journal (Refereed)
    Abstract [en]

    Grp170 and Hsp110 proteins constitute two evolutionary distinct branches of the Hsp70 family that share the ability to function as nucleotide exchange factors (NEFs) for canonical Hsp70s. Although the NEF mechanism of the cytoplasmic Hsp110s is well understood, little is known regarding the mechanism used by Grp170s in the endoplasmic reticulum. In this study, we compare the yeast Grp170 Lhs1 with the yeast Hsp110 Sse1. We find that residues important for Sse1 NEF activity are conserved in Lhs1 and that mutations in these residues in Lhs1 compromise NEF activity. As previously reported for Sse1, Lhs1 requires ATP to trigger nucleotide exchange in its cognate Hsp70 partner Kar2. Using site-specific cross-linking, we show that the nucleotide-binding domain (NBD) of Lhs1 interacts with the NBD of Kar2 face to face, and that Lhs1 contacts the side of the Kar2 NBD via its protruding C-terminal alpha-helical domain. To directly address the mechanism of nucleotide exchange, we have compared the hydrogen-exchange characteristics of a yeast Hsp70 NBD (Ssa1) in complex with either Sse1 or Lhs1. We find that Lhs1 and Sse1 induce very similar changes in the conformational dynamics in the Hsp70. Thus, our findings demonstrate that despite some differences between Hsp110 and Grp170 proteins, they use a similar mechanism to trigger nucleotide exchange.

  • 39. Anisimov, Vladimir N.
    et al.
    Egorov, Maxim V.
    Krasilshchikova, Marina S.
    Lyamzaev, Konstantin G.
    Manskikh, Vasily N.
    Moshkin, Mikhail P.
    Novikov, Evgeny A.
    Popovich, Irina G.
    Rogovin, Konstantin A.
    Shabalina, Irina G.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Physiology.
    Shekarova, Olga N.
    Skulachev, Maxim V.
    Titova, Tatiana V.
    Vygodin, Vladimir A.
    Vyssokikh, Mikhail Yu.
    Yurova, Maria N.
    Zabezhinsky, Mark A.
    Skulachev, Vladimir P.
    Effects of the mitochondria-targeted antioxidant SkQ1 on lifespan of rodents2011In: Aging, ISSN 1945-4589, E-ISSN 1945-4589, Vol. 3, no 11, 1110-1119 p.Article in journal (Refereed)
    Abstract [en]

    The effect of the mitochondria-targeted, plastoquinone-containing antioxidant SkQ1 on the lifespan of outbred mice and of three strains of inbred mice was studied. To this end, low pathogen (LP) or specific pathogen free (SPF) vivaria in St. Petersburg, Moscow, and Stockholm were used. For comparison, we also studied mole-voles and dwarf hamsters, two wild species of small rodents kept under simulated natural conditions. It was found that substitution of a LP vivarium for a conventional (non-LP) one doubled the lifespan of female outbred mice, just as SkQ1 did in a non-LP vivarium. SkQ1 prevented age-dependent disappearance of estrous cycles of outbred mice in both LP and non-LP vivaria. In the SPF vivarium in Moscow, male BALB/c mice had shorter lifespan than females, and SkQ1 increased their lifespan to the values of the females. In the females, SkQ1 retarded development of such trait of aging as heart mass increase. Male C57Bl/6 mice housed individually in the SPF vivarium in Stockholm lived as long as females. SkQ1 increased the male lifespan, the longevity of the females being unchanged. SkQ1 did not change food intake by these mice. Dwarf hamsters and mole-voles kept in outdoor cages or under simulated natural conditions lived longer if treated with SkQ1. The effect of SkQ1 on longevity of females is assumed to mainly be due to retardation of the age-linked decline of the immune system. For males under LP or SPF conditions, SkQ1 increased the lifespan, affecting also some other system(s) responsible for aging.

  • 40.
    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.

  • 41.
    Arama, Charles
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Understanding the immunobiology of DC subsets for rational design of novel malaria vaccines2011Licentiate thesis, monograph (Other academic)
  • 42.
    Arama, Charles
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Assefaw-Redda, Y.
    Rodriguez, A.
    Fernández, C.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Corradin, G.
    Kaufmann, S. H.
    Reece, S. T.
    Troye-Blomberg, Marita
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Heterologous prime–boost regimen adenovector 35-circumsporozoite protein vaccine/recombinant Bacillus Calmette-Guérin expressing the Plasmodium falciparum circumsporozoite induces enhanced long-term memory immunity in BALB/c miceManuscript (preprint) (Other academic)
  • 43.
    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, 4040-4045 p.Article 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.

  • 44.
    Arama, Charles
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Giusti, Pablo
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Boström, Stephanie
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Varani, Stefania
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Troye Blomberg, Marita
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Interethnic Differences in Antigen-Presenting Cell Activation and TLR Responses in Malian Children during Plasmodium falciparum Malaria2011In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 6, no 3, e18319- p.Article in journal (Refereed)
    Abstract [en]

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

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

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

  • 46.
    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, 5578-5584 p.Article 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.

  • 47.
    Arcot Jayaram, Satish
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    New roles for apical secretion and extracellular matrix assembly in Drosophila epithelial morphogenesis2010Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Branched tubular organs, such as the lung and vascular system fulfill the respiratory needs of most animals. Optimal tissue function relies on the uniform sizes and shapes of the constituting branches in each organ. The Drosophila tracheal airways provide a recognized genetic model system for identification and characterization of tube size regulators. We found that the programmed secretion and assembly of the apical extracellular matrix (ECM) is required for the expansion of the trachea and salivary glands (SG) tubes. We have characterized Vermiform (Verm) and Serpentine (Serp), two chitin-binding proteins with predicted polysaccharide deacetylase domains (ChLDs). Verm and Serp mutants show overelongated tubes, suggesting that luminal ECM modification restricts tracheal tube elongation. The luminal deposition of ChLDs, but not other secreted components, depends on paracellular septate junction integrity (SJs) in the tracheal epithelium. Deletion of the deacetylase domain renders Serp-GFP intracellular, arguing that the deacetylase domain harbors uncharacterized secretion signals. To explore this possibility we transferred the deacetylase domain from Serp to Gasp, another tracheal luminal protein, which requires the Emp24 adaptor for ER exit. The Gasp-Deac-GFP chimera was normally secreted in emp24 mutants indicating that the deacetylase domain contains potential ER-exit signals. To identify such signals we characterized conserved sequence motifs in the Serp deacetylase domain. Mutations of the N-glycosylation sites gradually reduced Serp-GFP luminal deposition suggesting that increased glycosylation enhances apical Serp secretion. By contrast, substitutions in three conserved amino acid stretches completely blocked the ER-exit of Serp-GFP. The mutated proteins were N-glycosylated suggesting that the motifs may be involved in a subsequent protein-folding step or facilitate ER exit through interactions with unidentified specific adaptors.

  • 48. 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, 23-29 p.Article 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.

  • 49. 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, 1024-1028 p.Article 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.

  • 50. Arko-Mensah, J
    et al.
    Julián, E
    Singh, M
    Fernández, C
    Stockholm University, Faculty of Science, Wenner-Gren Institute for Experimental Biology.
    TLR2 but not TLR4 signalling is critically involved in the inhibition of IFN-gamma-induced killing of mycobacteria by murine macrophages.2007In: Scand J Immunol, ISSN 0300-9475, Vol. 65, no 2, 148-57 p.Article in journal (Other academic)
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