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  • 1.
    Adam, Lucille
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    López-González, Moisés
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Björk, Albin
    Pålsson, Sandra
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Poux, Candice
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Wahren-Herlenius, Marie
    Fernández, Carmen
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Spetz, Anna-Lena
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Early Resistance of Non-virulent Mycobacterial Infection in C57BL/6 Mice Is Associated With Rapid Up-Regulation of Antimicrobial Cathelicidin Camp2018In: Frontiers in Immunology, ISSN 1664-3224, E-ISSN 1664-3224, Vol. 9, article id 1939Article in journal (Refereed)
    Abstract [en]

    Early clearance of tuberculosis is the successful eradication of inhaled bacteria before the development of an adaptive immune response. We previously showed, by utilizing a non-virulent mycobacteria infection model, that C57BL/6 mice are more efficient than BALB/c in their control of bacterial growth in the lungs during the first weeks of the infection. Here, we assessed early (within 1-3 days) innate immune events locally in the lungs to identify factors that may contribute to the control of non-virulent mycobacterial burden. We confirmed that C57BL/6 mice are more resistant to infection compared with BALB/c after intranasal inoculation with mycobacterium. Transcriptomic analyses revealed a remarkably silent signature in C57BL/6 mice despite effective control of bacterial growth. In contrast, BALB/c mice up-regulated genes associated with neutrophil and myeloid cell chemotaxis and migration. Flow cytometry analyses corroborated the transcriptomic analyses and demonstrated influx of both neutrophil and myeloid cell populations in BALB/c mice, while these did not increase in C57BL/6 mice. We further detected increased release of TNF-alpha from BALB/c lung cells but limited release from C57BL/6-derived cells. However, C57BL/6 mice showed a marked early up-regulation of the Camp gene, encoding the cathelicidin CRAMP peptide, post-mycobacterial exposure. CRAMP (LL-37 in human) expression in the lungs was confirmed using immunofluorescence staining. Altogether, these findings show that C57BL/6 mice can clear the mycobacterial infection early and that this early control is associated with high CRAMP expression in the lungs without concomitant influx of immune cells. The role of CRAMP/LL-37 during mycobacterial infection may be relevant for novel protective strategies, and warrants further studies of human cohorts.

  • 2.
    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, p. 387-394Article 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.

  • 3.
    Andreasson, Anna N.
    et al.
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska Institutet, Sweden.
    Jones, M. P.
    Walker, M. M.
    Talley, N. J.
    Nyhlin, H.
    Agréus, L.
    Prediction pathways for innate immune pathology, IBS, anxiety and depression in a general population (The POPCOL Study)2013In: Brain, behavior, and immunity, ISSN 0889-1591, E-ISSN 1090-2139, Vol. 32, p. e46-e46Article in journal (Other academic)
    Abstract [en]

    The aim of this study was to ascertain whether low grade innate inflammation contributes to a pathway of depression and anxiety via irritable bowel syndrome (IBS). We evaluated innate immune cell counts in colonic mucosa in normal subjects and those with IBS (Rome III) from a population based study in which 745 randomly selected subjects had a colonoscopy (mean age 51 years;57% women). Intraepithelial lymphocytes (IELs) per 100 enterocytes and eosinophils (eos) per five non-overlapping high power fields (HPF) were counted in 90 controls and 100 cases; immunocytochemistry (CD117) was performed for mast cells per 5HPF in 80 controls and 81 cases. IELs, mast cells and eos were individually summed over 5 sites (terminal ileum, caecum, transverse colon, sigmoid colon and rectum). Anxiety and depression scores were calculated from HADS. A causal model path model which hypothesises immune cells being associated with IBS which, in turn, is associated with elevated anxiety and depression was tested using path analysis implemented in the MPlus software. All hypothesised paths reached statistical significance (p < .05) supporting the individual hypothesized pathways. The overall model fit was reasonable although imperfect. In conclusion, a significant contribution of innate immune inflammatory load leading to anxiety and depression via IBS was found. Whether therapy directed to decreasing this inflammatory load also lifts depression and anxiety should be further explored.

  • 4.
    Arama, Charles
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Giusti, Pablo
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Boström, Stephanie
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Varani, Stefania
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Troye Blomberg, Marita
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Interethnic Differences in Antigen-Presenting Cell Activation and TLR Responses in Malian Children during Plasmodium falciparum Malaria2011In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 6, no 3, p. e18319-Article in journal (Refereed)
    Abstract [en]

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

  • 5.
    Arko-Mensah, John
    Stockholm University, Faculty of Science, Wenner-Gren Institute for Experimental Biology.
    Immune evasion and identification of biomarkers associated with mycobacterial infection2007Licentiate thesis, comprehensive summary (Other academic)
  • 6.
    Arko-Mensah, John
    Stockholm University, Faculty of Science, Wenner-Gren Institute for Experimental Biology.
    Mycobacterial infection: Immune evasion, host susceptibility and immunological markers of diagnostic importance2008Doctoral thesis, monograph (Other academic)
    Abstract [en]

    IIn the first study, we investigated the functional implications of prolonged TLR signalling on IFN-γ mediated killing of mycobacteria by murine macrophages in vitro. TLR2, but not TLR4 ligation interfered with IFN-γ mediated killing of mycobacteria in macrophages. In terms of mechanisms, neither TNF nor nitric oxide (NO) production was significantly affected, and the refractoriness induced could be reversed with increasing amounts of IFN-γ In the second study, we aimed to identify immunological markers of diagnostic importance in both the respiratory tract and serum during pulmonary mycobacterial infection in mice. We found that increased levels of immunological markers in the respiratory tract, but not serum, correlated better with active mycobacterial infection in the lungs, suggesting that the immune response in the respiratory tract is more reflective of the infection status and pathology than the systemic response. Finally, we investigated the level and nature of immune responses to pulmonary mycobacterial infection in BALB/c and C57BL/6 mice, two mouse strains known to exhibit different susceptibilities to infection with several intracellular pathogens, including mycobacteria. We showed that increased susceptibility of BALB/c mice to early mycobacterial infection was associated with reduced Th1 immune responses, and increased sTNFR secretion in the lung. Moreover, BALB/c mice recruited fewer monocytes/macrophages to the lung, and although IFN-γ stimulation of infected bone marrow derived macrophages in both mouse strains resulted in induction of antimycobacterial activity, BALB/c mice had a reduced capacity to kill ingested bacteria. The work presented in this thesis provide further insight into the mechanisms involved in the host-pathogen interaction; from persistence, to the immunological processes induced by the pathogen, to susceptibility of the host to infection.

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

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

  • 8.
    Attoff, Kristina
    et al.
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Kertika, Dimitra
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Lundqvist, Jessica
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Oredsson, S.
    Forsby, Anna
    Stockholm University, Faculty of Science, Department of Neurochemistry. Stockholm Univ, Dept Neurochem, S-10691 Stockholm, Sweden.
    Acrylamide affects proliferation and differentiation of the neural progenitor cell line C17.2 and the neuroblastoma cell line SH-SY5Y2016In: Toxicology in Vitro, ISSN 0887-2333, E-ISSN 1879-3177, Vol. 35, p. 100-111Article in journal (Refereed)
    Abstract [en]

    Acrylamide is a well-known neurotoxic compound and people get exposed to the compound by food consumption and environmental pollutants. Since acrylamide crosses the placenta barrier, the fetus is also being exposed resulting in a risk for developmental neurotoxicity. In this study, the neural progenitor cell line C17.2 and the neuroblastoma cell line SH-SY5Y were used to study proliferation and differentiation as alerting indicators for developmental neurotoxicity. For both cell lines, acrylamide reduced the number of viable cells by reducing proliferation and inducing cell death in undifferentiated cells. Acrylamide concentrations starting at 10 fM attenuated the differentiation process in SH-SY5Y cells by sustaining cell proliferation and neurite outgrowth was reduced at concentrations from 10 pM. Acrylamide significantly reduced the number of neurons starting at 1 mu M and altered the ratio between the different phenotypes in differentiating C17.2 cell cultures. Ten micromolar of acrylamide also reduced the expression of the neuronal and astrocyte biomarkers. Although the neurotoxic concentrations in the femtomolar range seem to be specific for the SH-SY5Y cell line, the fact that micromolar concentrations of acrylamide seem to attenuate the differentiation process in both cell lines raises the interest to further investigations on the possible developmental neurotoxicity of acrylamide.

  • 9.
    Awah, Nancy
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Studies on Plasmodium falciparum asexual blood stage antigens: RAP-2/RSP-2 and Pf332 in focus2011Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The life cycle of the malaria parasite is very complex and provides a number of potential targets for vaccination. In this thesis, data on two plasmodial asexual blood stage antigens (RAP-2 and Pf332) are presented.

    A partial aim of the work presented herein was to investigate the mechanisms responsible for the destruction of erythroid cells in anaemia, and more specifically to define the role of the rhoptry associated protein (RAP)-2 and other members of the RAP complex, RAP-1 and -3 in processes resulting in anaemia. Antibodies to the RAP complex were shown to have the potential to mediate the destruction of RAP-2-tagged erythroid cells by phagocytosis or by complement activation and lysis. In addition, antibodies to RAP-1 and RAP-2 could induce the apoptotic death of RAP-2- tagged erythroblasts. The frequency and functionality of naturally occurring RAP-2 antibodies in the sera of anaemic and non-anaemic Cameroonian children were also investigated. All sera tested contained RAP-2-reactive antibodies by both immunofluorescence and flow cytometry. The anaemic group of children had higher levels of IgG than the non-anaemic ones, while the levels of IgM were similar. With respect to IgG subclasses, higher levels of IgG3 were seen in the non-anaemic individuals as compared to anaemic subjects. The non-anaemic individuals recognised a greater proportion of RAP-2-tagged RBCs and activated complement to a greater extent than the anaemic ones.

    Earlier studies observed that humans continuously exposed to malaria, recognised Pf332 extensively. Further studies revealed that Pf332 antibodies were able to inhibit parasite growth and cytoadherence in vitro. Making use of Pf332-C231, a sub-fragment of Pf332, we studied the effects/mode of action of C231-specific antibodies on P. falciparum parasite growth and development in vitro. The antibodies appeared to act mainly on late stage parasites by two main mechanisms: 1) through the induction of abnormal/pyknotic parasites, and, 2) RBC lysis (disintegration of RBCs), thus limiting parasite growth and development. The antibody isotype in this context was IgG. Following the removal of immune pressure, parasites resumed growth, albeit at a much slower rate. The results suggest that during natural infections, antibodies to C231 could play a role in parasite control.

    In summary, these data suggest that antibodies to both antigens could be instrumental in immune responses leading to disease control, but could also mediate pathology.

  • 10.
    Awah, Nancy
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Balogun, Halima
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Achidi, E.
    Mariuba, L. A.
    Nogueira, P. A.
    Orlandi, P.
    Troye-Blomberg, Marita
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Gysin, J.
    Berzins, Klavs
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Antibodies to the Plasmodium falciparum rhoptry protein RAP-2/RSP-2 in relation to anaemia in Cameroonian children2011In: Parasite immunology (Print), ISSN 0141-9838, E-ISSN 1365-3024, Vol. 33, no 2, p. 104-115Article in journal (Refereed)
    Abstract [en]

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

  • 11.
    Balogun, Halima A.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Immunological characteristics of recombinant fragments of the Plasmodium falciparum blood-stage antigen Pf3322011Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Effective malaria vaccine might help improve control strategies against malaria, but the complexity of interactions between the parasite and its hosts poses challenges. The asexual blood stage P. falciparum antigen Pf332 has potentials as one of the proteins in understanding the complex host-parasite interactions. The interest in Pf332 as a target for parasite neutralizing antibodies, evolved from previous studies demonstrating that Pf332-reactive antibodies inhibits parasite growth in vitro. The presence of natural P. falciparum infection also indicated that Pf332 has the ability to induce protective antibodies.

    In paper I, we identified and characterized the immunogenicity of a C-terminal region of Pf332. Immunological analyses carried out with this fragment revealed that rabbit anti-C231 antibodies possess parasite in vitro inhibitory capabilities. In paper II, the functional activity of C231 specific antibodies was confirmed with human-affinity purified antibodies, where the antibodies inhibited late stage parasite development, by the presence of abnormal parasites and disintegrated red cell membranes.

    Epidemiological data from malaria endemic area of Senegal (Paper III & IV), showed that antibodies were reactive with two different fragments of Pf332 (C231 and DBL). Distribution of anti-C231 antibodies in the IgG subclasses, gave similar levels of IgG2 and IgG3. The levels of anti-C231 antibodies were associated with protection from clinical malaria, but with DBL reactive antibodies IgG3 was associated with protection from clinical malaria.

    We hereby conclude that antigen Pf332 contains immunogenic epitopes, and is a potential target for parasite neutralizing antibodies. The Pf332 protein should thus be considered as a candidate antigen for inclusion in a subunit P. falciparum malaria vaccine.

  • 12.
    Björkander, Sophia
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Hallberg, Jenny
    Persson, Jan-Olov
    Stockholm University, Faculty of Science, Department of Mathematics.
    Lilja, Gunnar
    Nilsson, Caroline
    Sverremark-Ekström, Eva
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    The allergic phenotype during the first 10 years of life in a prospective cohort2019In: Immunity, Inflammation and Disease, E-ISSN 2050-4527, Vol. 7, no 3, p. 170-182Article in journal (Refereed)
    Abstract [en]

    Background

    Heredity and environmental parameters jointly affect allergy development. Here, we used a Swedish prospective cohort to study the influence of heredity and factors usually associated with allergic disease and the development of allergic manifestations in combination with immunoglobulin E (IgE) sensitization at four different time points until 10 years of age.

    Methods

    Parents‐to‐be were characterized concerning allergy and their children (n = 281) were divided based on allergic heredity and followed from birth and clinically examined for IgE‐associated allergic symptoms until 10 years of age. The relation between allergy and early‐life parameters was analyzed by logistic regression. Group‐wise comparisons were made by nonparametrical tests.

    Results

    Early life eczema and/or asthma in combination with IgE sensitization, was a strong indicator of allergy at a later time point. Further, the early occurrence of multiple allergic symptoms among IgE‐sensitized children predisposed for a more complex allergic phenotype at later ages, independently of allergic heredity. At 10 years of age, allergic children had higher fractional exhaled nitrogen oxide (FeNO) levels, regardless of asthma, and FeNO levels were also influenced by heredity. Birth season was strongly associated with allergy development, but only in children with two allergic parents.

    Conclusion

    Allergic eczema/asthma in early life, being born during the autumn/winter, having multiple allergic symptoms and two allergic parents were all strong predictors for having allergic diseases at 5 and 10 years of age. However, the allergic march seems to be independent of heredity, as IgE‐mediated allergies follow the same trajectories in children with and without allergic heredity.

  • 13. Bolad, Ahmed
    et al.
    Farouk, Salah E.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Israelsson, Elisabeth
    Dolo, Amagana
    Doumbo, Ogobara K.
    Nebié, Issa
    Maiga, Boubacar
    Kouriba, Bourema
    Luoni, Gaia
    Sirima, Bienveu S.
    Distinct interethnic differences in IgG class/subclass and IgM antibody responses to malaria antigens but not in IgG responses to non-malarial antigens in sympatric tribes living in West Africa2005In: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 61, no 4, p. 380-386Article in journal (Refereed)
    Abstract [en]

    The well-established relative resistance to malaria observed in the Fulani as compared with other sympatric tribes in West Africa has been attributed to their higher levels of serum immunoglobulin (Ig) G antibodies to malarial antigens. In this study, we confirm and extend the previous findings by analyses of the levels of IgM, IgG and IgG subclasses of anti-malarial antibodies in asymptomatic individuals of different sympatric tribes in Burkina Faso (Fulani/Mossi) and Mali (Fulani/Dogon). The Fulani showed significantly higher median concentrations of anti-malarial IgG and IgM antibodies than the sympatric tribes at both locations. Although the overall subclass pattern of antibodies did not differ between the tribes, with IgG1 and IgG3 as dominant, the Fulani showed consistently significantly higher levels of these subclasses as compared with those of the non-Fulani individuals. No significant differences were seen in the levels of total IgG between the tribes, but the Fulani showed significantly higher levels of total IgM than their neighbours in both countries. While the antibody levels to some nonmalarial antigens showed the same pattern of differences seen for antibody levels to malaria antigens, no significant such differences were seen with antibodies to other nonmalarial antigens. In conclusion, our results show that the Fulani in two different countries show higher levels of anti-malarial antibodies than sympatric tribes, and this appears not to be a reflection of a general hyper-reactivity in the Fulani.

  • 14. Bolad, Ahmed
    et al.
    Farouk, Salah E.
    Modiano, David
    Berzins, Klavs
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Troye-Blomberg, Marita
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Israelsson, Elisabeth
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Dolo, Amagana
    Doumbo, Ogobara K.
    Nebié, Issa
    Maiga, Boubacar
    Kouriba, Bourema
    Luoni, Gaia
    Sirima, Bienveu Sodiomon
    Distinct interethnic differences in IgG class/subclass and IgM antibody responses to malaria antigens but not in IgG responses to non-malarial antigens in sympatric tribes living in West Africa2005In: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 61, no 4, p. 380-386Article in journal (Refereed)
    Abstract [en]

    The well-established relative resistance to malaria observed in the Fulani ascompared with other sympatric tribes in West Africa has been attributed totheir higher levels of serum immunoglobulin (Ig) G antibodies to malarialantigens. In this study, we confirm and extend the previous findings by analysesof the levels of IgM, IgG and IgG subclasses of anti-malarial antibodies inasymptomatic individuals of different sympatric tribes in Burkina Faso(Fulani/Mossi) and Mali (Fulani/Dogon). The Fulani showed significantlyhigher median concentrations of anti-malarial IgG and IgM antibodies thanthe sympatric tribes at both locations. Although the overall subclass pattern ofantibodies did not differ between the tribes, with IgG1 and IgG3 as dominant,the Fulani showed consistently significantly higher levels of these subclasses ascompared with those of the non-Fulani individuals. No significant differenceswere seen in the levels of total IgG between the tribes, but the Fulani showedsignificantly higher levels of total IgM than their neighbours in both countries.While the antibody levels to some nonmalarial antigens showed the same patternof differences seen for antibody levels to malaria antigens, no significant suchdifferences were seen with antibodies to other nonmalarial antigens. In conclusion,our results show that the Fulani in two different countries show higherlevels of anti-malarial antibodies than sympatric tribes, and this appears not tobe a reflection of a general hyper-reactivity in the Fulani.

  • 15.
    Bolad, Ahmed Kamal
    Stockholm University, Faculty of Science, Wenner-Gren Institute for Experimental Biology.
    Antibody responses in Plasmodium falciparum malaria and their relation to protection against the disease2004Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Protective immunity against Plasmodium falciparum may be obtained after repeated exposure to infection. Several studies indicate that immunity against the blood stages of the P. Falciparum infection is mainly antibody mediated. Protective antibodies may act either on their own, mediate antibody-dependent phagocytosis and/or cell-mediated neutralization of parasites. This thesis describes several aspects of humoral immune responses to P. falciparum infection in individuals of different age groups, different genetic background and with different degrees of malaria exposure.

    Several target antigens for antibody-mediated inhibition of parasite growth or invasion have been identified. One such antigen is Pf332, which appears on the surface of parasitized erythrocytes at late trophozoite and schizont stage. This surface exposure makes the antigen a possible target for opsonizing antibodies. We optimized an in vitro assay for studying cellmediated parasite neutralization in the presence of Pf332-reactive antibodies. Our data demonstrate that, Pf332 specific antibodies are able to inhibit parasite growth on their own and in cooperation with human monocytes.

    The P. falciparum parasites have evolved several mechanisms to evade the host neutralizing immune responses. In this thesis, we show that freshly isolated P. falciparum parasites from children living in a malaria endemic area of Burkina Faso were less sensitive for growth inhibition in vitro by autologous immunoglobulins (Ig) compared with heterologous ones. Analyses of two consecutive isolates taken 14 days apart, with regard to genotypes and sensitivity to growth inhibition in vitro, did not give any clear-cut indications on possible mechanisms leading to a reduced inhibitory activity in autologous parasite/antibody combinations. The frequent presence of persisting parasite clones in asymptomatic children indicates that the parasite possesses as yet undefined mechanisms to evade neutralizing immune responses.

    Transmission reducing measures such insecticide treated nets (ITNs) have been shown to be effective in reducing morbidity and mortality from malaria. However, concerns have been raised that ITNs usage could affect the acquisition of malaria immunity. We studied the effect of the use of insecticide treated curtains (ITC) on anti-malarial immune responses of children living in villages with ITC since birth. The use of ITC did neither affect the levels of parasite neutralizing immune responses nor the multiplicity of infection. These results indicate that the use of ITC does not interfere with the acquisition of anti-malarial immunity in children living in a malaria hyperendemic area.

    There is substantial evidence that the African Fulani tribe is markedly less susceptible to malaria infection compared to other sympatrically living ethnic tribes. We investigated the isotypic humoral responses against P. falciparum asexual blood stages in different ethnic groups living in sympatry in two countries exhibiting different malaria transmission intensities, Burkina Faso and Mali. We observed higher levels of the total malaria-specific-IgG and its cytophilic subclasses in individuals of the Fulani tribe as compared to non-Fulani individuals. Fulani individuals also showed higher levels of antibodies to measles antigen, indicating that the intertribal differences are not specific for malaria and might reflect a generally activated immune system in the Fulani.

  • 16. Cherif, Mariama K.
    et al.
    Sanou, Guillaume S.
    Bougouma, Edith C.
    Diarra, Amidou
    Ouedraogo, Alphonse
    Dolo, Amagana
    Troye-Blomberg, Marita
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Cavanagh, David R.
    Theisen, Michael
    Modiano, David
    Sirima, Sodiomon B.
    Nebie, Issa
    Is Fc gamma receptor IIA (Fc gamma RIIA) polymorphism associated with clinical malaria and Plasmodium falciparum specific antibody levels in children from Burkina Faso?2015In: Acta Tropica, ISSN 0001-706X, E-ISSN 1873-6254, Vol. 142, p. 41-46Article in journal (Refereed)
    Abstract [en]

    In the present study, the influences of Fc gamma RIIA polymorphism on susceptibility to malaria and antibody responses to Plasmodium falciparum antigens were analyzed in children. We recruited 96 healthy children between 3 and 10 years at the beginning of the high transmission season and we followed up for 5 months through the high transmission season to assess the parasitological, immunological and genetic endpoints in relation to clinical malaria status. There was a similar distribution of homozygous and heterozygous individuals carrying the Fc gamma RIIA-131R/R and Fc gamma RIIA-131R/H allele, whereas the number of Fc gamma RIIA-131H/H homozygous individuals was lower. P. falciparum infection frequency was not associated with the Fc gamma RIIa-131R/H polymorphism. Only IgG antibody responses to GLURP R0 showed a significant association between antibody levels and Fc gamma RIIA polymorphism (p = 0.02). IgG levels to MSP2a were significantly higher in children who did not experience any clinical malaria episode compared to those who experienced at least one malaria episode (p = 0.019). Cytophilic and non-cytophylic IgG subclass levels were higher in children without malaria than those who experienced at least one malaria episode. This difference was statistically significant for IgG1 to MSP3 (p = 0.003) and to MSP2a (p = 0.006); IgG3 to MSP2a (p = 0.007) and to GLURP R0 (p = 0.044); IgG2 to MSP2b (p = 0.007) and IgG4 to MSP3 (p = 0.051) and to MSP2a (p = 0.049). In this study, homozygous carriers of the Fc gamma RIIA-131R/R allele had higher malaria-specific antibody levels compare to the heterozygous carriers Fc gamma RIIA-131R/H alleles and to homozygous carriers of Fc gamma RIIA-131H/H alleles. The pre-existing antibodies responses were related to a reduced subsequent risk of clinical malaria.

  • 17. Chinh, Bkrong
    et al.
    Alsøe, Lene
    Lindvall, Jessica M.
    Stockholm University, Science for Life Laboratory (SciLifeLab). Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Sulheim, Dag
    Fagermoen, Even
    Winger, Anette
    Kaarbø, Mari
    Nilsen, Hilde
    Bruun Wyller, Vegard
    Whole blood gene expression in adolescent chronic fatigue syndrome: an exploratory cross-sectional study suggesting altered B cell differentiation and survival2017In: Journal of Translational Medicine, ISSN 1479-5876, E-ISSN 1479-5876, Vol. 15, article id 102Article in journal (Refereed)
    Abstract [en]

    Background

    Chronic fatigue syndrome (CFS) is a prevalent and disabling condition affecting adolescents. The pathophysiology is poorly understood, but immune alterations might be an important component. This study compared whole blood gene expression in adolescent CFS patients and healthy controls, and explored associations between gene expression and neuroendocrine markers, immune markers and clinical markers within the CFS group.

    Methods

    CFS patients (12-18 years old) were recruited nation-wide to a single referral center as part of the Nor-CAPITAL project. A broad case definition of CFS was applied, requiring 3 months of unexplained, disabling chronic/ relapsing fatigue of new onset, whereas no accompanying symptoms were necessary. Healthy controls having comparable distribution of gender and age were recruited from local schools. Whole blood samples were subjected to RNA sequencing. Immune markers were blood leukocyte counts, plasma cytokines, serum C-reactive protein and immunoglobulins. Neuroendocrine markers encompassed plasma and urine levels of catecholamines and cortisol, as well as heart rate variability indices. Clinical markers consisted of questionnaire scores for symptoms of post-exertional malaise, inflammation, fatigue, depression and trait anxiety, as well as activity recordings.

    Results

    A total of 29 CFS patients and 18 healthy controls were included. We identified 176 genes as differentially expressed in patients compared to controls, adjusting for age and gender factors. Gene set enrichment analyses suggested impairment of B cell differentiation and survival, as well as enhancement of innate antiviral responses and inflammation in the CFS group. A pattern of co-expression could be identified, and this pattern, as well as single gene transcripts, was significantly associated with indices of autonomic nervous activity, plasma cortisol, and blood monocyte and eosinophil counts. Also, an association with symptoms of post-exertional malaise was demonstrated.

    Conclusion

    Adolescent CFS is characterized by differential gene expression pattern in whole blood suggestive of impaired B cell differentiation and survival, and enhanced innate antiviral responses and inflammation. This expression pattern is associated with neuroendocrine markers of altered HPA axis and autonomic nervous activity, and with symptoms of post-exertional malaise.

  • 18. Ch'ng, Jun-Hong
    et al.
    Sirel, Madle
    Zandian, Arash
    del Pilar Quintana, Maria
    Chan, Sherwin Chun Leung
    Moll, Kirsten
    Tellgren-Roth, Åsa
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Nilsson, IngMarie
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Nilsson, Peter
    Qundos, Ulrika
    Wahlgren, Mats
    Epitopes of anti-RIFIN antibodies and characterization of rif-expressing Plasmodium falciparum parasites by RNA sequencing2017In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, article id 43190Article in journal (Refereed)
    Abstract [en]

    Variable surface antigens of Plasmodium falciparum have been a major research focus since they facilitate parasite sequestration and give rise to deadly malaria complications. Coupled with its potential use as a vaccine candidate, the recent suggestion that the repetitive interspersed families of polypeptides (RIFINs) mediate blood group A rosetting and influence blood group distribution has raised the research profile of these adhesins. Nevertheless, detailed investigations into the functions of this highly diverse multigene family remain hampered by the limited number of validated reagents. In this study, we assess the specificities of three promising polyclonal anti-RIFIN antibodies that were IgG-purified from sera of immunized animals. Their epitope regions were mapped using a 175,000-peptide microarray holding overlapping peptides of the P. falciparum variable surface antigens. Through immunoblotting and immunofluorescence imaging, we show that different antibodies give varying results in different applications/assays. Finally, we authenticate the antibody-based detection of RIFINs in two previously uncharacterized non-rosetting parasite lines by identifying the dominant rif transcripts using RNA sequencing.

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

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

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

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

  • 21.
    Dubicke, Aurelija
    et al.
    Department of Woman and Child Health, Karolinska Institute. Stockholm, Sweden.
    Sverremark-Ekström, Eva
    Stockholm University.
    Fransson, Emma
    Department of Woman and Child Health, Karolinska Institutet, Stockholm, Sweden.
    Centini, Gabriela
    Department of Pediatrics, Obstetrics and Reproductive Medicine, University of Siena, 53100 Siena, Ital.
    Andersson, Eva
    Department of Woman and Child Health, Karolinska Institute. Stockholm, Sweden.
    Byström, Birgitta
    Department of Woman and Child Health, Karolinska Institute. Stockholm, Sweden.
    Ekman-Ordeberga, Gunvor
    Department of Woman and Child Health, Karolinska Institute, Stockholm, Sweden.
    Malmström, Anders Malmström
    Department of Experimental Medical Science, University of Lund, 221 84 Lund, Sweden.
    Petraglia, Felice
    Department of Pediatrics, Obstetrics and Reproductive Medicine, University of Siena, 53100 Siena, Italy.
    Pro-inflammatory and anti-inflammatory cytokines in human preterm and term cervical ripening2010In: Journal of Reproductive Immunology, ISSN 0165-0378, E-ISSN 1872-7603, Vol. 84, no 2, p. 176-185Article in journal (Refereed)
    Abstract [en]

    Cervical ripening is necessary for successful delivery. Since cytokines are believed to be involved in this process, the aim of this study was to investigate possible changes in the mRNA and protein expression of pro-inflammatory cytokines (interleukin (IL)-1 alpha, IL-1 beta, IL-12, IL-18) and anti-inflammatory cytokines (IL-4, IL-10, IL-13)in the human cervix during pregnancy, term and preterm labor. Cervical biopsies were taken from 59 women: 21 at preterm labor, 24 at term labor, 10 at term not in labor and 4 from non-pregnant women. mRNA was analyzed with real-time RT-PCR and protein expression and/or secretion with immunohistochemistry and ELISA. There was an upregulation of mRNA for IL-10, IL-13, IL-1 alpha and IL-1 beta in the laboring groups, while mRNA for IL-12 and IL-18 was downregulated. IL-4 mRNA was detected more frequently, while IL-12 mRNA expression was lower, in the preterm labor group than in the term labor group. The protein levels of IL-4 and IL-12 were lower and IL-18 tended to be higher in the labor groups, while IL-10 protein levels were unaffected by labor. IL-4 protein levels were significantly higher in the preterm subgroup with bacterial infection than in the non-infected group. IL-10 had higher expression in squamous epithelium at preterm labor than at term. In conclusion, the major changes in pro-inflammatory and anti-inflammatory cytokine mRNA and protein expression in cervix occur during the labor process irrespective of the length of gestation. Our results indicate that dysregulation of anti-inflammatory cytokines in the human cervix could be involved in the pathogenesis of preterm labor.

  • 22.
    Farouk, Salah Eldin
    Stockholm University, Faculty of Science, Wenner-Gren Institute for Experimental Biology.
    T cell and antibody responses in Plasmodium falciparum malaria and their relation to disease susceptibility2004Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Malaria antigen-induced polarization of T cells into effectors Th1 and/or Th2 cells and their subsequent release of cytokines is known to affect antibody production. This thesis includes studies on early innate responses to the parasite, with a focus on γδT cells, and acquired specific responses in African sympatric ethnic tribes. In the last part of this thesis, a method for enrichment for the asexual blood stages of P. falciparum and their use in in vitro T-cell studies is presented.

    To investigate mechanisms involved in parasite growth inhibition by γδT cells, an in vitro system was set up using blood stage parasites co-cultured with differently treated γδT cells. The results showed that Vγ9/δ2+ γδT cells inhibited the in vitro growth of P. falciparum parasites whereas CD4+ and CD8+ T cells did not. This inhibition was positively correlated with the expression of cytolytic molecules in the cell lines tested. Anti-granulysin antibodies reversed γδT cell-mediated inhibition, suggesting a role for granulysin in the parasite growth inhibition. Thus, our data suggest that Vγ9/δ2+ γδT cells inhibit the parasite growth by a granulysin-exocytosis dependent cytotoxic pathway that needs perforin.

    To study the humoral responses and their relation to Th1/Th2 cytokine profiles, antibody levels, numbers of cytokine-producing cells and spleen rates were measured in two sympatric tribes living in Mali, the Fulani and the Dogon. Our results revealed significantly elevated malaria-specific IgG and IgE antibody levels and spleen rates in the Fulani compared to the Dogon. The Fulani exhibited elevated numbers of both IL-4 and IFN-γ-producing cells, a typical profile seen of CD1-restricted NKT cells. This together with the higher spleen rates and elevated anti-malarial antibodies suggests a role of CD1-restricted cells in the different responses seen between these tribes.

    To investigate whether such responses were specifically confined to malaria or a reflection of a generally activated immune system, total levels of IgG and of IgM as well as IgG antibodies to non-malarial antigens were examined in the Fulani in Burkina Faso and Mali. The results showed that the Fulani consistently mounted stronger malaria-specific IgG, IgG1, IgG3 and IgM responses. Total IgM levels were significantly higher in the Fulani than the non-Fulani, whereas total IgG did not differ between the two tribes. While IgG levels to some non-malarial antigens were significantly higher in the Fulani, no such differences were seen in the responses to several other non-malarial antigens suggesting that the Fulani are not generally hyper-reactive and that other specific factors are of importance for their higher malaria resistance.

    Finally, a new method to enrich for early and late asexual blood stages of P. falciparum parasite from a single parasite culture was developed, using a 3-step centrifugation procedure. Such enriched parasite fractions beside other malaria-parasite antigen preparations were used in an in vitro system to analyse T-cell responses in malaria-exposed and non-exposed donors. Such analysis revealed significant proliferative cell response and CD4+ T cell expansion to whole-cell parasite antigens, but not to acellular parasite fractions, in the malaria-exposed as compared to the non-exposed ones. Our data suggest that natural infection preferentially leads to formation of memory cells against certain antigen expressed in live parasites.

    Malaria antigen-induced polarization of T cells into effectors Th1 and/or Th2 cells and their subsequent release of cytokines is known to affect antibody production. This thesis includes studies on early innate responses to the parasite, with a focus on γδT cells, and acquired specific responses in African sympatric ethnic tribes. In the last part of this thesis, a method for enrichment for the asexual blood stages of P. falciparum and their use in in vitro T-cell studies is presented.

    To investigate mechanisms involved in parasite growth inhibition by γδT cells, an in vitro system was set up using blood stage parasites co-cultured with differently treated γδT cells. The results showed that Vγ9/δ2+ γδT cells inhibited the in vitro growth of P. falciparum parasites whereas CD4+ and CD8+ T cells did not. This inhibition was positively correlated with the expression of cytolytic molecules in the cell lines tested. Anti-granulysin antibodies reversed γδT cell-mediated inhibition, suggesting a role for granulysin in the parasite growth inhibition. Thus, our data suggest that Vγ9/δ2+ γδT cells inhibit the parasite growth by a granulysin-exocytosis dependent cytotoxic pathway that needs perforin.

    To study the humoral responses and their relation to Th1/Th2 cytokine profiles, antibody levels, numbers of cytokine-producing cells and spleen rates were measured in two sympatric tribes living in Mali, the Fulani and the Dogon. Our results revealed significantly elevated malaria-specific IgG and IgE antibody levels and spleen rates in the Fulani compared to the Dogon. The Fulani exhibited elevated numbers of both IL-4 and IFN-γ-producing cells, a typical profile seen of CD1-restricted NKT cells. This together with the higher spleen rates and elevated anti-malarial antibodies suggests a role of CD1-restricted cells in the different responses seen between these tribes.

    To investigate whether such responses were specifically confined to malaria or a reflection of a generally activated immune system, total levels of IgG and of IgM as well as IgG antibodies to non-malarial antigens were examined in the Fulani in Burkina Faso and Mali. The results showed that the Fulani consistently mounted stronger malaria-specific IgG, IgG1, IgG3 and IgM responses. Total IgM levels were significantly higher in the Fulani than the non-Fulani, whereas total IgG did not differ between the two tribes. While IgG levels to some non-malarial antigens were significantly higher in the Fulani, no such differences were seen in the responses to several other non-malarial antigens suggesting that the Fulani are not generally hyper-reactive and that other specific factors are of importance for their higher malaria resistance.

    Finally, a new method to enrich for early and late asexual blood stages of P. falciparum parasite from a single parasite culture was developed, using a 3-step centrifugation procedure. Such enriched parasite fractions beside other malaria-parasite antigen preparations were used in an in vitro system to analyse T-cell responses in malaria-exposed and non-exposed donors. Such analysis revealed significant proliferative cell response and CD4+ T cell expansion to whole-cell parasite antigens, but not to acellular parasite fractions, in the malaria-exposed as compared to the non-exposed ones. Our data suggest that natural infection preferentially leads to formation of memory cells against certain antigen expressed in live parasites.

    Malaria antigen-induced polarization of T cells into effectors Th1 and/or Th2 cells and their subsequent release of cytokines is known to affect antibody production. This thesis includes studies on early innate responses to the parasite, with a focus on γδT cells, and acquired specific responses in African sympatric ethnic tribes. In the last part of this thesis, a method for enrichment for the asexual blood stages of P. falciparum and their use in in vitro T-cell studies is presented.

    To investigate mechanisms involved in parasite growth inhibition by γδT cells, an in vitro system was set up using blood stage parasites co-cultured with differently treated γδT cells. The results showed that Vγ9/δ2+ γδT cells inhibited the in vitro growth of P. falciparum parasites whereas CD4+ and CD8+ T cells did not. This inhibition was positively correlated with the expression of cytolytic molecules in the cell lines tested. Anti-granulysin antibodies reversed γδT cell-mediated inhibition, suggesting a role for granulysin in the parasite growth inhibition. Thus, our data suggest that Vγ9/δ2+ γδT cells inhibit the parasite growth by a granulysin-exocytosis dependent cytotoxic pathway that needs perforin.

    To study the humoral responses and their relation to Th1/Th2 cytokine profiles, antibody levels, numbers of cytokine-producing cells and spleen rates were measured in two sympatric tribes living in Mali, the Fulani and the Dogon. Our results revealed significantly elevated malaria-specific IgG and IgE antibody levels and spleen rates in the Fulani compared to the Dogon. The Fulani exhibited elevated numbers of both IL-4 and IFN-γ-producing cells, a typical profile seen of CD1-restricted NKT cells. This together with the higher spleen rates and elevated anti-malarial antibodies suggests a role of CD1-restricted cells in the different responses seen between these tribes.

    To investigate whether such responses were specifically confined to malaria or a reflection of a generally activated immune system, total levels of IgG and of IgM as well as IgG antibodies to non-malarial antigens were examined in the Fulani in Burkina Faso and Mali. The results showed that the Fulani consistently mounted stronger malaria-specific IgG, IgG1, IgG3 and IgM responses. Total IgM levels were significantly higher in the Fulani than the non-Fulani, whereas total IgG did not differ between the two tribes. While IgG levels to some non-malarial antigens were significantly higher in the Fulani, no such differences were seen in the responses to several other non-malarial antigens suggesting that the Fulani are not generally hyper-reactive and that other specific factors are of importance for their higher malaria resistance.

    Finally, a new method to enrich for early and late asexual blood stages of P. falciparum parasite from a single parasite culture was developed, using a 3-step centrifugation procedure. Such enriched parasite fractions beside other malaria-parasite antigen preparations were used in an in vitro system to analyse T-cell responses in malaria-exposed and non-exposed donors. Such analysis revealed significant proliferative cell response and CD4+ T cell expansion to whole-cell parasite antigens, but not to acellular parasite fractions, in the malaria-exposed as compared to the non-exposed ones. Our data suggest that natural infection preferentially leads to formation of memory cells against certain antigen expressed in live parasites.

  • 23. Fergusson, J. R.
    et al.
    Huehn, M. H.
    Swadling, L.
    Walker, L. J.
    Kurioka, A.
    Llibre, A.
    Bertoletti, A.
    Hollaender, G.
    Newell, E. W.
    Davis, M. M.
    Sverremark-Ekström, Eva
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Powrie, F.
    Capone, S.
    Folgori, A.
    Barnes, E.
    Willberg, C. B.
    Ussher, J. E.
    Klenerman, P.
    CD161(int)CD8+T cells: a novel population of highly functional, memory CD8+T cells enriched within the gut2016In: Mucosal Immunology, ISSN 1933-0219, E-ISSN 1935-3456, Vol. 9, no 2, p. 401-413Article in journal (Refereed)
    Abstract [en]

    The C-type lectin-like receptor CD161 is expressed by lymphocytes found in human gut and liver, as well as blood, especially natural killer (NK) cells, T helper 17 (Th17) cells, and a population of unconventional Tcells known as mucosalassociated invariant T (MAIT) cells. The association of high CD161 expression with innate T-cell populations including MAITcells is established. Here we show that CD161 is also expressed, at intermediate levels, on a prominent subset of polyclonal CD8+ T cells, including antiviral populations that display a memory phenotype. These memory CD161(int)CD8+ Tcells are enriched within the colon and express both CD103 and CD69, markers associated with tissue residence. Furthermore, this population was characterized by enhanced polyfunctionality, increased levels of cytotoxic mediators, and high expression of the transcription factors T-bet and eomesodermin (EOMES). Such populations were induced by novel vaccine strategies based on adenoviral vectors, currently in trial against hepatitis C virus. Thus, intermediate CD161 expression marks potent polyclonal, polyfunctional tissue-homing CD8+ T-cell populations in humans. As induction of such responses represents a major aim of T-cell prophylactic and therapeutic vaccines in viral disease and cancer, analysis of these populations could be of value in the future.

  • 24.
    Gebremariam, Hanna G.
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Qazi, Khaleda Rahman
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Somiah, Tanvi
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Pathak, Sushil Kumar
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Sjölinder, Hong
    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.
    Jonsson, Ann-Beth
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Lactobacillus gasseri Suppresses the Production of Proinflammatory Cytokines in Helicobacter pylori-Infected Macrophages by Inhibiting the Expression of ADAM172019In: Frontiers in Immunology, ISSN 1664-3224, E-ISSN 1664-3224, Vol. 10, article id 2326Article in journal (Refereed)
    Abstract [en]

    The ability of Helicobacter pylori to evade the host immune system allows the bacterium to colonize the host for a lifetime. Long-term infection with H. pylori causes chronic inflammation, which is the major risk factor for the development of gastric ulcers and gastric cancer. Lactobacilli are part of the human microbiota and have been studied as an adjunct treatment in H. pylori eradication therapy. However, the molecular mechanisms by which lactobacilli act against H. pylori infection have not been fully characterized. In this study, we investigated the anti-inflammatory effects of Lactobacillus strains upon coincubation of host macrophages with H. pylori. We found that Lactobacillus gasseri Kx110A1 (L. gas), a strain isolated from a human stomach, but not other tested Lactobacillus species, blocked the production of the proinflammatory cytokines TNF and IL-6 in H. pylori-infected macrophages. Interestingly, L. gas also inhibited the release of these cytokines in LPS or LTA stimulated macrophages, demonstrating a general anti-inflammatory property. The inhibition of these cytokines did not occur through the polarization of macrophages from the M1 (proinflammatory) to M2 (anti-inflammatory) phenotype or through the altered viability of H. pylori or host cells. Instead, we show that L. gas suppressed the release of TNF and IL-6 by reducing the expression of ADAM17 (also known as TNF-alpha-converting enzyme, TACE) on host cells. Our findings reveal a novel mechanism by which L. gas prevents the production of the proinflammatory cytokines TNF and IL-6 in host macrophages.

  • 25.
    Gerasimcik, Natalija
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. University of Gothenburg, Sweden.
    He, Minghui
    Dahlberg, Carin I. M.
    Kuznetsov, Nikolai V.
    Severinson, Eva
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Westerberg, Lisa S.
    The small rho GTPases Rac1 and Rac2 are important for T-cell independent antigen responses and for suppressing switching to IgG2b in Mice2017In: Frontiers in Immunology, ISSN 1664-3224, E-ISSN 1664-3224, Vol. 8, article id 1264Article in journal (Refereed)
    Abstract [en]

    The Rho GTPases Cdc42, Rac1, and Rac2 coordinate receptor signaling to cell adhesion, migration, and proliferation. Deletion of Rac1 and Rac2 early during B cell development leads to failure in B cell entry into the splenic white pulp. Here, we sought to understand the role of Rac1 and Rac2 in B cell functionality and during the humoral antibody response. To circumvent the migratory deficiency of B cells lacking both Rac1 and Rac2, we took the approach to inducibly delete Rac1 in Rac2(-/-) B cells in the spleen (Rac1(B)Rac2(-/-) B cells). Rac1(B)Rac2(-/-) mice had normal differentiation of splenic B cell populations, except for a reduction in marginal zone B cells. Rac1(B)Rac2(-/-) B cells showed normal spreading response on antibody-coated layers, while both Rac2(-/-) and Rac1(B)Rac2(-/-) B cells had reduced homotypic adhesion and decreased proliferative response when compared to wild-type B cells. Upon challenge with the T-cell-independent antigen TNP-conjugated lipopolysaccharide, Rac1(B)Rac2(-/-) mice showed reduced antibody response. In contrast, in response to the T-cell-dependent antigen sheep red blood cells, Rac1(B)Rac2(-/-) mice had increased serum titers of IgG1 and IgG2b. During in vitro Ig class switching, Rac1(B)Rac2(-/-) B cells had elevated germline gamma 2b transcripts leading to increased Ig class switching to IgG2b. Our data suggest that Rac1 and Rac2 serve an important role in regulation of the B cell humoral immune response and in suppressing Ig class switching to IgG2b.

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

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

  • 27.
    Giusti, Pablo
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Dendritic cells and Plasmodium falciparum: studies in vitro and in the human host2009Licentiate thesis, comprehensive summary (Other academic)
    Abstract [en]

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

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

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

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

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

  • 28.
    Giusti, Pablo
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    The novel anti-rheumatic compound Rabeximod impairs differentiation and function of human pro-inflammatory dendritic cells and macrophages2011In: Immunobiology, ISSN 0171-2985, E-ISSN 1878-3279, Vol. 216, no 1-2, p. 243-250Article in journal (Refereed)
    Abstract [en]

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

  • 29.
    Giusti, Pablo
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Troye Blomberg, Marita
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Varani, Stefania
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Plasmodium falciparum-Infected Erythrocytes and beta-Hematin Induce Partial Maturation of Human Dendritic Cells and Increase Their Migratory Ability in Response to Lymphoid Chemokines2011In: Infection and Immunity, ISSN 0019-9567, E-ISSN 1098-5522, Vol. 79, no 7, p. 2727-2736Article in journal (Refereed)
    Abstract [en]

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

  • 30. Grunewald, Johan
    et al.
    Kaiser, Ylva
    Ostadkarampour, Mahyar
    Rivera, Natalia V.
    Vezzi, Francesco
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Lötstedt, Britta
    Olsen, Remi-André
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Sylwan, Lina
    Lundin, Sverker
    Käller, Max
    Sandalova, Tatiana
    Ahlgren, Kerstin M.
    Wahlström, Jan
    Achour, Adnane
    Ronninger, Marcus
    Eklund, Anders
    T-cell receptor-HLA-DRB1 associations suggest specific antigens in pulmonary sarcoidosis2016In: European Respiratory Journal, ISSN 0903-1936, E-ISSN 1399-3003, Vol. 47, no 3, p. 898-909Article in journal (Refereed)
    Abstract [en]

    In pulmonary sarcoidosis, CD4(+) T-cells expressing T-cell receptor V alpha 2.3 accumulate in the lungs of HLA-DRB1*03(+) patients. To investigate T-cell receptor-HLA-DRB1*03 interactions underlying recognition of hitherto unknown antigens, we performed detailed analyses of T-cell receptor expression on bronchoalveolar lavage fluid CD4(+) T-cells from sarcoidosis patients. Pulmonary sarcoidosis patients (n=43) underwent bronchoscopy with bronchoalveolar lavage. T-cell receptor alpha and beta chains of CD4(+) T-cells were analysed by flow cytometry, DNA-sequenced, and three-dimensional molecular models of T-cell receptor-HLA-DRB1*03 complexes generated. Simultaneous expression of V alpha 2.3 with the V beta 22 chain was identified in the lungs of all HLA-DRB1*03(+) patients. Accumulated V alpha 2.3/V beta 22-expressing T-cells were highly clonal, with identical or near-identical V alpha 2.3 chain sequences and inter-patient similarities in V beta 22 chain amino acid distribution. Molecular modelling revealed specific T-cell receptor-HLA-DRB1*03-peptide interactions, with a previously identified, sarcoidosis-associated vimentin peptide, (Vim)(429-443) DSLPLVDTHSKRTLL, matching both the HLA peptide-binding cleft and distinct T-cell receptor features perfectly. We demonstrate, for the first time, the accumulation of large clonal populations of specific V alpha 2.3/V beta 22 T-cell receptor-expressing CD4(+) T-cells in the lungs of HLA-DRB1*03(+) sarcoidosis patients. Several distinct contact points between V alpha 2.3/V beta 22 receptors and HLA-DRB1*03 molecules suggest presentation of prototypic vimentin-derived peptides.

  • 31. Guenot, Marianne
    et al.
    Loizon, Séverine
    Howard, Jennifer
    Costa, Giulia
    Baker, David A.
    Mohabeer, Shaneel Y.
    Troye-Blomberg, Marita
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Moreau, Jean-Francois
    Dechanet-Merville, Julie
    Mercereau-Puijalon, Odile
    Mamani-Matsuda, Maria
    Behr, Charlotte
    Phosphoantigen Burst upon Plasmodium falciparum Schizont Rupture Can Distantly Activate V gamma 9V delta 2 T Cells2015In: Infection and Immunity, ISSN 0019-9567, E-ISSN 1098-5522, Vol. 83, no 10, p. 3816-3824Article in journal (Refereed)
    Abstract [en]

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

  • 32. Göranson, Sofie Paues
    et al.
    Thålin, Charlotte
    Lundström, Annika
    Hållström, Lars
    Lasselin, Julie
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska Institutet, Sweden.
    Wallén, Håkan
    Soop, Anne
    Mobarrez, Fariborz
    Circulating H3Cit is elevated in a human model of endotoxemia and can be detected bound to microvesicles2018In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, article id 12641Article in journal (Refereed)
    Abstract [en]

    Early diagnosis of sepsis is crucial since prompt interventions decrease mortality. Citrullinated histone H3 (H3Cit), released from neutrophil extracellular traps (NETs) upon binding of platelets to neutrophils following endotoxin stimulation, has recently been proposed a promising blood biomarker in sepsis. Moreover, microvesicles (MVs), which are released during cell activation and apoptosis and carry a variety of proteins from their parental cells, have also been shown to be elevated in sepsis. In a randomized and placebo-controlled human model of endotoxemia (lipopolysaccharide injection; LPS), we now report significant LPS-induced elevations of circulating H3Cit in 22 healthy individuals. We detected elevations of circulating H3Cit by enzyme-linked immunosorbent assay (ELISA), as well as bound to MVs quantified by flow cytometry. H3Cit-bearing MVs expressed neutrophil and/or platelet surface markers, indicating platelet-neutrophil interactions. In addition, in vitro experiments revealed that H3Cit can bind to phosphatidylserine exposed on platelet derived MVs. Taken together; our results demonstrate that NETs can be detected in peripheral blood during endotoxemia by two distinct H3Cit-specific methods. Furthermore, we propose a previously unrecognized mechanism by which H3Cit may be disseminated throughout the vasculature by the binding to MVs.

  • 33.
    Haileselassie, Yeneneh
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    THE INFLUENCE OF LACTOBACILLI AND STAPHYLOCOCCUS AUREUS ON IMMUNE RESPONSIVENESS IN VITRO2013Licentiate thesis, comprehensive summary (Other academic)
    Abstract [en]

    Alteration of gut microbiota has been associated with development of immune mediated diseases, such as allergy. In part, this could be due to the influence of microbes in shaping the immune response. In paper I, we investigated the association of early-life gut colonization with bacteria, and numbers of IL-4, IL-10 and IFN-γ producing cells at two years of age in response to PBMC stimulation with phytohemagglutinin (PHA) in vitro. Early Staphylococcus (S) aureus colonization was directly proportional to increased numbers of IL-4 and IL-10 secreting cells, while early co-colonization with lactobacilli and S. aureus associated with a decrease in IL-4, IL-10 and IFN-γ secreting cells compared to S. aureus alone. This was also confirmed in in vitro stimulations of PBMC with Lactobacillus and/or S. aureus strains, where S. aureus-induced IFN-γ production by Th cells was down regulated by co-stimulation with Lactobacillus. In paper II, we investigated the effects of UV-killed and/or culture supernatant (sn) of Lactobacillus strains and S. aureus strains on IEC and immune cell responses. IEC exposed to S. aureus-sn produced CXCL-1/GRO-α and CXCL-8/IL-8, while UV-killed bacteria had no effect. Further, PBMC from healthy donors exposed to Lactobacillus-sn and S. aureus-sn were able to produce a plethora of cytokines, but only S. aureus induced the T-cell associated cytokines: IL-2, IL-17, IFN-γ and TNF-α; which were down regulated by co-stimulation with any of the different Lactobacillus strains. Intracellular staining verified S. aureus-induced IFN-γ and IL-17 production by Th cells, and increased CTLA-4 expression and IL-10 production by T reg cells.

    In conclusion, we show that colonization with gut microbiota at early age modulates the cytokine response in infancy. In addition, bacterial species influence cytokine response in a species-specific manner and we demonstrate that lactobacilli modulate S. aureus-induced immune response away from an inflammatory phenotype.

  • 34. Hales, B. J.
    et al.
    Hizawa, N.
    Jenmalm, M.
    Sverremark-Ekström, Eva
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Wardlaw, A. J.
    Developments in the field of allergy in 2014 through the eyes of Clinical and Experimental Allergy2015In: Clinical and Experimental Allergy, ISSN 0954-7894, E-ISSN 1365-2222, Vol. 45, no 12, p. 1723-1745Article, review/survey (Refereed)
    Abstract [en]

    The pathogenesis of asthma continues to be a major topic of interest to our authors with reviews and original papers on the role of viruses, mechanisms of inflammation, biomarkers, and phenotypes of asthma being major topics. A number of papers described new treatments for asthma focusing on blocking the Th2 response reflecting the fact that two decades of work in this area is finally bearing fruit. The pathogenesis of chronic rhinosinusitis is a growing area of interest, but there has been less on the genetics of airways disease than in previous years possibly reflecting the degree of rigour (and therefore a smaller body of work), with which these sorts of studies are now being undertaken. There continues to be a wide range of papers dealing with mechanisms of allergic disease ranging from clinical-based studies to basic research and the use of in vivo animal models especially mice. As before, mechanisms and new approaches to immunotherapy are common themes. Several were published in the allergens section investigating modification of allergens to increase their effectiveness and reduce the risk of adverse events. Risk factors for allergic disease was a common theme in the epidemiology section and food allergy a common theme in clinical allergy with papers on the development of protocols to induce tolerance and attempts to find biomarkers to distinguish sensitization from allergic disease. This was another exciting year for the editors, and we hope the readers of the journal.

  • 35.
    Hallander, Hans
    et al.
    Swedish Institute for Infectious Disease Control.
    Andersson, Mikael
    Stockholm University, Faculty of Science, Department of Mathematics.
    Gustafsson, Lennart
    Swedish Institute for Infectious Disease Control.
    Ljungman, Margaretha
    Swedish Institute for Infectious Disease Control.
    Netterlid, Eva
    Swedish Institute for Infectious Disease Control.
    Seroprevalence of pertussis antitoxin (anti-PT) in Sweden before and 10 years after the introduction of a universal childhood pertussis vaccination program2009In: Acta Pathologica, Microbiologica et Immunologica Scandinavica (APMIS), ISSN 0903-4641, E-ISSN 1600-0463, Vol. 117, no 12, p. 912-922Article in journal (Refereed)
    Abstract [en]

    The prevalence of IgG ELISA antibodies against pertussis toxin (anti-PT) was studied in two Swedish seroepidemiological studies. One was performed in 1997 when the new pertussis vaccination program was 1 year old (n = 3420). In 2007, when Pa vaccines had been used countrywide for 10 years in the universal child vaccination program, this study was repeated to analyze the effect of vaccination on anti-PT prevalence (n = 2379). Before the statistical analysis of seroprevalence, children vaccinated within the last 2 years before the serosurveys were excluded. The results indicate a reduced exposure to Bordetella pertussis in the population. The proportion of sera without measurable anti-PT antibodies increased significantly, aggregated over all comparable age groups, from 3.8% in people sampled in 1997 to 16.3% in people sampled in 2007. For cord blood, 1% was without measurable anti-PT antibodies in 1997 compared to a significantly higher level, 12%, in 2007. With anti-PT concentrations of ≥50 and ≥100 EU/ml as cutoff points for 'recent infection' the proportion above the cutoff points for younger children was significantly higher in 1997 than in 2007 at both cutoff points. For all adults, 20 years of age and older, the difference in proportions above the lower cutoff point was close to statistically significant, comparing 1997 with 2007. This was not the case at 100 EU/ml. In the 1997 samples of children, there was a significant downward trend of 'recent infections' at both cutoff points for three sampled age groups between 5 and 15 years of age from 21% at 5.0–5.5 years of age to 7% at 14.7–15.7 years for the lowest cutoff. In the 2007 samples of children, on the contrary, there was a significant continuous upward trend of 'recent infections', at both cutoff points, for four sampled age groups between 4 and 18 years of age – from 4% at 4–5 years of age to 16% at 17–18 years at the lowest cutoff. The continuous increase, with age of children with high anti-PT concentrations, supports the recent change in the general Swedish childhood vaccination program to include a pre-school booster at 5–6 years and a school-leaving booster at 14–16 years of age.

  • 36.
    Hansson, Monika
    Stockholm University, Faculty of Science, Wenner-Gren Institute for Experimental Biology.
    Mercury-induced autoimmunity: Genetics and immunoregulation2004Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The existence of immune self-tolerance allows the immune system to mount responses against infectious agents, but not against self-molecular constitutes. Although self-tolerance is a robust phenomenon, in some individuals as well as in experimental models, the self-tolerance breaks down and as a result, a self-destructive autoimmune disease emerges. The underlying mechanisms for the development of autoimmune diseases are not known, but genetic, environmental and immunological factors are suggested to be involved. In this thesis, we used murine mercury-induced autoimmunity to test this suggestion.

    In susceptible mice mercuric chloride induces a systemic autoimmune disease characterized by increased serum levels of IgG1 and IgE, production of anti-nucleolar autoantibodies (ANolA) and formation of renal IgG deposits. In contrast, in resistant DBA/2 (H-2d) mice, none of these characteristics develop after exposure to mercury. By crossing and backcrossing mercury-resistant DBA/2 mice to mercury susceptible strains, we found that the resistance was inherited as a dominant trait in F1 hybrids and that one gene or a cluster of genes located in the H-2 loci determined the resistance to ANolA production, whereas resistance to the other characteristics was found to be controlled by two or three non-H-2 genes.

    We further put forward the “cryptic peptide hypothesis” to investigate whether mercury and another xenobiotic metal use similar pathway(s) to induce the H-2 linked production of ANolA. We found that while mercury stimulated ANolA synthesis in all H-2 susceptible (H-2s, H-2q and H-2f) mouse strains, silver induced only ANolA responses in H-2s and H-2q mice, but not in H-2f mice. Further studies showed that the resistance to silver-induced ANolA production in H-2f mice was inherited as a dominant trait.

    We next tested the proposition that mercury induces more adverse immunological effects in mouse strains, which are genetically prone to develop autoimmune diseases, using tight-skin 1 mice, an animal model for human Scleroderma. It was found that in this strain, mercury induced a strong immune activation with autoimmune characteristics, but did not accelerate the development of dermal fibrosis, a characteristic in Tsk/1 mice.

    Finally we addressed the Th1/Th2 cross-regulation paradigm by examining if a Th1-type of response could interact with a Th2-type of response if simultaneous induced in susceptible mice. Our findings demonstrated that mercury-induced autoimmunity (Th2-type) and collagen-induced arthritis (CIA) (Th1-type) can interact in a synergistic, antagonistic or additive fashion, depending on at which stage of CIA mercury is administered.

  • 37. Howard, Jennifer
    et al.
    Loizon, Séverine
    Tyler, Christopher J.
    Duluc, Dorothée
    Moser, Bernhard
    Mechain, Matthieu
    Duvignaud, Alexandre
    Malvy, Denis
    Troye-Blomberg, Marita
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Moreau, Jean-Francois
    Eberl, Matthias
    Mercereau-Puijalon, Odile
    Déchanet-Merville, Julie
    Behr, Charlotte
    Mamani-Matsuda, Maria
    The Antigen-Presenting Potential of V gamma 9V delta 2 T Cells During Plasmodium falciparum Blood-Stage Infection2017In: Journal of Infectious Diseases, ISSN 0022-1899, E-ISSN 1537-6613, Vol. 215, no 10, p. 1569-1579Article in journal (Refereed)
    Abstract [en]

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

  • 38. Höglind, Ankie
    et al.
    Areström, Irene
    Ehrnfelt, Cecilia
    Masjedi, Khosro
    Zuber, Bartels
    Giavedoni, Luis
    Ahlborg, Niklas
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. Mabtech, Sweden.
    Systematic evaluation of monoclonal antibodies and immunoassays for the detection of Interferon-gamma and Interleukin-2 in old and new world non-human primates2017In: JIM - Journal of Immunological Methods, ISSN 0022-1759, E-ISSN 1872-7905, Vol. 441, p. 39-48Article in journal (Refereed)
    Abstract [en]

    Non-human primates (NHP) provide important animal models for studies on immune responses to infections and vaccines. When assessing cellular immunity in NHP, cytokines are almost exclusively analyzed utilizing cross-reactive anti-human antibodies. The functionality of antibodies has to be empirically established for each assay/application as well as NHP species.

    A rational approach was employed to identify monoclonal antibodies (mAb) cross-reactive with many NHP species. Panels of new and established mAbs against human Interferon (IFN)-gamma and Interleukin (IL)-2 were assessed for reactivity with eukaryotically expressed recombinant IFN-gamma and IL-2, respectively, from Old (rhesus, cynomolgus and pigtail macaques, African green monkey, sooty mangabey and baboon) and New World NHP (Ma's night monkey, squirrel monkey and common marmoset).

    Pan-reactive mAbs, recognizing cytokines from all NHP species, were further analyzed in capture assays and flow cytometry with NHP peripheral blood mononuclear cells (PBMC). Pan-reactive mAb pairs for IFN-gamma well as IL-2 were identified and used in ELISA to measure IFN-gamma and IL-2, respectively, in Old and New World NHP PBMC supernatants. The same mAb pairs displayed high functionality in ELISpot and FluoroSpot for the measurement of antigen-specific IFN-gamma and IL-2 responses using cynomolgus PBMC Functionality of pan-reactive mAbs in flow cytometry was also verified with cynomolgus PBMC.

    The development of well-defined immunoassays functional with a panel of NHP species facilitates improved analyses of cellular immunity and enables inclusion in multiplex cytokine assays intended for a variety of NHP.

  • 39.
    Högstrand, Kari
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Gene conversion of the mouse MHC class II1998Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The major histocompatibility complex (MHC) is the most polymorphic vertebrate gene loci known to exist. Gene products of the MHC are responsible for presentation of antigen derived peptides to T cells of the immune system, which thereby become activated and involved in the elimination of particles recognised as non-self. The mechanism of acquiring this extensive polymorphism is not known, but gene conversion has been suggested as one possible molecular genetic mechanism employed to generate new MHC alleles. A strict definition of gene conversion, based on the phenomenon in yeast, involves the transfer of a DNA fragment from a donor gene to a homologous acceptor gene without the donor gene being changed in the process. For practical reasons, the term gene conversion in higher organisms is rather used in the context of ìtemplated segmental mutationì.

    This thesis describes the first direct evidence of gene conversion events between two endogenous MHC class II genes in a mouse system using sperm as a representative for future potential individuals. A PCR assay was developed using primers for the acceptor gene as well as the donor gene to obtain a detectable product only in cells where a gene conversion event had occurred. Interchromosomal gene conversion between a MHC class II Ab and Eb gene located on separate chromosomes was found to occur at a frequency of 1/500.000 sperm, whereas no gene conversion was detected in somatic liver cells. Intrachromosomal gene conversions between Ab and Eb genes located on the same chromosome were detected at frequencies ranging from 1/35.000 sperm to 1/830.000 sperm depending on the alleles in ves gat ed. This difference in frequency was found although the investigated alleles coexisted in the same cell, which indicates that there is sequence restraints acting on the genes involved in a gene conversion event. Both inter- and intra-chromosomal gene conversions transferred DNA fragments which varied in length, but the transfer breakpoints investigated were usually in regions where the donor and acceptor genes showed a high nucleotide similarity.

    Investigation of gene conversion during male gametogenesis showed that most gene conversion events detected between MHC class II genes were completed already in the premeiotic spermatogonia cell stage, which indicates that gene conversion relies on other molecular genetic mechanisms than normal meiotic recombination. Sequence analysis of several MHC mutants proposed to have been caused by gene conversion events revealed that both donor and acceptor sequences resided in regions where normal mammalian CpG suppression was absent. CpG dinucleotides have been shown to be relatively mutation prone, which accordingly suggests that regions with a high CpG content could be targeted for mutation events. Moreover, gene conversion could be induced and increased up to 15 times of the background level in a cell line by DNA damage, which indicates that the DNA repair system is involved in the gene conversion mechanism.

    From an evolutionary point of view, gene conversion thus is a very potent mechanism for creation of new MHC alleles by shuffling of already existing and functional parts of genes into new homologous locations. This mechanism can efficiently produce new functional MHC variants, which could give the population a selective advantage in terms of the ability to cope with various pathogens as well as being a mean to avoid inbreeding that could result in a reproductive loss.

  • 40.
    Iriemenam, Nnaemeka C.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Antibody responses and Fc gamma receptor IIa polymorphism in relation to Plasmodium falciparum malaria2009Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Immunity to asexual blood-stage of Plasmodium falciparum malaria is believed to be associated with protective antibodies of certain immunoglobulin classes and subclasses. This thesis addressed the importance of antibodies in relation to malaria infection and their effective interactions with Fc gamma receptor IIa (FcyRIIa) polymorphisms. Our data indicate that the frequency of FcyRIIa-R/R131 genotype was statistically significantly higher in Sudanese patients with severe malaria, while the FcyRIIa-H/H131 genotype showed a significant association with mild malaria. The levels of IgG1 and IgG3 subclass antibodies were statistically higher in the mild malaria patients.

    The Fulani ethnic group in West Africa has been shown to be relatively resistant to malaria. We investigated the possible impact of FcyRIIa polymorphisms in the Fulani and non-Fulani in Mali and Sudan, and analysed their malaria-reactive IgG subclass profiles. The FcyRIIa-H/H131 genotype and H131-allele were found to be prevalent in the Fulani while R131-allele was prevalent in non-Fulani. The Fulani had higher serum levels of IgG1-3, with higher proportion of IgG2 than the non-Fulani.

    Most clinico-epidemiology studies have been in areas with holo- and hyper-malaria endemicity. We have analysed antibody responses to a panel of six blood-stage antigens in relation to clinical malaria outcome in mesoendemic Sudan. Our results revealed a linear association with anti-AMA-1 IgG1 antibodies and reduced risk of severe malaria while a non-linear relationship with IgG3 antibodies was observed for MSP-2, MSP-3 and GLURP. In the combined final model, the highest levels of IgG1 subclass antibodies to AMA-1, GLURP-R0, and the highest levels of IgG3 subclass antibodies reactive to 3D7 MSP-2 were independently associated with a reduced risk of clinical malaria.

    Taken together, these data suggest a possible association between FcyRIIa-R/H131 and anti-malarial antibody responses in the clinical outcome of malaria.

     

  • 41.
    Iriemenam, Nnaemeka C.
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Khirelsied, Atif H.
    Nasr, Amre
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    ElGhazali, Gehad
    Giha, Haider A.
    Elhassan A-Elgadir, Thoraya
    Agab-Aldour, Ahmed A.
    Montgomery, Scott M.
    Anders, Robin F.
    Theisen, Michael
    Troye-Blomberg, Marita
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Elbashir, Mustafa I.
    Berzins, Klavs
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Antibody responses to a panel of Plasmodium falciparum malaria blood-stage antigens in relation to clinical disease outcome in Sudan2009In: Vaccine, ISSN 0264-410X, E-ISSN 1873-2518, Vol. 27, no 1, p. 62-71Article in journal (Refereed)
    Abstract [en]

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

  • 42.
    Israelsson, Elisabeth
    Stockholm University, Faculty of Science, Wenner-Gren Institute for Experimental Biology.
    Host genetic factors and antibody responses with potential involvement in the susceptibility to malaria2008Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The relatively lower susceptibility to malaria seen in the Fulani ethnic group in Africa, as compared to other sympatric ethnic groups, has been related to genetic regulation of the immune responses. This thesis aimed to describe important pathways related to the regulation of antibodies in the immune responses during a malaria infection. Our results suggest that the higher anti-malarial immune responses seen in the Fulani are not a general hyper-responsiveness in this group, but neither a malaria specific response. Fcγ receptors are important structures in the immune responses, and polymorphisms in these genes were associated with IgG subclass levels, P. falciparum parasitemia and haemoglobin levels, suggesting that these polymorphisms may be a contributing factor to the differential susceptibility to malaria. C-reactive protein levels rise immediately in response to inflammatory stimuli, and the -286 CRP polymorphism was indicated to influence parasite levels, suggesting a possible involvement in the lower susceptibility to malaria seen in the Fulani ethnic group. Several cytokines are important in maintaining the optimal parasite-neutralizing milieu in the host, and we investigated polymorphisms in some of these cytokine genes, in order to establish a possible influence of these on malaria susceptibility. Several of these polymorphisms showed associations with haemoglobin levels, IgG subclass antibody levels and parasitemia, suggesting that IL-1β, IL-6, IL-10 and TNF could affect the susceptibility to malaria and the severity of the malaria infection.

    Taken together, these data suggest that genetic factors have the ability to affect the antibody responses, and that several pathways can be affected. Moreover, the Fulani have a genetic predisposition for a higher inflammatory response during a malaria infection, which could lower their susceptibility to the disease. However, the control measures for this inflammation still have to be established and evaluated.

  • 43.
    Israelsson, Elisabeth
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Ekström, Mattias
    Nasr, Amre
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Dolo, Amagana
    Kearsley, Susannah
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Arambepola, Gishanthi
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Homann, Manijeh V.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Maiga, Bakary
    Doumbo, Ogobara K.
    ElGhazali, Gehad
    Giha, Hayder A.
    Troye-Blomberg, Marita
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Berzins, Klavs
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Tornvall, Per
    Marked differences in CRP genotype frequencies between the Fulani and sympatric ethnic groups in Africa2009In: Malaria Journal, ISSN 1475-2875, E-ISSN 1475-2875, Vol. 8, no 136Article in journal (Refereed)
    Abstract [en]

    Background

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

    Methods

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

    Results

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

    Conclusion

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

  • 44. Jahnmatz, Peter
    et al.
    Bengtsson, Theresa
    Zuber, Bartek
    Farnert, Anna
    Ahlborg, Niklas
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. Mabtech AB, Sweden.
    An antigen-specific, four-color, B-cell FluoroSpot assay utilizing tagged antigens for detection2016In: JIM - Journal of Immunological Methods, ISSN 0022-1759, E-ISSN 1872-7905, Vol. 433, p. 23-30Article in journal (Refereed)
    Abstract [en]

    The FluoroSpot assay, a variant of ELISpot utilizing fluorescent detection, has so far been used primarily for assessment of T cells, where simultaneous detection of several cytokines has allowed a more qualitative analysis of functionally distinct T cells. The potential to measure multiple analytes also presents several advantages when analyzing B cells. Our aim was to develop a B-cell FluoroSpot assay adaptable to studies of a variety of antigens. The assay utilizes anti-IgG antibodies immobilized in 96-well filter membrane plates. During cell culture, IgG antibodies secreted by antibody-secreting cells (ASCs) are captured in the vicinity of each of these cells and the specificity of single ASCs is defined using antigens for detection. The antigens were labeled with biotin or peptide tags enabling secondary detection with fluorophore-conjugated streptavidin or tag-specific antibodies. The assay, utilizing up to four different tag systems and fluorophores simultaneously, was evaluated using hybridomas and immunized splenocytes as ASCs. Assay variants were developed that could: i) identify multiple ASCs with different antigen specificities; ii) detect ASCs showing cross-reactivity with different but related antigens; and iii) define the antigen-specificity and, by including anti-IgG subclass detection reagents, simultaneously determine the IgG subclass of antibodies secreted by ASCs. As demonstrated here, the B-cell FluoroSpot assay using tag-based detection systems provides a versatile and powerful tool to investigate antibody responses by individual cells that can be readily adapted to studies of a variety of antigen-specific ASCs.

  • 45.
    Johansson, Maria
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Early gut microbiota in relation to cytokine responses and allergic disease2011Licentiate thesis, comprehensive summary (Other academic)
  • 46.
    Johansson, Maria A.
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Björkander, Sophia
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Mata Forsberg, Manuel
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Qazi, Khaleda Rahman
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Salvany Celades, Maria
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Bittmann, Julia
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Eberl, Matthias
    Sverremark-Ekström, Eva
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Probiotic Lactobacilli Modulate Staphylococcus aureus-Induced Activation of Conventional and Unconventional T cells and NK Cells2016In: Frontiers in Immunology, ISSN 1664-3224, E-ISSN 1664-3224, Vol. 7, article id 273Article in journal (Refereed)
    Abstract [en]

    Lactobacilli are probiotic commensal bacteria and potent modulators of immunity. When present in the gut or supplemented as probiotics, they beneficially modulate ex vivo immune responsiveness. Further, factors derived from several lactobacilli strains act immune regulatory in vitro. In contrast, Staphylococcus aureus (S. aureus) is known to induce excessive T cell activation. In this study, we aimed to investigate S. aureus-induced activation of human mucosal-associated invariant T cells (MAIT cells), gamma delta T cells, NK cells, as well as of conventional CD4(+) and CD8(+) T cells in vitro. Further, we investigated if lactobacilli-derived factors could modulate their activation. PBMC were cultured with S. aureus 161: 2 cell-free supernatants (CFS), staphylococcal enterotoxin A or CD3/CD28-beads alone, or in combination with Lactobacillus rhamnosus GG-CFS or Lactobacillus reuteri DSM 17938-CFS and activation of T and NK cells was evaluated. S. aureus-CFS induced IFN-gamma and CD107a expression as well as proliferation. Costimulation with lactobacilli-CFS dampened lymphocyte-activation in all cell types analyzed. Preincubation with lactobacilli-CFS was enough to reduce subsequent activation, and the absence of APC or APC-derived IL-10 did not prevent lactobacilli-mediated dampening. Finally, lactate selectively dampened activation of unconventional T cells and NK cells. In summary, we show that molecules present in the lactobacilli-CFS are able to directly dampen in vitro activation of conventional and unconventional T cells and of NK cells. This study provides novel insights on the immune-modulatory nature of probiotic lactobacilli and suggests a role for lactobacilli in the modulation of induced T and NK cell activation.

  • 47.
    Jönsson, Gun
    Stockholm University, Faculty of Science, The Wenner-Gren Institute.
    Apoptosis regulation in bladder cancer and multiple sclerosis2003Doctoral thesis, comprehensive summary (Other academic)
  • 48. Karshikoff, B.
    et al.
    Jensen, K. B.
    Ingvar, M.
    Kosek, E.
    Kalpouzos, G.
    Soop, A.
    Olgart Höglund, C.
    Lekander, Mats
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska Institutet, Sweden.
    Axelsson, J.
    LPS increases pain sensitivity by decreased pain inhibition and increased insular activation2015In: Brain, behavior, and immunity, ISSN 0889-1591, E-ISSN 1090-2139, Vol. 49, p. e1-e1Article in journal (Refereed)
    Abstract [en]

    We have shown that women are more prone to developing LPS-induced pain sensitivity than men, and that the descending endogenous pain inhibition is disrupted in women during experimental systemic inflammation. The aim of the present study was to investigate some of the central neural mechanisms underlying our previous findings. 51 participants (29 women) were injected with 0.6 ng/kg LPS or saline and went through a thumb-pressure pain fMRI paradigm 2 h after injection. As hypothesized, the subjects injected with LPS had decreased activity in the ventromedial prefrontal cortex and rostral anterior cingulate cortex (rACC), areas involved in descending pain inhibition. In addition, the LPS group had higher activity in the anterior insula, an area involved in medial/affective pain processing and interoception. These effects were not sex dependent. However, the male participants had overall stronger descending pain inhibition, reflected as a stronger rACC activity compared to women. It is possible that the more robust activation of descending pain inhibition rendered the men more resistant to the immune provocation, which may explain previously seen sex differences in LPS-induced pain sensitivity. Our findings give an indication to how the pain matrix is affected during a sickness response. The results strengthen the proposed link between systemic inflammation and weakened pain regulation in chronic pain disorders, and offers a possible mechanism underlying the female predominance in chronic pain disorders.

  • 49. Karshikoff, B.
    et al.
    Lekander, Mats
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska Institutet, Sweden.
    Olgart Höglund, C.
    Axelsson, J.
    Pain sensitivity during experimentally induced systemic inflammation in humans2013In: Brain, Behavior, and Immunity, 2013, Vol. 32, p. e32-Conference paper (Refereed)
  • 50.
    Karshikoff, Bianka
    et al.
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska University Hospital, Sweden; Karolinska Institutet, Sweden.
    Jensen, K. B.
    Kosek, E.
    Kalpouzos, Grégoria
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Soop, A.
    Ingvar, M.
    Olgart Höglund, C.
    Lekander, Mats
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska University Hospital, Sweden; Karolinska Institutet, Sweden.
    Axelsson, John
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska University Hospital, Sweden; Karolinska Institutet, Sweden.
    Why sickness hurts: A central mechanism for pain induced by peripheral inflammation2016In: Brain, behavior, and immunity, ISSN 0889-1591, E-ISSN 1090-2139, Vol. 57, p. 38-46Article in journal (Refereed)
    Abstract [en]

    Low-grade systemic inflammation has been implicated in chronic pain, as well as in comorbid diseases like depression and fatigue. We have previously shown that women's pain perception and regulation is more affected by systemic inflammation than that of men. Here we investigated the neural substrates underlying these effects using an fMRI paradigm previously employed in a clinical population. Fifty-one participants (29 women) were injected with 0.6ng/kg lipopolysaccharide (LPS) or saline to induce a peripheral inflammatory response. The subjects were then tested with a pressure pain fMRI paradigm designed to capture descending pain inhibitory activity 2h after injection, and blood was sampled for cytokine analysis. The subjects injected with LPS became more pain sensitive compared to the placebo group, and the heightened pain sensitivity was paralleled by decreased activity in the ventrolateral prefrontal cortex and the rostral anterior cingulate cortex (rACC) compared to placebo; areas involved in descending pain regulation. The LPS group also had higher activity in the anterior insular cortex, an area underpinning affective and interoceptive pain processing. Women displayed overall less pain-evoked rACC activity compared to men, which may have rendered women less resilient to immune provocation, possibly explaining sex differences in LPS-induced pain sensitivity. Our findings elucidate the pain-related brain circuits affected by experimental peripheral inflammation, strengthening the theoretical link between systemic inflammation and weakened pain regulation in chronic pain disorders. The results further suggest a possible mechanism underlying the female predominance in many chronic pain disorders.

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