| 1. |
- Abarenkov, Kessy, et al.
(författare)
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Annotating public fungal ITS sequences from the built environment according to the MIxS-Built Environment standard – a report from a May 23-24, 2016 workshop (Gothenburg, Sweden)
- 2016
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Ingår i: MycoKeys. - : Pensoft Publishers. - 1314-4057 .- 1314-4049. ; 16, s. 1-15
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Tidskriftsartikel (refereegranskat)abstract
- Recent molecular studies have identified substantial fungal diversity in indoor environments. Fungi and fungal particles have been linked to a range of potentially unwanted effects in the built environment, including asthma, decay of building materials, and food spoilage. The study of the built mycobiome is hampered by a number of constraints, one of which is the poor state of the metadata annotation of fungal DNA sequences from the built environment in public databases. In order to enable precise interrogation of such data – for example, “retrieve all fungal sequences recovered from bathrooms” – a workshop was organized at the University of Gothenburg (May 23-24, 2016) to annotate public fungal barcode (ITS) sequences according to the MIxS-Built Environment annotation standard (http://gensc.org/mixs/). The 36 participants assembled a total of 45,488 data points from the published literature, including the addition of 8,430 instances of countries of collection from a total of 83 countries, 5,801 instances of building types, and 3,876 instances of surface-air contaminants. The results were implemented in the UNITE database for molecular identification of fungi (http://unite.ut.ee) and were shared with other online resources. Data obtained from human/animal pathogenic fungi will furthermore be verified on culture based metadata for subsequent inclusion in the ISHAM-ITS database (http://its.mycologylab.org).
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| 2. |
- Agianian, Bogos, et al.
(författare)
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Preliminary characterization of hemolymph coagulation in Anopheles gambiae larvae
- 2007
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Ingår i: Developmental and Comparative Immunology. - : Elsevier BV. - 0145-305X .- 1879-0089. ; 31:9, s. 879-888
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Tidskriftsartikel (refereegranskat)abstract
- Hemolymph coagulation is a first response to injury, impeding infection, and ending bleeding. Little is known about its molecular basis in insects, but clotting factors have been identified in the fruit fly Drosophila melanogaster. Here, we have begun to study coagulation in the aquatic larvae of the malaria vector mosquito Anopheles gambiae using methods developed for Drosophila. A delicate clot was seen by light microscopy, and pullout and proteomic analysis identified phenoloxidase and apolipophorin-I as major candidate clotting factors. Electron microscopic analysis confirmed clot formation and revealed it contains fine molecular sheets, most likely a result of lipophorin assembly. Phenoloxidase appears to be more critical in clot formation in Anopheles than in Drosophila. The Anopheles larval clot thus differs in formation, structure, and composition from the clot in Drosophila, confirming the need to study coagulation in different insect species to learn more about its evolution and adaptation to different lifestyles.
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| 3. |
- Kulma, Katarzyna, et al.
(författare)
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Malaria-infected female collared flycatchers (Ficedula albicollis) do not pay the cost of late breeding
- 2014
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 9:1, s. e85822-
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Tidskriftsartikel (refereegranskat)abstract
- Life-history theory predicts that the trade-off between parasite defense and other costly traits such as reproduction may be most evident when resources are scarce. The strength of selection that parasites inflict on their host may therefore vary across environmental conditions. Collared flycatchers (Ficedula albicollis) breeding on the Swedish island Oland experience a seasonal decline in their preferred food resource, which opens the possibility to test the strength of life-history trade-offs across environmental conditions. We used nested-PCR and quantitative-PCR protocols to investigate the association of Haemosporidia infection with reproductive performance of collared flycatcher females in relation to a seasonal change in the external environment. We show that despite no difference in mean onset of breeding, infected females produced relatively more of their fledglings late in the season. This pattern was also upheld when considering only the most common malaria lineage (hPHSIB1), however there was no apparent link between the reproductive output and the intensity of infection. Infected females produced heavier-than-average fledglings with higher-than-expected recruitment success late in the season. This reversal of the typical seasonal trend in reproductive output compensated them for lower fledging and recruitment rates compared to uninfected birds earlier in the season. Thus, despite different seasonal patterns of reproductive performance the overall number of recruits was the same for infected versus uninfected birds. A possible explanation for our results is that infected females breed in a different microhabitat where food availability is higher late in the season but also is the risk of infection. Thus, our results suggest that another trade-off than the one we aimed to test is more important for explaining variation in reproductive performance in this natural population: female flycatchers appear to face a trade-off between the risk of infection and reproductive success late in the season.
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| 4. |
- Bergonzini, Anna, 1990-, et al.
(författare)
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The challenge of establishing immunocompetent human intestinal 3D models
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Expression of typhoid toxin in Salmonella Typhimurium causes DNA damage, activating the DNA damage response (DDR), in absence of an inflammatory response in the colonic mucosa of infected mice. The anti-inflammatory effect is tissue specific and is not observed in the liver, suggesting that the local immune microenvironment modulates the DDR outcome.To assess the role of the immune cells in the DDR outcome induced by the genotoxigenic Salmonella, we have initiated the development of an immunocompetent 3D colonic mucosal model based on a collagen matrix containing colonic fibroblasts and different subtypes of immune cells, overlayed with colonic epithelial cells.Embedding of peripheral blood mononuclear cells in the collagen matrix did not influenced either the tissue integrity or the activation of the DDR, observed exclusively upon infection with the genotoxigenic strain. However, embedding of T cells, monocytes, or non-polarized macrophages altered the pattern of the DDR and the toxin specific effect was lost. Presence of macrophages was further associated with alteration of the epithelial layer integrity. This effect was infection-dependent, but not toxin specific.Our data demonstrated that addition of immune cells to a 3D mucosal model altered the DDR induced by a genotoxigenic bacterium, highlighting the need to develop and optimize immunocompetent in vitro models.
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| 5. |
- Lesch, Christine, et al.
(författare)
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A role for Hemolectin in coagulation and immunity in Drosophila melanogaster
- 2007
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Ingår i: Developmental and Comparative Immunology. - : Elsevier BV. - 0145-305X .- 1879-0089. ; 31:12, s. 1255-1263
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Tidskriftsartikel (refereegranskat)abstract
- Hemolectin has been identified as a candidate clotting factor in Drosophila. We reassessed the domain structure of Hemolectin (Hml) and propose that instead of C-type lectin domains, the two discoidin domains are most likely responsible for the protein's lectin activity. We also tested Hml's role in coagulation and immunity in Drosophila. Here we describe the isolation of a new hml allele in a forward screen for coagulation mutants, and our characterization of this and two other hml alleles, one of which is a functional null. While loss of Hml had strong effects on larval hemolymph coagulation ex vivo, mutant larvae survived wounding. Drosophila thus possesses redundant hemostatic mechanisms. We also found that loss of Hml in immune-handicapped adults rendered them more sensitive to Gram(-) bacteria infection. This demonstrates an immunological role of this clotting protein and reinforces the importance of the clot in insect immunity.
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| 6. |
- Courtin, David, et al.
(författare)
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G6PD A-variant influences the antibody responses to Plasmodium falciparum MSP2.
- 2011
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Ingår i: Infection, Genetics and Evolution. - : Elsevier BV. - 1567-1348 .- 1567-7257. ; 11:6, s. 1287-1292
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 7. |
- Giusti, Pablo, et al.
(författare)
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Plasmodium falciparum-infected erythrocytes and beta-hematin induce partial maturation of human dendritic cells and increase their migratory ability in response to lymphoid chemokines.
- 2011
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Ingår i: Infection and Immunity. - 0019-9567 .- 1098-5522. ; 79:7, s. 2727-2736
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Tidskriftsartikel (refereegranskat)abstract
- Acute and chronic Plasmodium falciparum infections alter the immune competence of the host possibly through changes in dendritic cell (DC) functionality. DCs are the most potent activators of T cells, and migration is integral to their function. Mature DCs express lymphoid chemokine receptors (CCRs), expression of which enables them to migrate to the lymph nodes, where they encounter naïve T cells. The present study aimed to investigate the impact of the synthetic analog to malaria parasite pigment hemozoin, i.e., β-hematin, or infected erythrocytes (iRBCs) on the activation status of human monocyte-derived DCs and on their expression of CCRs. Human monocyte-derived DCs partially matured upon incubation with β-hematin as indicated by an increased expression of CD80 and CD83. Both β-hematin and iRBCs provoked the release of proinflammatory and anti-inflammatory cytokines, such as interleukin-6 (IL-6), IL-10, and tumor necrosis factor alpha, but not IL-12, and induced upregulation of the lymphoid chemokine receptor CXCR4, which was coupled to an increased migration to lymphoid ligands. Taken together, these results suggest that the partial and transient maturation of human myeloid DCs upon stimulation with malaria parasite-derived products and the increased IL-10 but lack of IL-12 secretion may lead to suboptimal activation of T cells. This may in turn lead to impaired adaptive immune responses and therefore insufficient clearance of the parasites.
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| 8. |
- Gustafsson, Lars, et al.
(författare)
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Infectious disease, reproductive effort and the cost of reproduction in birds
- 1994
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Ingår i: Philosophical transactions of the Royal Society of London: Series B. ; :346, s. 1655-1658
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Tidskriftsartikel (populärvet., debatt m.m.)abstract
- Reproductive effort can have profound effects on subsequent performance. Field experiments on the collared flycatcher (Ficedula albicollis) have demonstrated a number of trade-offs between life-history traits at different ages. The mechanism by which reproductive effort is mediated into future reproductive performance remains obscure. Anti-parasite adaptations such as cell-mediated immunity may probably also be costly. Hence the possibility exists of a trade-off between reproductive effort and the ability to resist parasitic infection. Serological tests on unmanipulated collared flycatchers show that pre-breeding nutritional status correlates positively with reproductive success and negatively with susceptibility to parasitism (viruses, bacteria and protozoan parasites). Both immune response and several indicators of infectious disease correlate negatively with reproductive success. Similar relations are found between secondary sexual characters and infection parameters. For brood-size-manipulated birds there was a significant interaction between experimentally increased reproductive effort and parasitic infection rate with regard to both current and future fecundity. It seems possible that the interaction between parasitic infection, nutrition and reproductive effort can be an important mechanism in the ultimate shaping of life-history variation in avian populations.
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| 9. |
- Nilsson, C, et al.
(författare)
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Epstein-Barr virus and cytomegalovirus are differentially associated with numbers of cytokine-producing cells and early atopy
- 2009
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Ingår i: Clinical and Experimental Allergy. - Oxford : Blackwell. - 0954-7894 .- 1365-2222. ; 39:4, s. 509-517
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: We have previously shown that Epstein-Barr virus (EBV) seropositivity, at 2 years of age, was inversely related to IgE-sensitization and that this effect was enhanced when EBV is combined with cytomegalovirus (CMV) seropositivity. We hypothesize that early exposure to EBV or CMV will affect the cytokine balance in the individual.OBJECTIVE: The aim of this study was to relate the cytokine profile in peripheral blood mononuclear cells (PBMC) to the EBV and CMV serostatus and IgE-sensitization in children at 2 years of age.METHODS: Seventy-five children were followed prospectively from birth until 2 years of age. Their EBV and CMV serostatus was correlated to the numbers of IFN-gamma, IL-4, IL-10 and IL-12-producing PBMC following PHA stimulation in vitro. Skin prick tests and allergen-specific IgE antibodies were used to assess IgE-sensitization.RESULTS: In the study cohort, there was an inverse association between EBV seropositivity and IgE-sensitization but not with CMV seropositivity. Following linear regression analysis, we did not detect any statistically significant associations between children with IgG antibodies against EBV at 2 years of age and the investigated cytokines. However, there was a non-significant tendency to a positive association between high numbers of all individual cytokine-producing cells and EBV seropositivity. Children who were CMV seropositive had significantly higher numbers of IFN-gamma and lower numbers of IL-4-producing cells compared with CMV negative children. There was a significant, positive association between the number of IL-4-producing cells and IgE-sensitization.CONCLUSION: Taken together our results indicate that infections with EBV and CMV in different ways will interact with the immune system and may protect children from developing early atopy.
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| 10. |
- Simone, Olivia, et al.
(författare)
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TLRs innate immunereceptors and Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) CIDR1α-driven human polyclonal B-cell activation.
- 2011
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Ingår i: Acta Tropica. - : Elsevier BV. - 0001-706X .- 1873-6254. ; 119:2-3, s. 144-150
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Tidskriftsartikel (refereegranskat)abstract
- Chronic malaria severely affects the immune system and causes polyclonal B-cell activation, as evidenced by the presence of hypergammaglobulinemia, elevated levels of autoantibodies, loss of B-cell memory and the frequent occurrence of Burkitt's lymphomas (BL) in children living in malaria endemic areas. Previous studies have shown that the cysteine-rich interdomain region 1α (CIDR1α) of the Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) of the FCR3S1.2 strain, subsequently named CIDR1α, interacts with B cells partially through the binding to the B-cell receptor (BCR). This interaction leads to an activated phenotype, increased survival, and a low degree of proliferation. CIDR1α preferentially activates the memory B-cell compartment, therefore PfEMP1 is considered to act as a polyclonal B-cell activator and its role in memory maintenance has been suggested. In this report, we extend the analysis of the PfEMP1-CIDR1α B-cell interaction and demonstrate that PfEMP1-CIDR1α increases the expression of TLR7 and TLR10 mRNA transcripts and sensitizes B cells to TLR9 signalling via the MyD88 adaptor molecule. Furthermore, despite its ability to bind to surface Igs, PfEMP1-CIDR1α-induced B-cell activation does not seem to proceed through the BCR, since it does not induce Lyn and/or phospho-tyrosine mediated signalling pathways. Rather PfEMP1-CIDR1α induces the phosphorylation of downstream kinases, such as ERK1/2, p38 and IKBα, in human B cells. These findings indicate that PfEMP1-CIDR1α induces a persistent activation of B cells, which in turn can contribute to the exhaustion and impairment of B-cell functions during chronic malaria infection.
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| 11. |
- Kalbina, Irina, 1961-, et al.
(författare)
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Arabidopsis thaliana plants expressing Rift Valley fever virus antigens : Mice exhibit systemic immune responses as the result of oraladministration of the transgenic plants
- 2016
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Ingår i: Protein Expression and Purification. - San Diego, USA : Elsevier. - 1046-5928 .- 1096-0279. ; 127, s. 61-67
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Tidskriftsartikel (refereegranskat)abstract
- The zoonotic Rift Valley fever virus affects livestock and humans in Africa and on the Arabian Peninsula.The economic impact of this pathogen due to livestock losses, as well as its relevance to public health,underscores the importance of developing effective and easily distributed vaccines. Vaccines that can bedelivered orally are of particular interest.Here, we report the expression in transformed plants (Arabidopsis thaliana) of Rift Valley fever virusantigens. The antigens used in this study were the N protein and a deletion mutant of the Gn glycoprotein.Transformed lines were analysed for specific mRNA and protein content by RT-PCR and Westernblotting, respectively. Furthermore, the plant-expressed antigens were evaluated for their immunogenicityin mice fed the transgenic plants. After oral intake of fresh transgenic plant material, a proportionof the mice elicited specific IgG antibody responses, as compared to the control animals that were fedwild-type plants and of which none sero-converted.Thus, we show that transgenic plants can be readily used to express and produce Rift Valley Fever virusproteins, and that the plants are immunogenic when given orally to mice. These are promising findingsand provide a basis for further studies on edible plant vaccines against the Rift Valley fever virus.
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| 12. |
- Amoudruz, Petra, 1970-
(författare)
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Maternal immune characteristics and innate immune responses in the child in relation to allergic disease
- 2008
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The mechanistic factors responsible for the increase in allergic diseases are still not fully understood, but a reduced microbial stimulation seems to be one of the key issues. Research is now aiming at investigating the relationship between the innate immune system, involving the toll-like receptors, and allergy development. Further, the maternal influence on the child, possibly through in utero effects, but also through the breast milk, has shown to be of great importance. This thesis aimed at understanding how the maternal immune system is influenced by early exposures and allergic disease, but also to investigate the consequences of the maternal phenotype on the innate immune system of the developing child. The Th1/Th2 cytokine pattern in allergic diseases has been extensively studied. Here we were interested in comparing the innate cytokines in allergic and non-allergic women, and to see if the allergic status was influencing the effect of pregnancy differently. We demonstrate that IL-1β, IL-6, IL-10 and IL-12 production in cells from adult women are not influenced by allergic status, neither during pregnancy nor 2 years after. However, pregnancy had an apparent effect on cytokine levels, regardless of allergic status. Also, total IgE levels in allergic women were significantly lower 2 years after pregnancy in comparison with the levels during pregnancy, pointing to the fact that pregnancy indeed has an immunomodulatory role. We further wanted to investigate the immune system of mothers who had migrated to Sweden in comparison with indigenous mothers. The reason for our interest here was that children born from immigrated mothers have shown to have an increased risk of developing diseases such as allergy and Crohn’s disease. The results showed that immigrants from a developing country had significantly higher levels of breast milk IL-6, IL-8 and TGF-β1. Further, regardless of maternal country of birth, a larger number of previous pregnancies was associated with down-regulation of several substances, statistically significant for soluble CD14 and IL-8. The results suggest that maternal country of birth may indeed influence adult immune characteristics, potentially relevant to disease risk in offspring. The influence of allergic status of the mother on the expression of CD14, TLR2 and TLR4 was further investigated in monocytes from mothers and their newborn babies upon microbial stimulation. We could not find any differences in monocytic TLR levels between the groups. No significant differences regarding cytokine levels between allergic and non-allergic mothers in response to stimuli were found either. However, the cytokine and chemokine release triggered by TLR2 stimulation in CB revealed that CBMC from children with maternal allergic disease released significantly less IL-6, and a trend towards less IL-8. As we could not find differences in TLR levels attributed to maternal allergy, but an impaired IL-6 response, we turned our focus on an intracellular event taking place after TLR ligation. The results confirmed our results of decreased IL-6 levels in CB from children to allergic mothers. At 2 years of age, the children of allergic mothers still displayed a diminished IL-6 response. Additionally, they also had a decreased activity of p38 MAPK. p38 has an important role in driving Th1 responses, suggesting that the p38 pathway could be one of the responsible mechanisms behind the impaired responses correlated to allergic heredity found in CB as well as at 2 years of age. Infancy is a crucial time period for the developing immune system. Further, the relative composition of the two major monocytic subsets CD14++CD16- and CD14+CD16+ is altered in some allergic diseases. TLR levels are different in the two subsets, proposing a possible link to the reduced responding capacity of monocytes from children with allergic heredity. We followed up our earlier studies of children at birth and at 2 years of age by looking at 5 year old children. There were no differences regarding monocytic subsets, nor in TLR levels in unstimulated cells. However, when stimulating the cells with PGN, both monocytic subsets in allergic subjects were less capable of upregulating TLR2 compared to the age-matched controls. Taken together, the work in this thesis suggests that the maternal immune system is affected by the process of pregnancy and childhood exposures. It further suggests that maternal allergy affects the young child, in terms of impaired responses to microbial stimuli, which later in infancy correlates with allergic disease in the child. These impaired innate responses could lead to a diminished Th1 response, or alternatively to a deficiency in regulatory mechanisms, and thereby cause allergic disease.
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| 13. |
- Anchang-Kimbi, Judith K, et al.
(författare)
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Diagnostic comparison of malaria infection in peripheral blood, placental blood and placental biopsies in Cameroonian parturient women.
- 2009
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Ingår i: Malaria Journal. - : Springer Science and Business Media LLC. - 1475-2875. ; 8, s. 126-
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: In sub-Saharan Africa, Plasmodium falciparum malaria in pregnancy presents an enormous diagnostic challenge. The epidemiological and clinical relevance of the different types of malaria diagnosis as well as risk factors associated with malaria infection at delivery were investigated. METHOD: In a cross-sectional survey, 306 women reporting for delivery in the Mutenegene maternity clinic, Fako division, South West province, Cameroon were screened for P. falciparum in peripheral blood, placental blood and placental tissue sections by microscopy. Information relating to the use of intermittent preventive treatment in pregnancy with sulphadoxine/pyrimethamine, history of fever attack, infant birth weights and maternal anaemia were recorded. RESULTS: Among these women, P. falciparum infection was detected in 5.6%, 25.5% and 60.5% of the cases in peripheral blood, placental blood and placental histological sections respectively. Placental histology was more sensitive (97.4%) than placental blood film (41.5%) and peripheral blood (8.0%) microscopy. In multivariate analysis, age (< or = 20 years old) (OR = 4.61, 95% CI = 1.47 - 14.70), history of fever attack (OR = 2.98, 95% CI = 1.58 - 5.73) were significant risk factors associated with microscopically detected parasitaemia. The use of > or = 2 SP doses (OR = 0.18, 95% CI = 0.06 - 0.52) was associated with a significant reduction in the prevalence of microscopic parasitaemia at delivery. Age (>20 years) (OR = 0.34, 95% CI = 0.15 - 0.75) was the only significant risk factor associated with parasitaemia diagnosed by histology only in univariate analysis. Microscopic parasitaemia (OR = 2.74, 95% CI = 1.33-5.62) was a significant risk factor for maternal anaemia at delivery, but neither infection detected by histology only, nor past infection were associated with increased risk of anaemia. CONCLUSION: Placenta histological examination was the most sensitive indicator of malaria infection at delivery. Microscopically detected parasitaemia was associated with increased risk of maternal anaemia at delivery, but not low-grade parasitaemia detected by placental histology only.
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| 14. |
- Andersson, Måns Sverker, et al.
(författare)
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Glycosylated haemoglobin: a new measure of condition in birds
- 1995
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Ingår i: Proceedings of the Royal Society of London. ; :260, s. 299-303
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Tidskriftsartikel (refereegranskat)abstract
- Abstract: The influence of condition on time of breeding and reproductive success has been discussed since Darwin first suggested a relation in 1871. We used a novel method to investigate the influence of condition on the timing of breeding and reproductive success by measuring a relatively inert physiological parameter - the amount of glycosylated haemoglobin - in blood samples taken from the collared flycatcher Ficedula albicollis. The percentage of glycosylated haemoglobin (%HbG) was assumed to be proportional to the average blood glucose level, during the 3-5 weeks before the blood sampling. The %HbG was influenced neither by sex nor age. Date of arrival at the breeding ground was negatively correlated with %HbG so that early-arriving birds had significantly higher %HbG than those arriving later. Clutch size, corrected for the effect of laying date, correlated positively with %HbG in females, as did the number of fledged young, corrected for the effect of laying date, for both sexes. We found no correlation between body mass and the %HbG. We suggest that prebreeding condition influences the timing of breeding and subsequent reproductive performance and that %HbG can be used as an indicator of prebreeding-condition in migrating birds.
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| 15. |
- Arko-Mensah, John, et al.
(författare)
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Resistance to mycobacterial infection : a pattern of early immune responses leads to a better control of pulmonary infection in C57BL/6 compared with BALB/c mice.
- 2009
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Ingår i: Vaccine. - : Elsevier BV. - 0264-410X .- 1873-2518. ; 27:52, s. 7418-27
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Tidskriftsartikel (refereegranskat)abstract
- In this study, we have compared the immunological responses associated with early pulmonary mycobacterial infection in two mouse strains, BALB/c and C57BL/6 known to exhibit distinct differences in susceptibility to infection with several pathogens. We infected mice via the intranasal route. We have demonstrated that BALB/c was less able to control mycobacterial growth in the lungs during the early phase of pulmonary infection. Our results showed that during the early phase (day 3 to week 1), BALB/c mice exhibited a delay in the production of TNF and IFN-gamma in the lungs compared to C57BL/6 mice. Levels of IL-12 and soluble TNF receptors (sTNFR) were comparable between the mouse strains. The cellular subset distribution in these mice before and after infection showed a higher increase in CD11b+ cells in the lungs of C57BL/6, compared to BALB/c as early as day 3 postinfection. At early time points, higher levels of monocyte chemoattractant protein (MCP)-1 and macrophage inflammatory protein 1 (MIP)-alpha were detected in C57BL/6 than BALB/c mice. In vitro, BCG-infected bone marrow derived macrophages (BMM) from both mouse strains displayed similar capacities to either phagocytose bacteria or produce soluble mediators such as TNF, IL-12 and nitric oxide (NO). Although IFN-gamma stimulation of infected BMM in both mouse strains resulted in the induction of antimycobacterial activity, BALB/c mice had a reduced capacity to kill ingested bacteria. The above observations indicate that the chain of early, possibly innate immunological events occurring during pulmonary mycobacterial infection may directly impact on increased susceptibility or resistance to infection.
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| 16. |
- Awah, Nancy
(författare)
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Malarial anaemia : the potential involvement of Plasmodium falciparum rhoptry proteins
- 2009
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Licentiatavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Malaria remains a challenging health problem in malaria endemic regions. Infection with malaria invariably leads to anaemia. The groups at risk of developing malarial anaemia include children below the age of five years and pregnant women, especially primigravidae. Several factors have been suggested to be responsible for its aetiology, including increased destruction of infected and normal red blood cells together with bone marrow suppression. However, until recently, the molecular mechanisms involved have remained elusive. The aim of the work presented herein was to investigate the mechanisms responsible for the destruction of normal red blood cells in anaemia, and more specifically to define the role of the ring surface protein (RSP/RAP) -2 and other members of the low molecular weight rhoptry associated protein (RAP) complex, RAP-1 and -3. In the first study we showed that antibodies to the RAP complex could mediate the destruction of RSP-2 tagged erythroid cells by phagocytosis or by complement activation and then lysis. In addition, antibodies to RAP-1 and RAP-2 could induce the death of RSP-2/RAP-2 tagged erythroblasts. We further investigated the frequency and functionality of naturally occurring RSP-2/RAP-2 antibodies in the sera of anaemic and non-anaemic Cameroonian children. We found that all sera investigated contained RSP-2/RAP-2 reactive antibodies by both immunoflorescence and flow cytometry. The anaemic group of children had significantly higher levels of antibodies of the IgG isotype than the non-anaemic individuals, while the levels of IgM were similar in both groups. With respect to IgG subclasses, low levels of IgG1 and -3 antibodies were detected. Higher levels of IgG3 were seen in the non-anaemic individuals as compared to anaemic subjects. With regards to antibody functionality, the non-anaemic individuals recognised a greater proportion of RSP-2/RAP-2 tagged erythrocytes and activated complement to a greater extent than the anaemic individuals. From our findings, we can conclude that antibodies to the RAP complex are potentially involved in erythroid cell destruction during malaria which may result in anaemia, and that high levels of such antibodies may be detrimental to the host.
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| 17. |
- Bachmayer, Nora, 0061-
(författare)
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The role of natural killer cells and inflammatory mediators in preeclamptic pregnancies
- 2008
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The maternal immune system must be able to adjust during pregnancy and accept the foetus that expresses paternal antigens. These changes are found both in placenta and circulation, including a mild inflammatory response. NK cells are abundant during the early part of pregnancy in placenta and are thought to be important for placental development. During preeclampsia the placenta is poorly developed, together with an escalated pro-inflammatory profile noticed in both placenta and circulation. We wanted to study NK cells in placenta and circulation from preeclamptic cases as well as levels of cytokines. HMGB1, an alarmin involved in inflammation, was also measured in preeclamptic placentae.When studying preeclamptic placentae in third trimester we found higher numbers of NK cells as well as a higher expression of CD94+ NK cells. We also found slightly elevated levels of HMGB1 together with significantly lower expression of IL-12 in preeclamptic placentae. Further, the NK cell activating cytokines IL-12/IL-23p40 and IL-15 in sera from preeclamptic women were increased compared to healthy pregnancies. The elevated levels of NK cell activating IL-12/IL-23p40 and IL-15 found in preeclamptic sera, made us investigate the circulating NK cells in preeclampsia. However, no differences were seen between healthy and preeclamptic pregnancies.The main immunological alterations in third trimester preeclamptic pregnancies with regard to NK cells were found in placenta. Altered maternal cytokine levels in placenta could influence decidual NK cells in preeclampsia, noticed by their higher numbers and altered receptor expression. If these alterations also exist during early pregnancy it could result in a poorly developed and dysfunctional placenta.
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| 18. |
- Balogun, Halima A., et al.
(författare)
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Immunogenicity and antigenic properties of Pf332-C231, a fragment of a non-repeat region of the Plasmodium falciparum antigen Pf332
- 2009
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Ingår i: Vaccine. - : Elsevier BV. - 0264-410X .- 1873-2518. ; 28:1, s. 90-97
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Tidskriftsartikel (refereegranskat)abstract
- Antigen Pf332, a megadalton protein has been shown to be associated with the membrane of infected erythrocytes. Detailed functional studies on the antigen have remained hampered by the cross-reactive nature of antibodies generated to Pf332. Pf332-C231, identified in the C-terminal region of Pf332 was cloned and antibodies against the C231 fragment were shown to react with intact Pf332 antigen by both immunofluorescence and immunoblotting analyses. Antibodies to C231 inhibited in vitro Plasmodium falciparum growth efficiently. In addition, human sera from malaria-exposed individuals reacted with recombinant C231. We show that Pf332-C231 represents a functional domain and is expected to facilitate further studies on Pf332 as a potential target for protective immune responses and the function of the antigen.
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| 19. |
- Balogun, Halima Aramide, 1978-
(författare)
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Immunological characteristics of a C-terminal fragment of the Plasmodium falciparum blood-stage antigen Pf332
- 2006
-
Licentiatavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Till date, there are no effective control strategies against the deadly disease of malaria, and millions of children across Africa, Oceania, Asia, and Latin America are at the mercy of this long term enemy of man every second that passes by. Other control measures combined with vaccination might help improve control strategy against malaria, but the development of vaccines face various challenges as well, due to the complexity of the parasites’ life cycle and other host factors. The asexual blood stage antigen Pf332 of Plasmodium falciparum, is expressed during the trophozoite stage, and transported from the parasitophorous membrane to the outer erythrocyte membrane during schizogony. Previous studies have suggested this antigen as a potential vaccine candidate, because Pf332-reactive human monoclonal antibody (mAb 33G2) inhibits parasite growth and cytoadherence in vitro. Elucidating and understanding the immunological capabilities of antigen Pf332, as a vaccine candidate was the aim of the studies presented in this thesis. In our first study we identified and characterized the immunogenicity of a non-repeat fragment of antigen Pf332, termed Pf332-C231, a 231 amino acids long fragment corresponding to 13 percent of the total protein. Various analyses carried out with this fragment reveal that recombinant C231 was immunogenic in rabbits. In addition, anti- C231 antibodies have in vitro inhibitory capabilities. In immunoflourescence and immunoblot assays, rabbit anti-C231 antibodies were able to recognize the native protein. In the other study, we examined the distribution of antibodies regarding recombinant C231 and crude P. falciparum extract in a malaria endemic area of Senegal. IgG antibody reactivity with crude P. falciparum antigen was detected in the sera of all the donors while many of the children lacked or had low levels of such antibodies against C231. The distribution of the anti-C231 antibodies in the different IgG subclasses differed from that shown by crude P. falciparum antigen. The crude P. falciparum antigen gives a higher IgG3 response than IgG2 for all age-groups, while C231 gave similar levels of IgG2 and IgG3. Correlation studies showed that the levels of anti-C231antibodies were associated with protection from clinical malaria, but this only reached significance with IgE. These findings further emphasize the inclusion of antigen Pf332 as a subunit vaccine candidate against P. falciparum malaria.
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| 20. |
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| 21. |
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| 22. |
- Benton, Jeanne, et al.
(författare)
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Cells from the Immune System Generate Adult-Born Neurons in Crayfish
- 2014
-
Ingår i: Developmental Cell. - : Cell Press. - 1534-5807 .- 1878-1551. ; 30:3, s. 322-333
-
Tidskriftsartikel (refereegranskat)abstract
- Neurogenesis is an ongoing process in the brains of adult decapod crustaceans. However, the first-generation precursors that produce adult-born neurons, which reside in a neurogenic niche, are not self-renewing in crayfish and must be replenished. The source of these neuronal precursors is unknown. Here, we report that adult-born neurons in crayfish can be derived from hemocytes. Following adoptive transfer of 5-ethynyl-2′-deoxyuridine (EdU)-labeled hemocytes, labeled cells populate the neurogenic niche containing the first-generation neuronal precursors. Seven weeks after adoptive transfer, EdU-labeled cells are located in brain clusters 9 and 10 (where adult-born neurons differentiate) and express appropriate neurotransmitters. Moreover, the number of cells composing the neurogenic niche in crayfish is tightly correlated with total hemocyte counts (THCs) and can be manipulated by raising or lowering THC. These studies identify hemocytes as a source of adult-born neurons in crayfish and demonstrate that the immune system is a key contributor to adult neurogenesis.
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| 23. |
- Chapman, Joanne R., et al.
(författare)
-
The Evolution of Innate Immune Genes : Purifying and Balancing Selection on beta-Defensins in Waterfowl
- 2016
-
Ingår i: Molecular biology and evolution. - : Oxford University Press (OUP). - 0737-4038 .- 1537-1719. ; 33:12, s. 3075-3087
-
Tidskriftsartikel (refereegranskat)abstract
- In disease dynamics, high immune gene diversity can confer a selective advantage to hosts in the face of a rapidly evolving and diverse pathogen fauna. This is supported empirically for genes involved in pathogen recognition and signalling. In contrast, effector genes involved in pathogen clearance may be more constrained. beta-Defensins are innate immune effector genes; their main mode of action is via disruption of microbial membranes. Here, five beta-defensin genes were characterized in mallards (Anas platyrhynchos) and other waterfowl; key reservoir species for many zoonotic diseases. All five genes showed remarkably low diversity at the individual-, population-, and species-level. Furthermore, there was widespread sharing of identical alleles across species divides. Thus, specific beta-defensin alleles were maintained not only spatially but also over long temporal scales, with many amino acid residues being fixed across all species investigated. Purifying selection to maintain individual, highly efficacious alleles was the primary evolutionary driver of these genes in waterfowl. However, we also found evidence for balancing selection acting on the most recently duplicated beta-defensin gene (AvBD3b). For this gene, we found that amino acid replacements were more likely to be radical changes, suggesting that duplication of beta-defensin genes allows exploration of wider functional space. Structural conservation to maintain function appears to be crucial for avian beta-defensin effector molecules, resulting in low tolerance for new allelic variants. This contrasts with other types of innate immune genes, such as receptor and signalling molecules, where balancing selection to maintain allelic diversity has been shown to be a strong evolutionary force.
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| 24. |
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| 25. |
- Israelsson, E., et al.
(författare)
-
Antibody responses to a C-terminal fragment of the Plasmodium falciparum blood-stage antigen Pf332 in Senegalese individuals naturally primed to the parasite
- 2008
-
Ingår i: Clinical and Experimental Immunology. - : Oxford University Press (OUP). - 0009-9104 .- 1365-2249. ; 152:1, s. 64-71
-
Tidskriftsartikel (refereegranskat)abstract
- Previous studies have shown that antibodies from humans exposed continuously to malaria recognize the Plasmodium falciparum asexual blood-stage antigen Pf332. Here we analysed the antibody responses to a C-terminal fragment of Pf332, designated C231, in individuals from Senegal, by measuring the serum levels of immunoglobulin M (IgM), IgG class and subclass and IgE antibodies. IgG antibody reactivity with crude P. falciparum antigen was detected in all the donors, while many of the children lacked or had low levels of such antibodies against C231. The antibody levels increased significantly with age for both crude P. falciparum antigen and C231, and in the older age groups most of the donors displayed antibodies to C231. This was also true for IgM, IgE and IgG subclass reactivity against C231. Moreover, the ratio of IgG1/IgG2 was considerably lower for C231 than for crude P. falciparum antigen, and in age groups 10–14 and 15–19 years the levels of IgG2 against C231 even exceeded that of IgG1. The IgG2/IgG3 ratios suggest that C231 gives similar levels of IgG2 and IgG3, except for children aged 4–9 years, where IgG3 was higher. Raw IgM, IgG class and subclass and IgE antibody levels to C231 tended to be higher in those who did not experience a malaria attack, but following linear multivariate analysis the trends were not significant.
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| 26. |
- Kulane, Asli
(författare)
-
In Vitro Studies of Factors Potentially Affecting Plasmodium Falciparum Infection : (Heparin and Anti-P. falciparum Immune Responses)
- 1997
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Plasmodium falciparum malaria is considered one of the major infectious diseases in humans, with regard to mortality and morbidity. Growing resistance of malaria to most anti-malaria drugs and of the Anopheles mosquitoes to insecticides have resulted in a global resurgence of the disease. Therefore, the need to explore drugs with possible antimalarial effects or the development of vaccines against malaria are considered a high priority for control of the disease. In this thesis, the antimalarial effect of heparin and the identification of T- and B-cell epitopes in P. falciparum vaccine candidate antigens, Pf155/RESA and Pf332 have been addressed.Heparin, a drug included in the supportive or ancillary treatment of cerebral malaria, was tested for its anti-parasitic effect on the blood stages of P. falciparum malaria in vitro. Heparin was cleaved into fragments differing in molecular weight and in their affinity for antithrombin III. Both unfractionated heparin and heparin fractions inhibited the merozoite invasion into red blood cells. The mechanism by which heparin acts is not clear. However, the inhibition was reversible by washing heparin-treated P. falciparum cultures indicating a direct effect of heparin. The sensitivity of laboratory strains and/or fresh isolates obtained from individuals residing in malaria endemic areas was compared. Although varying in sensitivity none of the samples tested was found to be resistant to heparin and its derivates. A fraction of heparin with low affinity for antithrombin III was the most potent inhibitor of merozoite invasion. The fraction with low affinity for antithrombin III is devoid of anticoagulant activity, suggesting a potential role of this fraction for the treatment of malaria.For the development of subunit vaccines it is important to identify and characterise epitopes which activate relevant B- and T-cell functions. In this study we have investigated two putative malaria vaccine candidate antigens, Pf155/RESA and Pf332, for T- and B-cell reactive epitopes. A large number of donors had antibodies against the Pf155/RESA sequence 186-206. For the Pf332 derived fragment, EB200, the donors also exhibited high antibody levels in their plasma. In our studies we have measured multi parameters of T-cell activation (proliferation, IFN-g and/or IL-4 production). Peptides corresponding to the N-terminal region of Pf155 or to EB200, stimulated peripheral blood mononuclear cells from P. falciparum-immune donors to proliferate, to induce secretion of IFN-g and/or IL-4. In individual donors the cellular immune responses to the peptides varied considerably. However, there was no clear association between proliferation and production of the cytokines investigated. This lack of association underlines the importance of including multiple parameters when analysing T-cell responses to defined epitopes.In conclusion, the non-repeat region of Pf155/RESA and the EB200 fragment of Pf332 contains several B-cell epitopes as well as several epitopes inducing functionally distinct T-cell responses, which should be a useful tool for inclusion in a subunit malaria vaccine as well as in future immuno-epidemiological studies.
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| 27. |
- Nasr, Amre, 1975-
(författare)
-
Single nucleotide polymorphisms related to immune responses in Plasmodium falciparum malaria
- 2008
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The current research is directed towards dissection of host genetic factors involved in host immune response and the malaria disease outcome. A possible association between FcγRIIa polymorphism and anti-malarial antibody (A.M.A) responses were investigated in Sudanese patients in relation to clinical outcome of falciparum malaria. The frequency of the R/R131 genotype was significantly higher in patients with severe malaria as compared with mild malaria. A.M.A IgG3 was shown to be associated with reduced risk of clinical malaria in individuals carrying the H/H131 genotype. Low levels of IgG2 reactive with the Pf332-C231 antigen were associated with lower risk of severe malaria in individuals carrying the H131 allele. Fulani and Masaleit, two sympatric ethnic groups in Sudan, are characterized by marked differences in susceptibility to falciparum malaria. We investigated whether the two populations differ in the frequency of GM/KM allotypes. The distribution of GM/KM phenotypes differed significantly among the two groups, with Gm 6 being significantly lower among the Fulani, and the combined frequency of Km 1,3 and Gm 1,17 5,6,13,14 phenotypes was found to be higher among Masaleit. In interethnic study we investigated whether the two groups differ in the frequency of FcγRIIa and HbAS genotypes. The frequency of the H/H131, R/R13 and HbAS genotypes differed significantly among the two groups. Moreover, the Fulani showed higher levels of A.M.A IgG2 and lower IgG1 and IgG3 when compared to their sympatric non-Fulani neighbours.A tri-allelic SNP (C/T/A) in the CRP gene was investigated for possible ethnic associations. The A allele, which is associated with higher basal CRP levels, was found to be less frequent in the Fulani compared with non-Fulani ethnic groups both in Sudan and Mali. In conclusion, our results suggest possible associations between FcγRIIa, CRP genotypes, GM/KM allotypes, and anti-malarial antibody responses and the clinical outcome of falciparum malaria.
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| 28. |
- Nilsson, Anna, 1978-, et al.
(författare)
-
CD47 promotes both phosphatidylserine-independent and phosphatidylserine-dependent phagocytosis of apoptotic murine thymocytes by non-activated macrophages
- 2009
-
Ingår i: Biochemical and Biophysical Research Communications - BBRC. - : Elsevier. - 0006-291X .- 1090-2104. ; 387:1, s. 58-63
-
Tidskriftsartikel (refereegranskat)abstract
- The ubiquitously expressed cell surface glycoprotein CD47 on host cells can inhibit phagocytosis of unopsonized or opsonized viable host target cells. Here we studied the role of target cell CD47 in macrophage uptake of viable or apoptotic murine thymocytes. As expected, IgG-opsonized viable CD47-/- thymocytes were taken up more efficiently than equally opsonized Wt thymocytes. However IgG-opsonized apoptotic thymocytes from Wt and CD47-/- mice were taken up equally. Although uptake of apoptotic thymocytes by non-activated bone marrow-derived macrophages was phosphatidylserine (PS)-independent, while uptake by non-activated resident peritoneal macrophages was PS-dependent, both macrophage populations showed a reduced uptake of non-opsonized apoptotic CD47-/- thymocytes, as compared with the uptake of apoptotic Wt thymocytes. This difference was only seen with non-activated macrophages, and not with β-1,3-glucan-activated macrophages. CD47 promoted binding of thymocytes to macrophages, which did not require F-actin polymerization. CD47 became clustered on apoptotic thymocytes, both colocalized with or separated from, clustered PS and cholesterol-rich GM-1 domains. Thus, CD47 does not inhibit, but rather support, both PS-independent and PS-dependent uptake of apoptotic cells in the murine system. This mechanism only comes into play in non-activated macrophages.
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| 29. |
- Nilsson, Anna, 1978-
(författare)
-
Mechanisms involved in macrophage phagocytosis of apoptotic cells
- 2009
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Efficient removal of apoptotic cells is critical for development, tissue remodelling, maintenance of homeostasis, and response to injury. Phagocytosis of apoptotic cells is mediated by many phagocytic receptors, soluble bridging molecules, and pro-phagocytic ligands on the surface of apoptotic cells. Macrophage phagocytosis in general is controlled by stimulatory and inhibitory mechanisms. An example of the latter mechanism is that mediated by the cell surface glycoprotein CD47, which by binding to the inhibitory receptor Signal Regulatory Protein alpha (SIRPα) on macrophages, is known to inhibit phagocytosis of viable host cells. The studies of the present thesis aimed at investigating possible changes to CD47 on apoptotic cells, which could influence their elimination by macrophages. The endoplasmatic protein calreticulin (CRT), in conjunction with Low density lipoprotein Receptorrelated Protein 1 (LRP1) on the phagocyte, can act as a receptor for collectin family members and mediate uptake of apoptotic cells. However, CRT itself was found to also be expressed on the surface of many viable cell types, and the CRT expression increased on apoptotic cells. By using antibodies to LRP1 or receptor‐associated protein (RAP), an antagonist blocking LRP1 ligand binding, we found that CRT on target cells could interact in trans with LRP1 on a phagocyte and stimulate phagocytosis. CD47 on the target cell inhibited LRP1‐mediated phagocytosis of viable cells (e.g. lymphocytes or erythtocytes), but not that of apoptotic cells. The inability of CD47 on apoptotic cells to inhibit LRP1‐ mediated phagocytosis could be explained in two ways: 1) Some apoptotic cell types (fibroblasts and neutrophils, but not Jurkat T cells) lost CD47 from the cell surface, or 2) CD47 is evenly distributed on the surface of viable cells, while it was redistributed into patches on apoptotic cells, segregated away from areas of the plasma membrane where the pro‐phagocytic ligands CRT and phoaphatidylserine (PS) were concentrated. Apoptotic murine thymocytes also showed a patched distribution of CD47, but no significant loss of the receptor. However, both PS‐independent and PS‐dependent macrophage phagocytosis of apoptotic CD47‐/‐ thymocytes was less efficient than uptake of apoptotic wild‐type (wt) thymocytes. This contradictory finding was explained by the fact that CD47 on apoptotic thymocytes did no longer inhibit phagocytosis, but rather mediated binding of the apoptotic cell to the macrophage. These effects could in part be dependent on the apoptotic cell type, since uptake of experimentally senescent PS+ wt or CD47‐/‐ erythrocytes by macrophage in vitro, or by dendritic cells (DC) in vivo, were the same. In vivo, PS+ erythrocytes were predominantly trapped by marginal zone macrophages and by CD8+ CD207+ DCs in the splenic marginal zone. DCs which had taken up PS+ erythrocytes showed a slight increase in expression levels of CD40, CD86 and MHC class II. These findings suggest that PS+ erythrocytes may be recognized by splenic macrophages and DCs in ways similar to that reported for apoptotic T cells. Uptake of senescent erythrocytes by DCs may serve as an important mechanism to maintain self‐tolerance to erythrocyte antigens, and defects in this function may facilitate development of AIHA. Glucocorticoids are used to treat inflammatory conditions and can enhance macrophage uptake of apoptotic cells. We found that the glucocorticoid dexamethasone time‐ and dose‐dependently stimulated macrophage cell surface LRP1 expression. Dexamethasone‐stimulated macrophages also showed enhanced phagocytosis of apoptotic thymocytes and unopsonized viable CD47‐/‐ erythrocytes. In summary, LRP1 can mediate phagocytosis of both viable and apoptotic cells by binding CRT on the target cell. Macrophage expression of LRP1 is increased by glucocorticoids, which could be one explanation for the anti‐inflammatory role of glucocorticoids. While CD47 on viable cells efficiently inhibits phagocytosis in macrophages, CD47 on apoptotic cells does not and can sometimes even promote their removal.
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| 30. |
- Nilsson, Anna, 1978-, et al.
(författare)
-
Role of CD47 in regulating macrophage and dendritic cell uptake of calcium-induced experimentally senescent erythrocytes in vitro and in vivo
-
Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- During senescence, erythrocytes are rapidly eliminated by phagocytes in the spleen and liver,and the interplay between macrophages or dendritic cells (DCs) with lymphocytes in the spleen could be of importance to regulate self-tolerance and to prevent development of autoimmune hemolytic anemia (AIHA).The cell surface glycoprotein CD47 on the surface of host target cells can inhibit phagocytosis of normal circulating blood cells by binding to signal regulatory protein alpha (SIRPα) on macrophages and DCs. Here we investigated the clearance of Ca2+-ionophore-treated experimentally senescent erythrocytes (Ca2+-RBCs) in vivo, and if CD47 on Ca2+-RBCs regulated their uptake by macrophages in vitro or their clearance in vivo. Ca2+-RBCs exposed phosphatidylserine (PS) on their surface and were rapidly phagocytosed by macrophages in vitro. This uptake was dependent on heat-stable serum factors, but was not inhibited by CD47 on the erythrocytes. Following intravenous injection, a large fraction of PKH26-labeled Ca2+-RBCs were trapped by splenic marginal zone macrophages and DCs within 1 hour. In addition, at 20 hours after injection fluorescence from the injected cells could also be detected within the T cell area of the splenic white pulp and associated with both CD8+ and CD8- DCs. We found that DCs in wild-type (Wt) recipient mice showed equal uptake of transfused Wt and CD47-/- Ca2+-RBCs. DCs which had taken up Ca2+-RBCs showed a slight increase in expression levels of CD40, CD86 and MHC class II. In recipients of CD47-/- Ca2+-RBCs, DCs negative for RBC-uptake showed strongly increased expression of CD86, as compared with that in recipients of Wt Ca2+-RBCs. These findings suggest that PS+ erythrocytes may be recognized by splenic macrophages and DCs in ways similar to that reported for nucleated apoptotic cells. Uptake of senescent erythrocytes by DCs may serve as an important mechanism to maintain self-tolerance to erythrocyte antigens, and defects in this function may facilitate development of AIHA.
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| 31. |
- Rizzo, Roberta, et al.
(författare)
-
Allergic women have reduced sHLA-G plasma levels at delivery.
- 2009
-
Ingår i: American Journal of Reproductive Immunology and Microbiology. - : Wiley. - 8755-8920 .- 1046-7408 .- 1600-0897. ; 61:5, s. 368-76
-
Tidskriftsartikel (refereegranskat)abstract
- PROBLEM: HLA-G antigen maintains a tolerogenic condition at the foeto-maternal interface, counteracts inflammation in autoimmune diseases and soluble HLA-G (sHLA-G) levels decrease in allergic-asthmatics. Taking into consideration these findings, we analyzed if sHLA-G and interleukin-10 (IL-10) could be influenced by pregnancy and labour in allergic and non-allergic women. METHOD OF STUDY: sHLA-G isoforms and IL-10 levels were determined in the plasma samples of 43 women (15 non-allergic, 28 allergic) during third trimester, at delivery and 2 years after pregnancy by immunoenzymatic assays. RESULTS: A significant increase in sHLA-G and IL-10 levels was documented at delivery in both allergic and non-allergic women. Allergic women showed lower sHLA-G concentrations. sHLA-G1 was evidenced as the predominant plasma isoform. CONCLUSION: The data showed increased sHLA-G and IL-10 concentrations at delivery, regardless of the allergic status. The sHLA-G1 isoform is mainly responsible for the increased sHLA-G levels at delivery.
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| 32. |
- Ruck, Anders, 1966-
(författare)
-
Autocrine growth stimulation in human bladder cancer
- 1998
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Bladder cancer is one of the most common human cancers which, on a worldwide basis, represents 3-4 % of all malignancies. It is primarily occuring in people over 60 and males are about 2-3 times more likely to develop bladder cancer than are women. The formation of tumors is a multistep process in which the normal regulatory systems that govern cell proliferation and differentiation have been distorted or eliminated, which, in turn, leads to a selective growth advantage over the neighbouring normal cells. In vitro, this is reflected by that tumor cells are often less dependent on external growth factors to survive and proliferate than are their normal counterparts. This capacity to grow more or less autonomously has for several types of tumors been shown to depend on autocrine growth stimulation, i.e. the ability of cells to produce and respond to their own growth factors. In this thesis we have shown that this is a characteristic feature also of bladder tumors and we were able to identify the EGF-receptor and its ligands as being potentially responsible. This was demonstrated by the use of EGF-receptor-blocking antibodies as well as by neutralizing antibodies to the various ligands (EGF, TGFa, AR and HB-EGF) operating through this receptor. The observation supports and extends previous indications of this receptor/ligand system as being important for the development and progession of bladder tumors.During the course of the studies we could also demonstrate the production of a number of other cytokines by the tumor cells, several of which are known to be immunoregulatory (IL-1a/b, IL-6, IL-8, G-CSF, GM-CSF and TNFa/b). Although none of these appeared to affect tumor cell growth they could potentially act to modulate the natural or induced immune responses. To look at one potential mechanism behind the effective immunotherapy with BCG (Bacillus Calmette-Guerin) we analysed the effect on tumor cell growth of the three cytokines, IL-4, IL-10 and IFNg which all are likely to be induced in repsonse to the BCG-treatment. IL-4 and IL-10 were both inhibtory whereas IFNg either inhibited or stimulated growth depending on the cell line investigated. This shows that these factors may contribute to the positive effects of BCG treatment.The observations made in this study may contribute to a better understanding of the molecular background of bladder cancer as well as of the mechanism behind immunotherapy. This information will, hopefully, also have practical consequences for defining new or refined approaches to therapy and tumor diagnosis.
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| 33. |
- Schmid, Martin Rudolf, 1979-, et al.
(författare)
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Control of Drosophila blood cell activation via toll signaling in the fat body
- 2014
-
Ingår i: PLOS ONE. - : Public library of science. - 1932-6203. ; 9:8
-
Tidskriftsartikel (refereegranskat)abstract
- The Toll signaling pathway, first discovered in Drosophila, has a well-established role in immune responses in insects as well as in mammals. In Drosophila, the Toll-dependent induction of antimicrobial peptide production has been intensely studied as a model for innate immune responses in general. Besides this humoral immune response, Toll signaling is also known to activate blood cells in a reaction that is similar to the cellular immune response to parasite infections, but the mechanisms of this response are poorly understood. Here we have studied this response in detail, and found that Toll signaling in several different tissues can activate a cellular immune defense, and that this response does not require Toll signaling in the blood cells themselves. Like in the humoral immune response, we show that Toll signaling in the fat body (analogous to the liver in vertebrates) is of major importance in the Toll-dependent activation of blood cells. However, this Toll-dependent mechanism of blood cell activation contributes very little to the immune response against the parasitoid wasp, Leptopilina boulardi, probably because the wasp is able to suppress Toll induction. Other redundant pathways may be more important in the defense against this pathogen.
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| 34. |
- Sjögren, Ylva Margareta, 1981-, et al.
(författare)
-
Altered early infant gut microbiota in children developing allergy up to 5 years of age.
- 2009
-
Ingår i: Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology. - : Wiley. - 1365-2222 .- 0954-7894. ; 39:4, s. 518-526
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Early colonization with bifidobacteria and lactobacilli is postulated to protect children from allergy, while Clostridium (C.) difficile colonization might be associated with allergic disease. Previous studies of infant gut microbiota in relation to subsequent allergy development have mostly employed culture-dependent techniques, studied genera of bacteria and the follow-up period was limited to 2 years. OBJECTIVE: To relate gut microbiota in early infancy, notably bifidobacteria and lactobacilli at species level, to allergy development during the first 5 years of life and study if environmental factors influence the early infant gut microbiota. METHODS: Fecal samples were collected at 1 week, 1 month and 2 months after birth from 47 Swedish infants, followed prospectively to 5 years of age. Bacterial DNA was analysed with real-time PCR and related to allergy development, family size as well as endotoxin and Fel d 1 levels in house dust samples. Primers binding to C. difficile, four species of bifidobacteria, two lactobacilli groups and Bacteroides fragilis were used. Children regarded as allergic manifested allergic symptoms and were skin prick test positive during their first 5 years while non-allergic children were neither. RESULTS: Children who developed allergy were significantly less often colonized with lactobacilli group I (Lactobacillus (L.) rhamnosus, L. casei, L. paracasei), Bifidobacterium adolescentis and C. difficile during their first 2 months. Infants colonized with several Bifidobacterium species had been exposed to higher amounts of endotoxin and grew up in larger families than infants harbouring few species. CONCLUSION: A more diverse gut microbiota early in life might prevent allergy development and may be related to the previously suggested inverse relationship between allergy, family size and endotoxin exposure.
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| 35. |
- Sjögren, Ylva Margareta, 1981-
(författare)
-
Early-life gut microbiota and breast milk oligosaccharides in relation to childhood immune maturation and allergy
- 2009
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Atopic allergy is the most common chronic disease among children in the developed world. This high prevalence could be associated with low microbial exposure. The early gut microbiota appears to be important for immune maturation. Immunomodulatory components in human milk might differ between mothers and could therefore explain the contradictory results seen regarding breastfeeding and allergy development. The aim of this thesis was to investigate whether early colonization with certain gut microbiota species influences childhood immune responses and allergy development up to age five. Also, as human milk oligosaccharides (HMOs) might stimulate the growth of certain gut microbiota species, the consumption of neutral colostrum HMOs was investigated for their role in allergy development up to 18 months. The concentrations of neutral colostrum HMOs varied considerably between women; however this variation could not be explained by their allergic status. Neither was the consumption of neutral colostrum HMOs related to allergy development in their children up to 18 months. Infants who harboured lactobacilli group I and Bifidobacterium adolescentis one week after birth developed allergic disease less frequently during their first five years than infants who did not harbour these bacteria at the same time. Also, colonization with several Bifidobacterium species was associated with higher levels of house dust endotoxin and larger family size. The early Bifidobacterium flora influenced levels of salivary secretory IgA at six and 12 months but not during later childhood. Moreover, the intensity of early Bacteroides fragilis colonization was inversely associated with spontaneous Toll-like receptor 4 mRNA expression in peripheral blood cells collected 12 months after birth. In conclusion, these results indicate that the early infant gut microbiota influences systemic and mucosal immune maturation during infancy, and that it might be altered in infants developing allergic disease.
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| 36. |
- Sjögren, Ylva Margareta, 1981-, et al.
(författare)
-
Influence of early gut microbiota on the maturation of childhood mucosal and systemic immune responses
-
Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Introduction: Among sensitized infants those with high, as compared with low levels, of salivary secretory IgA (SIgA) are less likely to develop allergic symptoms. Also, early colonization with certain gut microbiota, e.g. Lactobacilli and Bifidobacterium species, might be associated with less allergy development. Although animal and in vitro studies emphasize the role of the commensal gut microbiota in the development of the immune system, the influence of the gut microbiota on immune development in infants is unclear. Objective: To assess whether early colonization with certain gut microbiota species associates with mucosal and systemic immune responses i.e. salivary SIgA and the spontaneous toll like receptor (TLR) 2 and TLR4 mRNA expression and LPS-induced cytokine/chemokine responses in peripheral blood mononuclear cells (PBMC). Methods: Faecal samples were collected at one week, one month and two months after birth from 64 Swedish infants, followed prospectively to five years of age. Bacterial DNA was analyzed with real-time PCR using primers binding to Clostridium difficile, four species of bifidobacteria, two lactobacilli groups and Bacteroides fragilis. Saliva was collected at age six and twelve months and at two and five years and SIgA was measured with ELISA. The PBMC, collected twelve months after birth, were analyzed for TLR2 and TLR4 mRNA expression with real-time PCR. Further, the PBMC were stimulated with LPS and cytokine/chemokine responses were measured with Luminex. Results: The number of Bifidobacterium species in the early faecal samples correlated significantly with the total salivary SIgA levels at six months. Early colonization with Bifidobacterium species, lactobacilli groups or C. difficile did not influence TLR2 and TLR4 expression in PBMC. However, PBMC from infants colonized early with high amounts of Bacteroides fragilis expressed lower levels of TLR4 mRNA spontaneously. Furthermore, LPS-induced production of inflammatory cytokines and chemokines, e.g. IL-6 and CCL4 (MIP-1β), were inversely correlated to the relative amounts of Bacteroides fragilis in the early faecal samples. Conclusion: Bifidobacterial diversity may enhance the maturation of the mucosal SIgA system and early high colonization with Bacteroides fragilis might down-regulate LPS responsiveness in infancy.
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| 37. |
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| 38. |
- Sundström, Yvonne, 1973-
(författare)
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Phenotypic and functional studies of NK cells in neonates and during early childhood
- 2008
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- During infancy, before adaptive immunity has matured, innate immunity is thought to be relatively more important. Human natural killer (NK) cells are innate immune cells involved in the control of virus-infected cells and can influence adaptive immunity mainly through cytokine production. This thesis aimed at investigating function and phenotype of NK cells in children from birth and during early childhood and to see if these features are altered in children that develop early allergy, in children latently infected by herpes viruses or born by preeclamptic mothers.Our results suggest that NK-cell populations are dynamic during the first years of life and start to resemble the phenotype of adults after five years of age. Early alterations in the NK-cell populations could lead to insufficient Th1 priming, with an increased risk to develop allergic disease. Early infection by common herpes viruses can influence NK-cell function and might be one important factor involved in early maturation processes of adaptive immunity. The altered NK-cell function and cytokine levels, noticed in CB from pathological pregnancies, suggest that NK cells could be influenced already in utero. These early alterations of innate immunity may affect the development of the child’s immune system, sometimes with beneficial outcome but could in some cases promote pathology.
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| 39. |
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| 40. |
- Tangteerawatana, Piyatida, et al.
(författare)
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IL4 gene polymorphism and previous malaria experiences manipulate anti-Plasmodium falciparum antibody isotype profiles in complicated and uncomplicated malaria.
- 2009
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Ingår i: Malaria Journal. - : Springer Science and Business Media LLC. - 1475-2875. ; 8:1, s. 286-
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Tidskriftsartikel (refereegranskat)abstract
- ABSTRACT: BACKGROUND: The IL4-590 gene polymorphism has been shown to be associated with elevated levels of anti-Plasmodium falciparum IgG antibodies and parasite intensity in the malaria protected Fulani of West Africa. This study aimed to investigate the possible impact of IL4-590C/T polymorphism on anti-P. falciparum IgG subclasses and IgE antibodies levels and the alteration of malaria severity in complicated and uncomplicated malaria patients with or without previous malaria experiences. METHODS: Anti-P.falciparum IgG subclasses and IgE antibodies in plasma of complicated and uncomplicated malaria patients with or without previous malaria experiences were analysed using ELISA. IL4-590 polymorphisms were genotyped using RFLP-PCR. Statistical analyses of the IgG subclasses and IgE levels were done by Oneway ANOVA. Genotype differences were tested by Chi-squared test. RESULTS: The IL4-590T allele was significantly associated with anti-P. falciparum IgG3 antibody levels in patients with complicated (P=0.031), but not with uncomplicated malaria (P=0.622). Complicated malaria patients with previous malaria experiences carrying IL4-590TT genotype had significantly lower levels of anti-P. falciparum IgG3 (P=0.0156), while uncomplicated malaria patients with previous malaria experiences carrying the same genotype had significantly higher levels (P=0.0206) compared to their IL4-590 counterparts. The different anti-P. falciparum IgG1 and IgG3 levels among IL4-590 genotypes were observed. Complicated malaria patients with previous malaria experiences tended to have lower IgG3 levels in individuals carrying TT when compared to CT genotypes (P=0.075). In contrast, complicated malaria patients without previous malaria experiences carrying CC genotype had significantly higher anti-P. falciparum IgG1 than those carrying either CT or TT genotypes (P=0.004, P=0.002, respectively). CONCLUSIONS: The results suggest that IL4-590C or T alleles participated differently in the regulation of anti-malarial antibody isotype profiles in primary and secondary malaria infection and, therefore, could play an important role in alteration of malaria severity.
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| 41. |
- Tjärnlund, Anna
(författare)
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Mucosal Immunity in Mycobacterial infections
- 2007
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- More than a century after the identification of the tubercle bacillus and the first attempts at vaccination, tuberculosis (TB) still remains one of the world’s most serious infectious diseases. TB, caused by the bacterium Mycobacterium tuberculosis, is typically a disease of the lung, which serves both as port of entry and as the major site of disease manifestation. The currently used vaccine, BCG, is administered parenterally and induces a systemic immune response. However, it fails to protect against pulmonary TB, thereby raising the question whether vaccination targeting the mucosal immunity in the lungs could be favourable. The respiratory mucosal surfaces represent the first line of defence against a multitude of pathogens. Secretory IgA, in mucosal secretions has an important function by blocking entrance of pathogenic organisms and preventing infections. Additionally, a role for IgA in modulation of immune responses is currently being revealed. In this work, we investigated the relevance of mucosal IgA in protection against mycobacterial infections using mice deficient for IgA and the polymeric Ig receptor, the receptor responsible for mucosal secretions of IgA. Gene-targeted mice were more susceptible to mycobacterial infections in the respiratory tract and displayed reduced production of proinflammatory, and protective, factors such as IFN-γ and TNF-α in the lungs. The mechanisms explaining the defective proinflammatory responses in the lungs of deficient mice might involve impaired signalling through Fcα receptors, or homologous receptors, which could lead to inadequate activation of pulmonary macrophages. This could subsequently result in suboptimal induction and production of cytokines and chemokines important for attraction and migration of immune cells to the site of infection. Induction of optimal adaptive immune responses to combat mycobacterial infections requires prompt innate immune activation. Toll-like receptors (TLRs) are vital components of the innate branch of the immune system, ensuring early recognition of invading pathogens. Using TLR-deficient mice we demonstrated an important role for TLR2, and partly TLR4, in protection against mycobacterial infection in the respiratory tract. TLR2-deficient mice failed to induce proper proinflammatory responses at the site of infection, and macrophages derived from the knockout mice displayed impaired anti-mycobacterial activity. Experimental evidence has concluded that the immune response upon an infection can influence the outcome of succeeding infections with other pathogens. Concurrent infections might additionally interfere with responses to vaccinations and have deleterious effects. We developed an in vitro model to study the effect of a malaria infection on a successive M. tuberculosis infection. Our results demonstrate that a malaria blood-stage infection enhances the innate immune response to a subsequent M. tuberculosis infection with a Th1 prone profile. Reduced infectivity of malaria-exposed dendritic cells implies that a malaria infection could impose relative resistance to ensuing M. tuberculosis infection. However, a prolonged Th1 response may interfere with malaria parasite control. The outcome of this work emphasizes the importance of generating effective immune responses in the local mucosal environment upon respiratory mycobacterial infections. It furthermore puts new light on the immunological interaction between parasites and mycobacteria, which could have implications for future vaccine research.
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| 42. |
- Vafa Homann, Manijeh, 1970-
(författare)
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Human genetic factors involved in immunity to Plasmodium falciparum infection
- 2008
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This study investigated the associations between IL-4 -590 C/T and IL-10 -1087 A/G polymorphisms and malariometric indexes in the Fulani and the Dogon ethnic groups living in sympatry in Mali and differing in susceptibility to malaria. The correlations between antibodies level and parasitological data as well as splenomegaly were assessed. The impact of IL-4 -590 variants on the levels of the studied antibodies was also studied. The allele and genotype frequencies of both studied SNPs differed significantly between the two groups. The Fulani IL-4 T allele carriers had a significantly higher infection prevalence compared with those carrying the CC genotype. No correlation between anti-malarial antibody levels and parasite prevalence was seen in any of the communities. In the Fulani, the increase in total IgE levels was related to the presence of infection. Malaria-specific IgG4 levels were negatively correlated to the number of clones within the Fulani. The Fulani IL-4 T allele carriers had higher total and malaria-specific IgE levels, compared to the CC genotype carriers. These results suggest that the amount of antibodies may not be the key element in the protection against malaria. IgG4 might be involved in protection against malaria. The impact of IL-4 -590 variants on the antibody levels may be affected by other genetic/epigenetic/epistatic or environmental factors. In the study in Senegal, multiplicity of infection (MOI) increased after the transmission season in all subjects, except in α-thalassaemic and in G6PD-mutated children, suggesting that α-thalassaemia may protect against infection by certain parasite strains. G6PD-mutated individuals may resist against increase in MOI after the transmission season due to rapid clearance of infection at an early stage. HbAs and the ABO system do not affect MOI in asymptomatic individuals. MOI was positively correlated to parasitemia, and did not vary over age (in the range of 2 to 10 years). No relation between MOI and clinical attack was noted.
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| 43. |
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| 44. |
- Nandakumar, Mridula
(författare)
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Pathogen-mediated selection in the immune system of rodents : Exploring selection targets, functional effects and trade-offs
- 2024
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Pathogens cause disease and play an important role in shaping evolution of the host immune system. They create pressure on host immunity to evolve in numerous ways, most commonly by increasing divergence between species (positive selection) or increasing polymorphisms within a population (balancing selection). Especially with balancing selection, trade-offs between different traits, for example responses to different pathogens, are essential. Across five papers, questions related to what immune genes are under selection, how this translates to an effect on the immune response and what trade-offs occur, are addressed using rodents as study system. Paper I utilised genomes from 30 rodent species to identify signatures of positive selection in immune genes. In general, function of immune genes was a significant determinant for signs of positive selection. This effect was significant even after accounting for potential confounding factors like gene expression and protein-protein interactions. In Paper II, the focus is on a local population of bank voles in Sweden, to look for signatures of balancing selection in the complement system – a branch of innate immunity. One complement gene, FCNA, was found to be under strong balancing selection. In Paper III, FCNA polymorphism was linked to associations with natural infections of Borrelia afzelii, a common pathogen for bank voles. Papers IV and V look at how the immune response of bank voles of various genotypes differ on stimulation with B. afzelii and the human pathogen Streptococcus pyogenes, captured with transcriptome sequencing of spleen cells. In Paper IV, the analysis is focused on various genotypes of TLR2, an immune gene under balancing selection in bank voles and associated with infection prevalence of B. afzelii in the wild. A stimulation-specific effect of TLR2 on immune response was found, where the magnitude of immune response to B. afzelii, but not S. pyogenes, depends on TLR2 expression level in a TLR2 genotype-specific way. In Paper V, tradeoffs at the cis-regulatory level between the response to B. afzelii and S. pyogenes was tested by searching for polymorphisms where the alleles are expressed differently to these two stimulations. Abundant cis-regulatory variation for responses to the two bacteria was found, but there was no evidence for trade-offs. In summary, this work pushes our knowledge of what immune genes can be expected to be under pathogen-mediated selection, as heretofore understudied categories of immune function showed signs of selection. A novel basis – the combination of genotype and expression – was uncovered for functional effects of polymorphic genes. Finally, there was no evidence for trade-offs between responses to different pathogens. Investigating the nature of trade-offs in the immune system further would be necessary towards understanding the causes and consequences of pathogen-mediated selection.
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| 45. |
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| 46. |
- Razaghi, Ali, et al.
(författare)
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Effects of nitrogen on growth and carbohydrate formation in Porphyridium cruentum
- 2014
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Ingår i: Central European Journal of Biology. - : Walter de Gruyter GmbH. - 1895-104X .- 1644-3632. ; 9:2, s. 156-162
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Tidskriftsartikel (refereegranskat)abstract
- The microalga Porphyridium cruentum (Rhodophyta) has several industrial and pharmaceutical uses, especially for its polysaccharide production. This study aimed to investigate the influence of nitrogen levels as reflected by altered N:P ratios on the production and content of biomass and carbohydrate. N:P molar ratios were altered in batch cultures to range from 1.6 to 50 using the Redfield ratio of 1:16 as reference. Algal growth (estimated as final cell number, biomass concentration and maximum specific growth rate) was negatively affected at low N:P ratios. The optimal N:P ratio for growth was identified at 35-50, with specific growth rates of 0.19 day(-1) and maximum cell concentrations of 59 center dot 10(8) cells L-1 and 1.2 g dry weight of biomass L-1. In addition, variation in cell size was seen. Cells with larger diameters were at higher N:P ratios and smaller cells at lower ratios. The cellular carbohydrate content increased under reduced nitrogen availability. However, because accumulation was moderate at the lowest N:P ratio, 0.4 g per g dry weight biomass compared to 0.24 at the Redfield ratio of 16:1, conditions for increased total carbohydrate formation were identified at the N:P ratios optimal for growth. Additionally, carbohydrates were largely accumulated in late exponential to stationary phase.
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| 47. |
- Hamad, Osama A., 1978-, et al.
(författare)
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Non-proteolytically activated C3 promotes binding of activated platelets and platelet-derived microparticles to leukocytes via CD11b/CD18
- 2012
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Ingår i: Immunobiology. - : Elsevier BV. - 0171-2985 .- 1878-3279. ; 217:11, s. 1191-1191
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Tidskriftsartikel (refereegranskat)abstract
- Background:We have previously demonstrated that complement component C3 binds to the surface of activated platelets, independent of proteolytic activation. The resulting form of C3, termed C3(H2O), was shown to be a ligand for recombinant CD35 (complement receptor 1, CR1). Previous studies by others have indicated that platelet-leukocyte complex (PLC) formation is dependent on the interaction between platelet exposed P-selectin (CD62P) and its ligand, PSGL-1, on leukocytes. In addition, CD11b/CD18 (Mac-1 or CR3) has been shown to participate in this reaction, but its ligand has not yet been identified.Objective:To test the hypothesis that C3 bound to activated platelets and platelet-derived microparticles (PMPs) can act as a ligand for CD11b/CD18 (CR3) and contribute to PLC formation.Methods and results:Blood cells were depleted of plasma proteins. After extensive washing, C3 was added, and the leukocytes were activated with C5a and the platelets with thrombin receptor-activating peptide (TRAP). PLC formation was detected by flow cytometry (monocytes: CD14+/CD42a+, granulocytes: CD16+/CD42a+). For both granulocytes and monocytes, the addition of C3 significantly enhanced PLC formation. Formation of PLC was inhibited by both anti-P-selectin and anti-CD11b monoclonal antibodies. In addition, PMPs isolated from serum, were found to expose C3(H2O) and bind to leukocytes in a fashion similar to activated platelets.Conclusion:We have identified proteolytically non-activated C3 as a ligand for CD11b in the formation of PLC and possibly the binding of PMPs to leukocytes. This observation most likely has pathophysiological implications for the recently reported links between thrombotic disease and the complement system.
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| 48. |
- Akula, Srinivas
(författare)
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The mast cell transcriptome and the evolution of granule proteins and Fc receptors
- 2019
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Protection against disease-causing pathogens, known as immunity, involves numerous cells organs, tissues and their products. To able to understand the biology of immune cells (hematopoietic cells) and their role in an immune system, we have used several different methods, including transcriptome analyses, bioinformatics, production of recombinant proteins and analyses of some of them, focusing on the granule proteases by substrate phage display.Hematopoietic cells express surface receptors interacting with the constant region of immunoglobulins (Igs) known as Fc receptors (FcRs). These receptors play major roles in the immune system, including enhancing phagocytosis, activating antibody dependent cellular cytotoxicity and cell activation. A detailed bioinformatics analysis of FcRs reveals that the poly-Ig receptors (PIGR), FcR-like molecules and common signalling γ chain all appeared very early with the appearance of the bony fishes, and thereby represent the first major evolutionary step in FcR evolution. The FcμR, FcαμR, FcγR and FcεR receptors most likely appeared in reptiles or early mammals, representing the second major step in FcR evolution.Cells of several of the hematopoietic cell lineages contain large numbers of cytoplasmic granules, and serine proteases constitute the major protein content of these granules. In mammals, these proteases are encoded from four different loci: the chymase, the met-ase, the granzyme (A/K) and the mast cell tryptase loci. The granzyme (A/K) locus was the first to appear and came with the cartilaginous fishes. This locus is also the most conserved of the three. The second most conserved locus is the met-ase locus, which is found in bony fishes. The chymase locus appeared relatively late, and we find the first traces in frogs, indicating it appeared in early tetrapods.To study the early events in the diversification of these hematopoietic serine proteases we have analyzed key characteristics of a protease expressed by an NK-like cell in the channel catfish, catfish granzyme–like I. We have used phage display and further validated the results using a panel of recombinant substrates. This protease showed a strict preference for Met at the P1 (cleavage) position, which indicates met-ase specificity. From the screening of potential in vivo substrates, we found an interesting potential target caspase 6, which indicates that caspase-dependent apoptosis mechanisms have been conserved from fishes to mammals.A larger quantitative transcriptome analysis of purified mouse peritoneal mast cells, cultured mast cells (BMMCs), and mast cells isolated from mouse ear and lung tissue identified the major tissue specific transcripts in these mast cells as the granule proteases. Mast cell specific receptors and processing enzymes were expressed at approximately 2 orders of magnitude lower levels. The levels of a few proteases were quite different at various anatomical sites between in vivo and cultured BMMCs. These studies have given us a new insights into mast cells in different tissues, as well as key evolutionary aspects concerning the origins of a number of granule proteases and FcRs.
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| 49. |
- Cerenius, Lage, 1956-, et al.
(författare)
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High sequence variability among hemocyte-specific Kazal-type proteinase inhibitors in decapod crustaceans
- 2010
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Ingår i: Developmental and Comparative Immunology. - : Elsevier. - 0145-305X .- 1879-0089. ; 34:1, s. 69-75
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Tidskriftsartikel (refereegranskat)abstract
- Crustacean hemocytes were found to produce a large number of transcripts coding for Kazal-type proteinase inhibitors (KPIs). A detailed study performed with the crayfish Pacifastacus leniusculus and the shrimp Penaeus monodon revealed the presence of at least 26 and 20 different Kazal domains from the hemocyte KPIs, respectively. Comparisons with KPIs from other taxa indicate that the sequences of these domains evolve rapidly. A few conserved positions, e.g. six invariant cysteines were present in all domain sequences whereas the position of P1 amino acid, a determinant for substrate specificity, varied highly. A study with a single crayfish animal suggested that even at the individual level considerable sequence variability among hemocyte KPIs produced exist. Expression analysis of four crayfish KPI transcripts in hematopoietic tissue cells and different hemocyte types suggest that some of these KPIs are likely to be involved in hematopoiesis or hemocyte release as they were produced in particular hemocyte types or maturation stages only.
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| 50. |
- Gräns, Albin, 1979, et al.
(författare)
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Behavioural fever boosts the inflammatory response in rainbow trout Oncorhynchus mykiss
- 2012
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Ingår i: Journal of Fish Biology. - : Wiley. - 1095-8649 .- 0022-1112. ; 81:3, s. 1111-1117
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Tidskriftsartikel (refereegranskat)abstract
- Behavioural fever, manifested as an increased preferred temperature, was shown in rainbow trout Oncorhynchus mykiss following an injection of bacterial lipopolysaccharide. Simulated behavioural fever, through a 2·5° C water temperature rise following bacterial lipopolysaccharide injection, enhanced the expression of the cytokine interleukin-1β, in comparison with an untreated group held at the initial temperature. The present findings show that an important mediator in the immune response can be boosted through behavioural fever in fishes.
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