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T cell and antibody responses in Plasmodium falciparum malaria and their relation to disease susceptibility
Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut för experimentell biologi.
2004 (engelsk)Doktoravhandling, med artikler (Annet vitenskapelig)
Abstract [en]

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

sted, utgiver, år, opplag, sider
Stockholm: Wenner-Grens institut för experimentell biologi , 2004. , s. 74
Emneord [en]
P. falciparum, Malaria, Granulysin, Fulani, Schizont
HSV kategori
Identifikatorer
URN: urn:nbn:se:su:diva-320ISBN: 91-7265-987-4 (tryckt)OAI: oai:DiVA.org:su-320DiVA, id: diva2:192443
Disputas
2005-01-21, Nordenskiöldsalen, Geovetenskapens hus, Svante Arrhenius väg 8 C, Stockholm, 10:00
Opponent
Veileder
Tilgjengelig fra: 2004-12-20 Laget: 2004-12-20 Sist oppdatert: 2018-01-13bibliografisk kontrollert
Delarbeid
1. γδT cells inhibit the in vitro growth of the asexual blood stages of Plasmodium falciparum by a granule exocytosis-dependent cytotoxic pathway that requires granulysin
Åpne denne publikasjonen i ny fane eller vindu >>γδT cells inhibit the in vitro growth of the asexual blood stages of Plasmodium falciparum by a granule exocytosis-dependent cytotoxic pathway that requires granulysin
Vise andre…
2004 Inngår i: Eur J Immunol, ISSN 0014-2980, Vol. 34, nr 8, s. 2248-2256Artikkel i tidsskrift (Fagfellevurdert) Published
Identifikatorer
urn:nbn:se:su:diva-23514 (URN)
Merknad
Part of urn:nbn:se:su:diva-320Tilgjengelig fra: 2004-12-20 Laget: 2004-12-20bibliografisk kontrollert
2. Different antibody and cytokine-mediated responses to Plasmodium falciparum parasite in two sympatric ethnic tribes living in Mali
Åpne denne publikasjonen i ny fane eller vindu >>Different antibody and cytokine-mediated responses to Plasmodium falciparum parasite in two sympatric ethnic tribes living in Mali
Vise andre…
2005 (engelsk)Inngår i: Microbes and infection, ISSN 1286-4579, E-ISSN 1769-714X, Vol. 7, nr 1, s. 110-117Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

The Fulani are known to be less susceptible to Plasmodium falciparum malaria infections and to have lower parasitaemia despite living under similar malaria transmission intensity compared with other ethnic tribes. The aim of the present study was to examine whether the Fulani were more polarised towards Th2 as reflected by higher numbers of malaria-specific IL-4- and IL-10-producing cells and lower numbers of IFN-γ- and IL-12-producing cells as compared to their neighbour ethnic tribe, the Dogon of Mali. Total IgE and both anti-malaria IgE and IgG antibodies were measured by ELISA and the numbers of IL-4-, IFN-γ-, IL-10- and IL-12-producing cells were enumerated using enzyme-linked ImmunoSpot assay (ELISPOT). Numbers of parasite clones were detected by polymerase chain reaction (PCR). The study was performed outside the transmission period and all individuals included were asymptomatic. The results revealed that the Fulani were less parasitised, had fewer circulating parasite clones in their blood, had significantly higher anti-malaria IgG and IgE antibodies and higher proportions of malaria-specific IL-4- and IFN-γ-producing cells compared to the Dogon. The higher antigen-specific production of IL-4 among the Fulani was statistically significant both before and after adjustment for level of spontaneous cytokine production, while greater IFN-γ production only attained statistical significance after adjustment for spontaneous levels. Taken together, the association of higher anti-malarial IgE and IgG antibodies and increased numbers of specific IL-4- and IFN-γ-producing cells compared to the ethnic sympatric tribe, the Dogon, may assist in explaining the lower susceptibility to malaria observed in the Fulani.

sted, utgiver, år, opplag, sider
Elsevier SAS, 2005
Emneord
Plasmodium falciparum; IgE; IFN-γ; IL-4; Susceptibility
HSV kategori
Identifikatorer
urn:nbn:se:su:diva-23515 (URN)10.1016/j.micinf.2004.09.012 (DOI)
Merknad
Part of urn:nbn:se:su:diva-320Tilgjengelig fra: 2004-12-20 Laget: 2004-12-20 Sist oppdatert: 2017-12-13bibliografisk kontrollert
3. Distinct interethnic differences in IgG class/subclass and IgM antibody responses to malaria antigens but not in IgG responses to non-malarial antigens in sympatric tribes living in West Africa
Åpne denne publikasjonen i ny fane eller vindu >>Distinct interethnic differences in IgG class/subclass and IgM antibody responses to malaria antigens but not in IgG responses to non-malarial antigens in sympatric tribes living in West Africa
Vise andre…
2005 (engelsk)Inngår i: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 61, nr 4, s. 380-386Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

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

Emneord
*IMMUNOGLOBULIN G *MALARIA *PROTOZOAN diseases *ANTIGENS *IMMUNITY
HSV kategori
Identifikatorer
urn:nbn:se:su:diva-23516 (URN)10.1111/j.1365-3083.2005.01587.x (DOI)
Merknad
Part of urn:nbn:se:su:diva-320Tilgjengelig fra: 2004-12-20 Laget: 2004-12-20 Sist oppdatert: 2018-01-13bibliografisk kontrollert
4. Analaysis of T-cell responses in malaria-exposed and non-exposed donors using Plasmodium falciparum asexual blood stages enriched by a simple centrifugation method
Åpne denne publikasjonen i ny fane eller vindu >>Analaysis of T-cell responses in malaria-exposed and non-exposed donors using Plasmodium falciparum asexual blood stages enriched by a simple centrifugation method
Vise andre…
Artikkel i tidsskrift (Fagfellevurdert) Submitted
Identifikatorer
urn:nbn:se:su:diva-23517 (URN)
Merknad
Part of urn:nbn:se:su:diva-320Tilgjengelig fra: 2004-12-20 Laget: 2004-12-20bibliografisk kontrollert

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