Antibody responses in Plasmodium falciparum malaria and their relation to protection against the disease

Protective immunity against Plasmodium falciparum may be obtained after repeated exposure to infection. Several studies indicate that immunity against the blood stages of the P. Falciparum infection is mainly antibody mediated. Protective antibodies may act either on their own, mediate antibody-dependent phagocytosis and/or cell-mediated neutralization of parasites. This thesis describes several aspects of humoral immune responses to P. falciparum infection in individuals of different age groups, different genetic background and with different degrees of malaria exposure. Several target antigens for antibody-mediated inhibition of parasite growth or invasion have been identified. One such antigen is Pf332, which appears on the surface of parasitized erythrocytes at late trophozoite and schizont stage. This surface exposure makes the antigen a possible target for opsonizing antibodies. We optimized an in vitro assay for studying cellmediated parasite neutralization in the presence of Pf332-reactive antibodies. Our data demonstrate that, Pf332 specific antibodies are able to inhibit parasite growth on their own and in cooperation with human monocytes. The P. falciparum parasites have evolved several mechanisms to evade the host neutralizing immune responses. In this thesis, we show that freshly isolated P. falciparum parasites from children living in a malaria endemic area of Burkina Faso were less sensitive for growth inhibition in vitro by autologous immunoglobulins (Ig) compared with heterologous ones. Analyses of two consecutive isolates taken 14 days apart, with regard to genotypes and sensitivity to growth inhibition in vitro, did not give any clear-cut indications on possible mechanisms leading to a reduced inhibitory activity in autologous parasite/antibody combinations. The frequent presence of persisting parasite clones in asymptomatic children indicates that the parasite possesses as yet undefined mechanisms to evade neutralizing immune responses. Transmission reducing measures such insecticide treated nets (ITNs) have been shown to be effective in reducing morbidity and mortality from malaria. However, concerns have been raised that ITNs usage could affect the acquisition of malaria immunity. We studied the effect of the use of insecticide treated curtains (ITC) on anti-malarial immune responses of children living in villages with ITC since birth. The use of ITC did neither affect the levels of parasite neutralizing immune responses nor the multiplicity of infection. These results indicate that the use of ITC does not interfere with the acquisition of anti-malarial immunity in children living in a malaria hyperendemic area. There is substantial evidence that the African Fulani tribe is markedly less susceptible to malaria infection compared to other sympatrically living ethnic tribes. We investigated the isotypic humoral responses against P. falciparum asexual blood stages in different ethnic groups living in sympatry in two countries exhibiting different malaria transmission intensities, Burkina Faso and Mali. We observed higher levels of the total malaria-specific-IgG and its cytophilic subclasses in individuals of the Fulani tribe as compared to non-Fulani individuals. Fulani individuals also showed higher levels of antibodies to measles antigen, indicating that the intertribal differences are not specific for malaria and might reflect a generally activated immune system in the Fulani.

Living conditions in old age: Coexisting disadvantages across life domains

The aim of this thesis was to analyse coexisting disadvantages in the older Swedish population. Coexisting disadvantages are those that occur simultaneously in various life domains. A person who simultaneously experiences several disadvantages may be particularly vulnerable and less well-equipped to manage daily life and may also need support from several different welfare service providers. Concerted actions may be needed for older people who experience not only physical health problems and functional limitations, but also other problems. Research that encompasses a wide range of living conditions provides a basis for setting political priorities and making political decisions. The studies in this thesis used data from two Swedish nationally representative surveys: the Level of Living Survey, which includes people aged 18 through 75, and the Swedish Panel Study of Living Conditions of the Oldest Old, which includes people aged 77 and older. Study I showed that the probability of experiencing coexisting disadvantages was higher in people 77 and older than in those aged 18 through 76. These age differences were partly driven by a high prevalence of physical health problems in older people. In all age groups, coexisting disadvantages were more common in women than men. The longitudinal analyses in Study II indicated that coexisting disadvantages in old age persist in some people but are temporary in others. Moreover, the results suggested a pattern of accumulating disadvantages: reporting one disadvantage in young old age (in particular, psychological health problems) increased the probability of reporting coexisting disadvantages in late old age.   Study III showed that physical health problems were a central component of coexisting disadvantages. The results also showed that being older; female; previously employed as a manual labourer; and divorced/separated, widowed or never married were associated with an increased probability of experiencing coexisting disadvantages. However, the experience of coexisting disadvantages differed: the groups associated with coexisting disadvantages tended to report different combinations of disadvantage. Study IV showed that the prevalence of coexisting disadvantages in those 77 and older increased slightly between 1992 and 2011. Physical health problems became more common over time, whereas limited ability to manage daily activities (ADL limitations), limited financial resources and limited political resources became less common. Associations between different disadvantages were found in all survey years, but certain associations changed over time. The results suggest that in general, the composition of coexisting disadvantages in the older population may have altered over time. In sum, results showed that coexisting disadvantages were associated with specific demographic and socio-economic groups. Physical health problems and psychological health problems were of particular importance to the accumulation and coexistence of disadvantages in old age.