Elevated anti-malarial IgE in asymptomatic individuals is associated with reduced risk for subsequent clinical malaria
Introduction
Malaria remains a major threat to global health and yet the mechanisms for protective immunity are still incompletely understood. In areas of high malaria transmission, young children are the most vulnerable to disease and death due to their lack of protective immunity. Prolonged exposure to new inoculations and repeated infections, results in successive acquisition of protective immunity and part of this effect may be associated with controlled persistence of parasites without clinical symptoms.
Mechanisms for malaria immunity are highly complex with involvement of several components of immune function. Antibody-dependent mechanisms are presumed to play an important role in protection, with a wide range of antigen-specific antibodies as well as polyclonal-antibody production. Studies on passively transferred immunoglobulins from immune adults have suggested that IgG antibodies are important in reducing parasite density during clinical malaria disease (Cohen et al., 1961, Sabchareon et al., 1991). There is also accumulating evidence of a protective role for certain IgG subclasses (Aribot et al., 1996, Taylor et al., 1998, Aucan et al., 2000, Ndungu et al., 2002). Although both total and malaria-specific IgE levels are elevated in individuals living in areas of high endemicity (Desowitz, 1989, Perlmann et al., 1994), the role of IgE in malaria is not as clearly established as for other parasites (Hussain et al., 1986, Hagan et al., 1991, Rihet et al., 1991). The elevated IgE levels seen in severe acute malaria patients indicate a pathogenic role of these antibodies (Perlmann et al., 1994, Perlmann et al., 1997, Perlmann et al., 1999, Perlmann et al., 2000). A protective role for P. falciparum-specific IgE has also been proposed (Perlmann et al., 1997, Perlmann et al., 1999) but this has not been previously demonstrated.
Here, we investigated if plasma levels of the antibody isotypes IgG and IgE are predictive of risk for subsequent acute malaria episodes. In a longitudinal study of a population in Nyamisati village, a highly endemic area the Rufiji Region, coastal Tanzania (Rooth and Bjorkman, 1992), a prospective malariometric survey measured several baseline characteristics, and subsequently recorded episodes of acute malaria over 40 weeks of follow-up. To avoid potential confounding through acute disease activity or treatment, only the individuals with no clinical malaria episodes during the baseline survey, 4 weeks before or 1 week after the survey were included in the analysis. Baseline characteristics included plasma levels of anti-P. falciparum (crude) IgE and IgG, total IgE as well as genetic diversity of P. falciparum defined as number of clones per infection.
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Study area and population
The study was conducted in Nyamisati village, situated by the Rufiji River Delta, coastal Tanzania. The area is holoendemic for malaria, with perennial transmission and some seasonal fluctuation. A research team, which also provides health care including antimalarial drugs, has lived in the village since 1985, and studied the malaria epidemiology with longitudinal follow up of the population of about 1000 individuals (Rooth and Bjorkman, 1992). In March–April 1999, preceding the heavy rain
Results
Baseline characteristics were analysed in the 700 individuals (1–84 years, median 23 years) who were asymptomatic at the time of survey. The P. falciparum prevalence, including results from microscopy and PCR, was highest in children 0–16 years (59%) and decreased in adults with 32% of individuals over 16 years infected with P. falciparum. Including the results from PCR analysis increased P. falciparum prevalence by 25% in all age groups. The mean number of clones detected by the PCR genotyping
Discussion
In this study we investigated factors among subjects free of acute malaria, associated with the risk of subsequent acute malaria episodes. After adjustment for multiple potential confounding factors, we observed independent associations of older age and higher levels of anti-P. falciparum IgE with a reduced risk of clinical malarial disease. The non-linear association of malaria-specific IgE with disease risk may reflect antagonistic influences.
The importance of anti-malarial IgE in protective
Acknowledgements
We are most grateful to the villagers and research team in Nyamisati; Hedvig Perlmann for methodological expertise and comments, Danielle Carpenter, Hind Abushama and Margareta Hagstedt for excellent technical assistance; Professor Anders Björkman and Dr Ze Pedro Gil for remarks on the manuscript. This work was supported by the Swedish International Development Cooperation Agency—SAREC (Project grant SWE 2002-066 and 1995-117), the Swedish Medical Research Council and the Bergvall's Foundation.
References (37)
- et al.
Reduced risk of clinical malaria in children infected with multiple clones of Plasmodium falciparum in a highly endemic area: a prospective community study
Trans. R. Soc. Trop. Med. Hyg.
(1997) Plasmodium-specific immunoglobulin E in sera from an area of holoendemic malaria
Trans. R. Soc. Trop. Med. Hyg.
(1989)- et al.
Nitric oxide production by human monocytes: evidence for a role of CD23
Immunol. Today
(1995) - et al.
TNF concentration in fatal cerebral, non-fatal cerebral, and uncomplicated Plasmodium falciparum malaria
Lancet
(1990) - et al.
IgE and tumor necrosis factor in malaria infection
Immunol. Lett.
(1999) - et al.
Fever episodes in a holoendemic malaria area of Tanzania: parasitological and clinical findings and diagnostic aspects related to malaria
Trans. R. Soc. Trop. Med. Hyg.
(1992) - et al.
Premunition in Plasmodium falciparum infection: insights from the epidemiology of multiple infections
Trans. R. Soc. Trop. Med. Hyg.
(1999) - et al.
Pattern of immunoglobulin isotype response to Plasmodium falciparum blood-stage antigens in individuals living in a holoendemic area of Senegal (Dielmo, west Africa)
Am. J. Trop. Med. Hyg.
(1996) - et al.
High immunoglobulin G2 (IgG2) and low IgG4 levels are associated with human resistance to Plasmodium falciparum malaria
Infect. Immun.
(2000) - et al.
Immunoepidemiology of Dracunculus medinensis infections II. Variation in antibody responses in relation to transmission season and patency
Am. J. Trop. Med. Hyg.
(1998)
Gamma-globulin and acquired immunity to human malaria
Nature
What does a single determination of malaria parasite density mean? A longitudinal survey in Mali
Trop. Med. Int. Health
Plasmodium falciparum-specific immunoglobulin G (IgG), IgM, and IgE antibodies in paired maternal-cord sera from east Sepik Province, Papua New Guinea
Infect. Immun.
Daily dynamics of Plasmodium falciparum subpopulations in asymptomatic children in a holoendemic area
Am. J. Trop. Med. Hyg.
Complexity of Plasmodium falciparum infections is consistent over time and protects against clinical disease in Tanzanian children
J. Infect. Dis.
Human IgE, IgG4 and resistance to reinfection with Schistosoma haematobium
Nature
IgE-mediated enhancement of antibody responses: the beneficial function of IgE?
Allergy
The immunogenetics of resistance to malaria
Proc. Assoc. Am. Physicians
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