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Background:  Pregnant women living in unstable malaria transmission settings may develop severe malaria (SM). The pathogenesis of SM in pregnancy is poorly understood., Methods:  To determine whether SM in pregnancy is associated with lower malarial antibody responses and higher cytokine responses, plasma samples were collected from 121 Sudanese pregnant women of whom 39 were diagnosed with SM. Antibodies to pregnancy-specific and non-pregnancy-specific Plasmodium falciparum variant surface antigens (VSA) and concentrations of cytokines TNF, IFNγ, IL-1β, IL-6, IL-8 and IL-10 were measured., Results:  Pregnant women with SM demonstrated significantly lower antibody levels to pregnancy-specific VSA (P = .020) and higher plasma IFNγ (P = .020), IL-10 (P = .0002) and IL-6 levels (P < .0001) than uninfected pregnant women. Concentrations of inflammatory cytokines IL-1β (P = .001), IL-6 (P = .004) and IL-8 (P = .020) were inversely correlated with antibodies to VAR2CSA-DBL5 in pregnant women with SM. Lower haemoglobin levels and higher parasite densities were associated with lack of pregnancy-specific antibodies (P = .028) and higher levels of inflammatory cytokines, in particular IL-6 and IL-8., Conclusions:  Pregnant women with SM lack pregnancy-specific malaria immunity, and this correlates with heightened inflammatory cytokine concentrations, low haemoglobin levels and high parasite density, suggesting that failure of antibody to control parasitaemia may contribute to SM pathogenesis.

BACKGROUND: Tumour necrosis factor (TNF) is a pleiotropic cytokine with a wide range of immunoregulatory effects. Variation in the promoter region of TNF and the neighbouring lymphotoxin alpha (LTA) gene might be associated with endometriosis. [ABSTRACT FROM PUBLISHER]

The cytokine IL-10 has an important role in limiting inflammation in many settings, including toxoplasmosis. In the present studies, an IL-10 reporter mouse was used to identify the sources of this cytokine following challenge with Toxoplasma gondii. During infection, multiple cell types expressed the IL-10 reporter but NK cells were a major early source of this cytokine. These IL-10 reporter+ NK cells expressed high levels of the IL-12 target genes T-bet, KLRG1, and IFN-γ, and IL-12 depletion abrogated reporter expression. However, IL-12 signaling alone was not sufficient to promote NK cell IL-10, and activation of the aryl hydrocarbon receptor (AHR) was also required for maximal IL-10 production. NK cells basally expressed the AHR, relevant chaperone proteins, and the AHR nuclear translocator, which heterodimerizes with the AHR to form a competent transcription factor. In vitro studies revealed that IL-12 stimulation increased NK cell AHR levels, and the AHR and AHR nuclear translocator were required for optimal production of IL-10. Additionally, NK cells isolated from T. gondii-infected Ahr-/- mice had impaired expression of IL-10, which was associated with increased resistance to this infection. Taken together, these data identify the AHR as a critical cofactor involved in NK cell production of IL-10. [ABSTRACT FROM AUTHOR]