Genetic susceptibility to systemic lupus erythematosus protects against cerebral malaria in mice

Laboratories of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 01/2011; 108(3):1122-7. DOI: 10.1073/pnas.1017996108
Source: PubMed


Plasmodium falciparum has exerted tremendous selective pressure on genes that improve survival in severe malarial infections. Systemic lupus erythematosus (SLE) is an autoimmune disease that is six to eight times more prevalent in women of African descent than in women of European descent. Here we provide evidence that a genetic susceptibility to SLE protects against cerebral malaria. Mice that are prone to SLE because of a deficiency in FcγRIIB or overexpression of Toll-like receptor 7 are protected from death caused by cerebral malaria. Protection appears to be by immune mechanisms that allow SLE-prone mice better to control their overall inflammatory responses to parasite infections. These findings suggest that the high prevalence of SLE in women of African descent living outside of Africa may result from the inheritance of genes that are beneficial in the immune control of cerebral malaria but that, in the absence of malaria, contribute to autoimmune disease.

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Available from: Carolina Barillas-Mury
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    • "Hemoglobin levels were measured every other day using an Hp201+ (HemoCue, Ängelholm, Sweden) using blood from the tail tip. All mice were evaluated daily for the presence of clinical signs of severe malaria using simple scoring adapted from the SNAP scoring system [26], [75], [76]. Animals were scored by evaluating five categories: interactions, cage grasp, visual placing, gait/posture/appearance, and capacity to hold their body weight on a baton [75]. "
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    ABSTRACT: The role of intracellular radical oxygen species (ROS) in pathogenesis of cerebral malaria (CM) remains incompletely understood. We undertook testing Tempol-a superoxide dismutase (SOD) mimetic and pleiotropic intracellular antioxidant-in cells relevant to malaria pathogenesis in the context of coagulation and inflammation. Tempol was also tested in a murine model of CM induced by Plasmodium berghei Anka infection. Tempol was found to prevent transcription and functional expression of procoagulant tissue factor in endothelial cells (ECs) stimulated by lipopolysaccharide (LPS). This effect was accompanied by inhibition of IL-6, IL-8, and monocyte chemoattractant protein (MCP-1) production. Tempol also attenuated platelet aggregation and human promyelocytic leukemia HL60 cells oxidative burst. In dendritic cells, Tempol inhibited LPS-induced production of TNF-α, IL-6, and IL-12p70, downregulated expression of co-stimulatory molecules, and prevented antigen-dependent lymphocyte proliferation. Notably, Tempol (20 mg/kg) partially increased the survival of mice with CM. Mechanistically, treated mice had lowered plasma levels of MCP-1, suggesting that Tempol downmodulates EC function and vascular inflammation. Tempol also diminished blood brain barrier permeability associated with CM when started at day 4 post infection but not at day 1, suggesting that ROS production is tightly regulated. Other antioxidants-such as α-phenyl N-tertiary-butyl nitrone (PBN; a spin trap), MnTe-2-PyP and MnTBAP (Mn-phorphyrin), Mitoquinone (MitoQ) and Mitotempo (mitochondrial antioxidants), M30 (an iron chelator), and epigallocatechin gallate (EGCG; polyphenol from green tea) did not improve survival. By contrast, these compounds (except PBN) inhibited Plasmodium falciparum growth in culture with different IC50s. Knockout mice for SOD1 or phagocyte nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (gp91(phox-/-)) or mice treated with inhibitors of SOD (diethyldithiocarbamate) or NADPH oxidase (diphenyleneiodonium) did not show protection or exacerbation for CM. Results with Tempol suggest that intracellular ROS contribute, in part, to CM pathogenesis. Therapeutic targeting of intracellular ROS in CM is discussed.
    Full-text · Article · Feb 2014 · PLoS ONE
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    • "This mutation confers susceptibility to SLE by 70%, but is protective against malaria by 44% [233]. Studies with Fcγ RIIB-deficient or TLR7-transgenic mice, which spontaneously develop SLE, are protected from death due to cerebral malaria [234]. Maintainence of this polymorphism could be due to selective pressure to improve survival from malaria [233]. "
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    ABSTRACT: Infectious agents are considered to be crucial environmental factor in the etiopathogenesis of systemic lupus erythematosus (SLE). Infections may serve as initial trigger to the development of autoimmunity and carry an overall greater risk of morbidity and mortality than the general population. Initial presentation of SLE can mimic infections, and in turn infections can mimic disease flares in established SLE. Infections due to predisposition by commonly used immunosuppressive therapies are a significant cause of morbidity and mortality. In this review, viral, bacterial, fungal, and parasitic infections that contribute to the etiology of SLE, potentially mimic or precipitate flares, create diagnostic dilemmas, complicate treatment, or protect against disease, are discussed. Infection risks of current immunosuppressive therapies used in the treatment of SLE are outlined. Strategies to prevent infection, including vaccines, prophylactic antibiotic therapies, toll-like receptor antagonism, and antioxidant treatment that may decrease disease burden and improve quality of life in lupus patients will be discussed.
    Full-text · Article · Jan 2014 · International Reviews Of Immunology
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    • "We infected mice that were susceptible to SLE (SLEs mice) due to a deficiency in the immune inhibitory receptor, FcγRIIB [9], with P. berghei ANKA (Pb ANKA), a parasite that causes lethal CM [10]. SLEs mice develop lethal SLE by 9 months of age, however, when infected at 4 to 6 weeks of age before the onset of any overt autoimmune inflammation, the SLEs mice were protected from CM [11]. Protection appeared to be mediated by mechanisms that allowed the SLEs mice to better control inflammation possibly through the heightened production of the anti-inflammatory cytokine IL-10. "
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    ABSTRACT: Severe malaria, including cerebral malaria (CM) and placental malaria (PM), have been recognized to have many of the features of uncontrolled inflammation. We recently showed that in mice genetic susceptibility to the lethal inflammatory autoimmune disease, systemic lupus erythematosus (SLE), conferred resistance to CM. Protection appeared to be mediated by immune mechanisms that allowed SLE-prone mice, prior to the onset of overt SLE symptoms, to better control their inflammatory response to Plasmodium infection. Here we extend these findings to ask does SLE susceptibility have 1) a cost to reproductive fitness and/or 2) an effect on PM in mice? The rates of conception for WT and SLE susceptible (SLE(s)) mice were similar as were the number and viability of fetuses in pregnant WT and SLE(s) mice indicating that SLE susceptibility does not have a reproductive cost. We found that Plasmodium chabaudi AS (Pc) infection disrupted early stages of pregnancy before the placenta was completely formed resulting in massive decidual necrosis 8 days after conception. Pc-infected pregnant SLE(s) mice had significantly more fetuses (∼1.8 fold) but SLE did not significantly affect fetal viability in infected animals. This was despite the fact that Pc-infected pregnant SLE(s) mice had more severe symptoms of malaria as compared to Pc-infected pregnant WT mice. Thus, although SLE susceptibility was not protective in PM in mice it also did not have a negative impact on reproductive fitness.
    Full-text · Article · May 2013 · PLoS ONE
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