Impaired inflammasome activation and bacterial clearance in G6PD deficiency due to defective NOX/p38 MAPK/AP-1 redox signaling.

Glucose-6-phosphate dehydrogenase (G6PD) is the rate-limiting enzyme of the pentose phosphate pathway that modulates cellular redox homeostasis via the regeneration of NADPH. G6PD-deficient cells have a reduced ability to induce the innate immune response, thus increasing host susceptibility to pathogen infections. An important part of the immune response is the activation of the inflammasome. G6PD-deficient peripheral blood mononuclear cells (PBMCs) from patients and human monocytic (THP-1) cells were used as models to investigate whether G6PD modulates inflammasome activation. A decreased expression of IL-1ß was observed in both G6PD-deficient PBMCs and PMA-primed G6PD-knockdown (G6PD-kd) THP-1 cells upon lipopolysaccharide (LPS)/adenosine triphosphate (ATP) or LPS/nigericin stimulation. The pro-IL-1ß expression of THP-1 cells was decreased by G6PD knockdown at the transcriptional and translational levels in an investigation of the expression of the inflammasome subunits. The phosphorylation of p38 MAPK and downstream c-Fos expression were decreased upon G6PD knockdown, accompanied by decreased AP-1 translocation into the nucleus. Impaired inflammasome activation in G6PD-kd THP-1 cells was mediated by a decrease in the production of reactive oxygen species (ROS) by NOX signaling, while treatment with hydrogen peroxide (H2O2) enhanced inflammasome activation in G6PD-kd THP-1 cells. G6PD knockdown decreased Staphylococcus aureus and Escherichia coli clearance in G6PD-kd THP-1 cells and G6PD-deficient PBMCs following inflammasome activation. These findings support the notion that enhanced pathogen susceptibility in G6PD deficiency is, in part, due to an altered redox signaling, which adversely affects inflammasome activation and the bactericidal response.

The association between low glucose-6-phosphate dehydrogenase activity level and hepatitis B virus infection among pre-pregnant reproductive-age Chinese females.

The relationship between females with low glucose-6-phosphate dehydrogenase activity level (LG6PD) and HBV infection is unclear. We conducted a cross sectional study of 124 406 reproductive-age Chinese females who participated in the National Free Pre-conception Check-up Projects to investigate the risk of HBV infection among females with LG6PD and its effect on liver enzyme. Based on HBV serological test results, the participants were divided into the susceptible, immunized, and HBV infected groups. The multivariable-adjusted odds ratios (ORs) for HBV infection in LG6PD participants were 1.71 (95% confidence interval (CI): 1.45-2.01) and 1.41 (95% CI: 1.23-1.62), respectively with the susceptible and immunized participants as references, compared to those without LG6PD. Participants with HBV infection only and combined with HBV infection and LG6PD had 184% and 249% significantly higher risks of elevated alanine transaminase (ALT) (susceptible participants as reference). If the immunized participants were used as reference, significant higher odds of elevated ALT occurred (3.48 (95% CI: 3.18-3.80), 4.28 (95% CI: 2.92-6.28)). Thus, reproductive-age females with LG6PD had a higher prevalence of HBV infection, and LG6PD might exacerbate ALT elevation in HBV infected females. Our findings underscore the need to explore collaborative management approaches for these two diseases among reproductive-age females for maternal and child health.

Antibody responses to P. falciparum Apical Membrane Antigen 1(AMA-1) in relation to haemoglobin S (HbS), HbC, G6PD and ABO blood groups among Fulani and Masaleit living in Western Sudan.

Fulani and Masaleit are two sympatric ethnic groups in western Sudan who are characterised by marked differences in susceptibility to Plasmodium falciparum malaria. It has been demonstrated that Glucose-6-phosphate dehydrogenase (G6PD) deficiency and Sickle cell trait HbAS carriers are protected from the most severe forms of malaria. This study aimed to investigate a set of specific IgG subclasses against P. falciparum Apical Membrane Antigen 1 (AMA-1 3D7), haemoglobin variants and (G6PD) in association with malaria susceptibility among Fulani ethnic group compared to sympatric ethnic group living in Western Sudan. A total of 124 children aged 5-9 years from each tribe living in an area of hyper-endemic P. falciparum unstable malaria transmission were recruited and genotyped for the haemoglobin (Hb) genes, (G6PD) and (ABO) blood groups. Furthermore, the level of plasma IgG antibody subclasses against P. falciparum antigen (AMA-1) were measured using enzyme linked immunosorbent assays (ELISA). Higher levels of anti-malarial IgG1, IgG2 and IgG3 but not IgG4 antibody were found in Fulani when compared to Masaleit. Individuals carrying the HbCC phenotype were significantly associated with higher levels of IgG1 and IgG2. Furthermore, individuals having the HbAS phenotype were associated with higher levels of specific IgG2 and IgG4 antibodies. In addition, patients with G6PD A/A genotype were associated with higher levels of specific IgG2 antibody compared with those carrying the A/G and G/G genotypes. The results indicate that the Fulani ethnic group show lower frequency of HbAS, HbSS and HbAC compared to the Masaleit ethnic group. The inter-ethnic analysis shows no statistically significant difference in G6PD genotypes (P value = 0.791). However, the intra-ethnic analysis indicates that both ethnic groups have less A/A genotypes and (A) allele frequency of G6PD compared to G/G genotypes, while the HbSA genotype was associated with higher levels of IgG2 (AMA-1) and IgG4 antibodies. In addition, patients carrying the G6PD A/A genotype were associated with higher levels of specific IgG2 antibody compared with those carrying the A/G and G/G genotypes. The present results revealed that the Fulani ethnic group has statistically significantly lower frequency of abnormal haemoglobin resistant to malaria infection compared to the Masaleit ethnic group.

Hepatic transcriptional profiling response to fava bean-induced oxidative stress in glucose-6-phosphate dehydrogenase-deficient mice.

Favism is an acute hemolytic syndrome caused by the ingestion of fava bean (FB) in glucose 6-phosphate dehydrogenase (G6PD) deficient individuals. However, little is known about the global transcripts alteration in liver tissue after FB ingestion in G6PD-normal and -deficient states. In this study, deep sequencing was used to analyze liver genes expression alterations underlying the effects of FB in C3H (Wild Type, WT) and G6PD-deficient (G6PDx) mice and to evaluate and visualize the collective annotation of a list of genes to Gene Ontology (GO) terms associated with favism. Our results showed that FB resulted in a decrease of glutathione (GSH)-to-oxidized glutathione (GSSG) ratio and an increase of malondialdehyde (MDA) both in the G6PDx and WT-control check (CK) mice plasma. Significantly, liver transcript differences were observed between the control and FB-treated groups of both WT and G6PDx mice. A total of 320 differentially expressed transcripts were identified by comparison of G6PDx-CK with WT-CK and were associated with immune response and oxidation-reduction function. A total of 149 differentially expressed genes were identified by comparison of WT-FB with WT-CK. These genes were associated with immune response, steroid metabolic process, creatine kinase activity, and fatty acid metabolic process. A total of 438 differential genes were identified by comparing G6PDx-FB with G6PD-CK, associated with the negative regulation of fatty acid metabolic process, endoplasmic reticulum, iron binding, and glutathione transferase activity. These findings indicate that G6PD mutations may affect the functional categories such as immune response and oxidation-reduction.

Expanding the clinical and genetic spectrum of G6PD deficiency: The occurrence of BCGitis and novel missense mutation.

Glucose-6-phosphate dehydrogenase (G6PD) is a key enzyme in the pentose phosphate pathway that ensures sufficient production of coenzyme nicotinamide adenine dinucleotide phosphate (NADPH) by catalyzing the reduction of NADP+ to NADPH. Noteworthy, the latter mediates the production of reactive oxygen species (ROS) by phagocytic cells such as neutrophils and monocytes. Therefore, patients with severe forms of G6PD deficiency may present impaired NADPH oxidase activity and become susceptible to recurrent infections. This fact, highlights the importance to characterize the immunopathologic mechanisms underlying the susceptibility to infections in patients with G6PD deficiency. Here we report the first two cases of G6PD deficiency with Bacille Calmette-Guérin (BCG) adverse effect, besides jaundice, hemolytic anemia and recurrent infections caused by Staphylococcus aureus. The qualitative G6PD screening was performed and followed by oxidative burst analysis using flow cytometry. Genetic and in silico analyses were carried out by Sanger sequencing and mutation pathogenicity predicted using bioinformatics tools, respectively. Activated neutrophils and monocytes from patients displayed impaired oxidative burst. The genetic analysis revealed the novel missense mutation c.1157T>A/p.L386Q in G6PD. In addition, in silico analysis indicated that this mutation is pathogenic, thereby hampering the oxidative burst of neutrophils and monocytes from patients. Our data expand the clinical and genetic spectrum of G6PD deficiency, and suggest that impaired oxidative burst in this severe primary immune deficiency is an underlying immunopathologic mechanism that predisposes to mycobacterial infections.

Co-occurrence of biphenotypic acute leukaemia, glucose 6-phosphate dehydrogenase deficiency and haemoglobin E trait in a single child.

Acute leukaemias occur as the result of clonal expansion subsequent to transformation and arrest at a normal differentiation stage of haematopoietic precursors, which commit to a single lineage, such as myeloid or B-lymphoid or T-lymphoid cells. Biphenotypic acute leukaemia (BAL) constitutes a biologically different group of leukaemia arising from a precursor stem cell and co-expressing more than one lineage specific marker. The present report describes a child with unusual co-occurrence of biphenotypic (B-precursor cell and Myeloid) acute leukaemia, haemoglobin E trait and glucose 6-phosphate dehydrogenase (G6-PD) deficiency. To the best of our knowledge, this constellation of haematological conditions in a single child has never been described before.

Neutrophil functional disorder in childhood.

Neutrophil functional disorders thought to be uncommon, yet important as a cause of morbidity and mortality in infants and children. During the first years of life, when the immune system is still not completely mature, when the viral infections are frequent and antibiotic overuse can damage and alter the immune response, the inadequate nutrition followed with iron deficient anemia and malnutrition can lead the child`s organism in state of immunodeficiency. Sometimes is difficult to distinguish at the beginning weather the cause of patient suffering from frequent infections is existing of primary immunodeficiency disorder or the cause of the immunodeficiency state is just from exogenous factors. Fortunately, primary immune deficiencies are rare diseases and only 6-7% of all of them, due to the neutrophilic functional disorders. Unfortunately, many exogenous and environmental factors have influence to the immune system, and the percentage of secondary caused neutrophilic functional disorders is much higher and should be considered when children are investigated for immunodeficiency. So, when to suspect neutrophil functional disorder? The hallmarks for diseases related to the neutrophilic functional disorders are discussed in this article.

Cytokine responses of TNF-α, IL-6, and IL-10 in G6PD-deficient infants.

G6PD-deficient adults are reported to be susceptible to severe infection, and decreased cytokine responses have been postulated as the underlying mechanism. However, investigating the association of G6PD deficiency and cytokine responses during infancy is lacking. The current study aims to determine whether cytokine responses of tumor necrosis factor ()-α, interleukins (IL)-6, and IL-10 are impaired in the G6PD-deficient infants. Upon agreements with informed consents, peripheral blood mononuclear cells (PBMCs) of enrolled infants were collected twice at 1 month and 1 year of age. PBMCs were then stimulated with toll-like receptor (TLR) agonists-including PAM3csk4 for TLR1-2, poly (I:C) for TLR3, and lipopolysaccharide for TLR4-to analyze the expression of TNF-α, IL-6, and IL-10. Males (P = .004) and phototherapy during neonatal period (P = .008) were more common among G6PD-deficient infants than G6PD-normal subjects. After the stimulation of TLR agonists, there was no significant difference in the expression of TNF-α, IL-6, and IL-10 between PBMCs of G6PD-deficient and -normal infants at both 1 month and 1 year of age. In conclusion, the clinical characteristics of G6PD-deficient infants are different from those of G6PD-normal subjects. The data suggest that the innate immune responses to TLR agonists in G6PD-deficient infants are not different from those of G6PD-normal infants.

Acute haemolytic crisis due to concomitant presence of infection and possible altered acetaminophen catabolism in a Philipino child carrying the G6PD-Vanua Lava mutation.

Glucose-6-phosphate dehydrogenase (G6PD), an X-linked hereditary deficiency, is the most common of all clinically significant enzyme defects. While many drugs are responsible for haemolytic anaemia in G6PD-deficient patients, acetaminophen's imputability is still under debate, although an overdose of this drug can provoke acute haemolytic events. We report a case of a Philipino child carrying the G6PD-Vanua Lava mutation with acute haemolytic crisis related to infection in progress and acetaminophen's administration. Fever and concomitant infection, through an increment of erythrocyte glutathione depletion, sensitized the infant to the haemolytic event. In this condition, acetaminophen (or paracetamol [PCM]) was capable of inducing a haemolytic crisis in our G6PD-deficient patient although administered under standard conditions. PCM seems to have induced the haemolytic event, probably by the alteration of its catabolism due to dehydration and fever. The enzymatic G6PD instability associated to the presence of the G6PD-Vanua Lava mutation could have led to an increment of red blood cells' sensitivity to lysis; hence, it is possible that PCM toxicity may also be due to the presence of this particular mutation. Finally, we propose a new biochemical classification of this G6PD variant.

Naturally occurring anti-band 3 antibodies and red blood cell removal under physiological and pathological conditions.

Naturally occurring antibodies (NAbs) directed to band 3 protein (major erythrocyte membrane protein) are involved in the clearance of red blood cell (RBC) at the end of their lifespan as well as in the removal of RBC in different hereditary haemolytic disorders and in malaria. In all cited situations RBC undergoes oxidative stress and hemichromes (haemoglobin degradation products) are formed. Hemichromes possess a strong affinity for band 3 cytoplasmic domain and, following their binding, lead to band 3 oxidation and clusterisation. Those band 3 clusters show increased affinity for NAbs which activate complement and finally trigger the phagocytosis of altered RBC. During intra-erythrocytic malaria parasite growth, NAbs begin to bind to RBC surface at early parasite development stages increasing their abundance in parallel with parasite development. Interestingly, a number of hereditary haemolytic disorders, known to exert a protective effect on malaria, tend to exacerbate this phenomenon leading to a more precocious and effective opsonization of diseased RBC infected by malaria parasites. The exact definition of band 3 neo-antigens and the mechanism of their surface exposure are still unclear. Also band 3 clusterisation is only superficially understood, new insights about band 3 phosphorylation by Src kinases suggest the presence of a complex regulatory pathway.

Endotoxemia down-regulates bone marrow lymphopoiesis but stimulates myelopoiesis: the effect of G6PD deficiency.

Bone marrow (BM) dysfunction is an important component of immunomodulation. This study investigated alterations in cell content, apoptotic responses, and cell proliferation in BM, blood, and spleen in endotoxemic mice (LPS from Escherichia coli). As the decreased antioxidant status associated with glucose-6-phosphate dehydrogenase (G6PD) deficiency has been shown to modulate the innate immune response, we also tested whether a G6PD mutation (80% decrease in cellular enzyme activity) alters BM responses during endotoxemia. LPS decreased BM myeloid (CD45(+)CD11b(+)) and B lymphoid (CD45(+)CD19(+)CD11b(-)) cell content compared with controls. In contrast, LPS increased CD11b(+) myeloid but decreased T and B cell counts in the circulation. Endotoxemia inhibited spontaneous, heat shock, and H(2)O(2)-induced apoptosis as well as proliferative activity in BM lymphoid cells. In contrast, BM myeloid cell apoptosis was not altered, and their proliferative activity was increased during endotoxemia. Following LPS, splenic myeloid cell content was increased, and T and B cell content was unchanged; furthermore, splenocytes showed increased apoptosis compared with controls. BM cell content, including lymphoid and myeloid cells, was greater in G6PD mutant than wild-type (WT) mice, and LPS decreased BM cell counts to a greater degree in mutant than WT mice. Endotoxemia caused widespread inhibition of BM cytokine and chemokine production; however, IL-6 production was increased compared with controls. LPS-induced IL-6 production was decreased in G6PD mutant animals compared with WT. This study indicates that endotoxin inversely affects BM myeloid and lymphoid cell production. LPS-induced down-regulation of B cell production contributes to the generalized lymphopenia and lymphocyte dysfunction observed following nonspecific immune challenges.

Production of inflammatory molecules in peripheral blood mononuclear cells from severely glucose-6-phosphate dehydrogenase-deficient subjects.

OBJECTIVE: We have previously demonstrated that Mediterranean glucose-6-phosphate dehydrogenase (G6PD)-deficient peripheral blood mononuclear cells (PBMC) respond to mitogenic stimuli with a reduced cholesterol synthesis and growth. In the present study, we have investigated the release of inflammatory molecules by PBMC following a mitogenic stimulus, as well as the transformation to foam cells of monocyte-derived macrophages from severely G6PD-deficient and normal subjects. METHODS AND RESULTS: PBMC from G6PD-deficient subjects produced interleukin (IL)-1beta and IL-6 to a lower extent compared with normal subjects. 5-Hydroxyeicosatetraenoic acid, a primary product of 5-lipoxygenase, was slightly decreased. Tumour necrosis factor-alpha and IL-1beta secretion was significantly reduced in monocyte-derived macrophages. No difference was found in IL-10 secretion, whereas transforming growth factor-beta was invariably found to be significantly higher in G6PD-deficient cells. In cells incubated with acetylated low-density lipoprotein, cholesterol esterification and its storage in lipid droplets were lower than in normal G6PD cells. CONCLUSIONS: We conclude that by reducing the secretion of inflammatory molecules by PBMC and increasing the secretion of transforming growth factor-beta and the capability of monocyte-derived macrophages to accumulate lipid droplets and convert into foam cells, G6PD deficiency may confer a partial protection against atherosclerosis leading to the reduced risk of cardiovascular diseases reported in G6PD-deficient subjects.

Glucose-6-phosphate dehydrogenase deficiency and the inflammatory response to endotoxin and polymicrobial sepsis.

OBJECTIVE: Glucose-6-phosphate dehydrogenase (G6PD) deficiency is a common human genetic polymorphism. The deficiency protects against malaria but was shown to worsen the clinical course after severe trauma. This study tested whether the deficiency is associated with altered cytokine responses in vitro and in vivo and affects survival after endotoxemia or polymicrobial sepsis (cecal ligation and puncture). DESIGN: Genotyping of animals was carried out using a novel and improved allele-specific polymerase chain reaction assay. Macrophage and splenocyte responses in vitro and ex vivo were compared using gene array analyses and enzyme-linked immunosorbent assays and flow cytometry under both baseline and lipopolysaccharide-stimulated conditions. Endotoxemia- or sepsis-induced mortality was compared under a variety of treatment and resuscitation protocols. SETTINGS: Medical school research laboratories. SUBJECTS: Litter mates of wild-type and G6PD-mutant mice that display a degree of G6PD deficiency similar to that observed in the African-type human deficiency (20% of normal). MEASUREMENTS AND MAIN RESULTS: Lipopolysaccharide in vivo (lipopolysaccharide from Escherichia coli, 10-35 mg/kg body weight intraperitoneally) resulted in greater interleukin-1beta, interleukin-6, and interleukin-10 levels in serum and peritoneal lavage in G6PD-deficient mice compared with wild type. Prevailing doses of lipopolysaccharide in vivo increased mortality in G6PD-deficient animals (40-70%) as compared with wild type (5-40%). In contrast, mortality after cecal ligation and puncture-induced sepsis was similar in G6PD-deficient and wild-type animals either in saline-resuscitated or antibiotic-treated animals. Splenic and blood phagocytes from septic G6PD-deficient and wild-type animals displayed attenuated ex vivo lipopolysaccharide responsiveness. CONCLUSIONS: This study demonstrates that G6PD deficiency augments cytokine responses after inflammatory challenges. The deficiency is disadvantageous as reflected in increased mortality after hyperinflammation caused by acute endotoxemia. However, the deficiency may not manifest worsened survival after the immunosuppressed condition associated with severe sepsis.

[Erythrocyte polymorphism in Mali: epidemiology and resistance mechanisms against severe Plasmodium falciparum malaria]. / Polymorphismes érythrocytaires au Mali: épidémiologie et mécanismes de résistance contre la progression vers les formes graves du paludisme à Plasmodium falciparum.

Homo sapiens and Plasmodium falciparum have co-evolved since the beginning of agriculture, 10,000 to 20,000 years ago. By domesticating plants and animals, humans linked their destiny to one of the main vectors of malaria, Anopheles gambiae sl complex. The biological interaction between these three species led to exchanges of genes and biochemical processes with significant mutual influence. Humans acquired mutations with selective protective advantages against serious and fatal forms of this hemosporidiosis. This is the case of hemoglobin S, hemoglobin C, hemoglobin E, thalassemias, ovalocytosis and G6PD deficiency, among others. Many epidemiological studies published since 1949 have shown a geographic link between malaria and certain erythrocyte polymorphisms. The link with hemoglobin C was discovered only recently, in 2000, initially in Mali in the Dogon population, then in Burkina Faso. Epidemiological and molecular and cellular biology studies done in Mali and elsewhere showed that the C and S alleles, and G6PD deficiency [A-], conferred significant protection against lethal forms of Plasmodium falciparum malaria. Molecular genetic studies, based on functional genomics, transcriptomics and proteomics, provided possible explanations. Advances in molecular biology and a better understanding of the immune mechanisms underlying this protection will hopefully lead to the development of effective second- and third-generation malaria vaccines. Epidemiological and fundamental research efforts have identified some of the mechanisms by which these erythrocyte polymorphisms protect against the most lethal hematozoan parasite, Plasmodium falciparum.

Augmented IL-10 production and redox-dependent signaling pathways in glucose-6-phosphate dehydrogenase-deficient mouse peritoneal macrophages.

Glucose-6-phosphate dehydrogenase (G6PD) supports cellular antioxidant pathways. G6PD deficiency is associated with malaria protection but was shown to worsen the clinical course to injury. This study tested whether G6PD deficiency manifests in altered cytokine responses using peritoneal macrophages from a G6PD-deficient mouse model with a degree of defect similar to the common type A(-) human G6PD deficiency. Lipopolysaccharide (LPS)-induced interleukin (IL)-10 and IL-12 production was doubled in G6PD-deficient macrophages compared with wild-type (WT). Protein kinase C (PKC) activation by phorbol-ester prior to LPS resulted in a fivefold greater IL-10 production in G6PD-deficient macrophages compared with WT. Interferon-gamma treatment prior to LPS augmented IL-12 production in G6PD-deficient and WT macrophages and partially inhibited IL-10 production by G6PD-deficient macrophages. The antioxidants (N-acetyl-L-cysteine and glutathione ethyl-ester) blunted IL-10 and IL-12 production, indicating a role for oxidative stress in the observed response differences between deficient and WT macrophages. LPS-induced activation of nuclear factor-kappaB, cyclic adenosine monophosphate response element-binding protein, and specificity protein 3 was augmented in G6PD-deficient cells compared with WT. The PKCdelta inhibitor Rottlerin inhibited IL-10 and IL-12 production at different 50% effective-dose concentrations between deficient and WT macrophages, indicating elevated PKCdelta activity in deficient cells. This study reveals that activated G6PD-deficient macrophages display an augmented production of cytokines with a prominent impact on IL-10 production. The altered cytokine responses are associated with augmented activation of redox-dependent transcription factors and PKCdelta. Alterations in signaling pathways and associated changes in cytokine production may play a role in modulating the inflammatory responses following bacterial or malarial infections in G6PD deficiency.

Dominance of high-producing interleukin 6 and low-producing interleukin 10 and interferon gamma alleles in glucose-6-phosphate dehydrogenase-deficient trauma patients.

Glucose-6-phosphate dehydrogenase (G6PD) deficiency, a condition associated with malaria resistance, is a common genetic polymorphism. Decreased interleukin (IL)-10 production was demonstrated in vivo and in vitro in the African and Mediterranean forms of G6PD deficiencies. We hypothesized that low-producing IL-10 alleles are more abundant in the G6PD-deficient than nondeficient population. One hundred eleven men with African American ancestry were tested for G6PD deficiency (Type A-202/376) and for the cytokine gene promoter polymorphisms of IL-10 (-1082 G/A, -819 T/C, and -592 A/C), tumor necrosis factor (TNF)-alpha (-308 G/A), transforming growth factor (TGF)-beta1 (C/T codon 10 and C/G codon 25), IL-6 (-174 G/C), and interferon (IFN)-gamma (+874 A/T). There were no differences in the allele frequencies for TNF-alpha, IL-6, or TGF-beta1 between the G6PD-deficient and nondeficient population. In contrast, the low-producing IL-10 alleles (-592A) and low-producing IFN-gamma (+874A) allele frequencies were greater in G6PD-deficient than nondeficient samples (P = 0.035 and 0.009). Seventy-one percent of G6PD-deficient and 50% of nondeficient samples carried the high-producing IL-6(G) allele with low-producing IL-10(A) allele (P = 0.03). Furthermore, 95% of deficient and 81% of nondeficient samples carried the IL-6(G) allele together with low-producing IFN-gamma(A) allele (P = 0.017). These investigations indicate a predominant presence of high-producing IL-6 alleles together with low-producing IL-10 and IFN-gamma alleles in individuals with ancestry from malaria-endemic regions. The frequency of low-producing IL-10 genotypes is greater in the G6PD-deficient compared with nondeficient patients. The fact that these genetic differences are preserved in the current African American G6PD-deficient population indicates their potential role in pathophysiological processes in the absence of the selective pressure caused by tropical diseases.

[Influence of human genetic variants on resistance and immunity against malaria]. / Einfluss genetischer Varianten des Menschen auf Resistenz und Immunität gegen Malaria.

Certain human genetic variants occur on-ly in areas endemic for malaria. They protect against fatal malaria complications and cause inhibition of growth or development of malaria parasites in vitro. Among these are the haemoglobins (Hb) S and C, alpha-thalassaemias, glucose-6-phosphate dehydrogenase deficiency, as well as a deletion in the erythrocyte band 3 protein. Evidence for similar effects has been obtained for HbD and HbE, glycophorins A and C as well as for a number of immunologically relevant molecules such as human leukocyte antigens,tumour-necrosis-factor a and the inducible nitric oxide synthase. The findings indicate that malaria in endemic areas has caused a substantial selection of the human genome.

Evolutionary and historical aspects of the burden of malaria.

Malaria is among the oldest of diseases. In one form or another, it has infected and affected our ancestors since long before the origin of the human line. During our recent evolution, its influence has probably been greater than that of any other infectious agent. Here we attempt to trace the forms and impacts of malaria from a distant past through historical times to the present. In the last sections, we review the current burdens of malaria across the world and discuss present-day approaches to its management. Only by following, or attempting to follow, malaria throughout its evolution and history can we understand its character and so be better prepared for our future management of this ancient ill.