Role of IgG3 in Infectious Diseases Damelang, Timon; Rogerson, Stephen J.; Kent, Stephen J. ...
Trends in immunology,
March 2019, 2019-03-00, 20190301, Letnik:
40, Številka:
3
Journal Article
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IgG3 comprises only a minor fraction of IgG and has remained relatively understudied until recent years. Key physiochemical characteristics of IgG3 include an elongated hinge region, greater ...molecular flexibility, extensive polymorphisms, and additional glycosylation sites not present on other IgG subclasses. These characteristics make IgG3 a uniquely potent immunoglobulin, with the potential for triggering effector functions including complement activation, antibody (Ab)-mediated phagocytosis, or Ab-mediated cellular cytotoxicity (ADCC). Recent studies underscore the importance of IgG3 effector functions against a range of pathogens and have provided approaches to overcome IgG3-associated limitations, such as allotype-dependent short Ab half-life, and excessive proinflammatory activation. Understanding the molecular and functional properties of IgG3 may facilitate the development of improved Ab-based immunotherapies and vaccines against infectious diseases.
IgG3 has been associated with enhanced control or protection against a range of intracellular bacteria, parasites, and viruses.
IgG3 Abs are potent mediators of effector functions, including enhanced ADCC, opsonophagocytosis, complement activation, and neutralization, compared with other IgG subclasses.
Future Ab-based therapeutics and vaccines should consider utilizing IgG3, based on features of enhanced functional capacity.
Investigating the impact of glycosylation patterns and allotypes on IgG3 function may expand our understanding of IgG3 responses and their therapeutic potential.
Over the past 10 years, knowledge of the burden, economic costs, and consequences of malaria in pregnancy has improved, and the prevalence of malaria caused by Plasmodium falciparum has declined ...substantially in some geographical areas. In particular, studies outside of Africa have increased the evidence base of Plasmodium vivax in pregnancy. Rapid diagnostic tests have been poor at detecting malaria in pregnant women, while PCR has shown a high prevalence of low density infection, the clinical importance of which is unknown. Erythrocytes infected with P falciparum that express the surface protein VAR2CSA accumulate in the placenta, and VAR2CSA is an important target of protective immunity. Clinical trials for a VAR2CSA vaccine are ongoing, but sequence variation needs to be carefully studied. Health system and household costs still limit access to prevention and treatment services. Within the context of malaria elimination, pregnant women could be used to monitor malaria transmission. This Series paper summarises recent progress and highlights unresolved issues related to the burden of malaria in pregnancy.
Relative resistance of Plasmodium falciparum parasites to artesunate (AS) has been ascribed to mutations in the Kelch 13 gene. Lee et al. describe another potential contributor to resistance: the ...induction of increased rosetting by trophozoite-infected erythrocytes following short exposures to AS. Dissecting this phenomenon may lead to new insights into AS resistance.
While half of the world's population is at risk of malaria, the most vulnerable are still children under five, pregnant women and returning travelers. Anopheles mosquitoes transmit malaria parasites ...to the human host; but how
interact with the innate immune system remains largely unexplored. The most recent advances prove that monocytes are a key component to control parasite burden and to protect host from disease. Monocytes' protective roles include phagocytosis, cytokine production and antigen presentation. However, monocytes can be involved in pathogenesis and drive inflammation and sequestration of infected red blood cells in organs such as the brain, placenta or lungs by secreting cytokines that upregulate expression of endothelial adhesion receptors.
DNA, hemozoin or extracellular vesicles can impair the function of monocytes. With time, reinfections with
change the relative proportion of monocyte subsets and their physical properties. These changes relate to clinical outcomes and might constitute informative biomarkers of immunity. More importantly, at the molecular level, transcriptional, metabolic or epigenetic changes can "prime" monocytes to alter their responses in future encounters with
. This mechanism, known as trained immunity, challenges the traditional view of monocytes as a component of the immune system that lacks memory. Overall, this rough guide serves as an update reviewing the advances made during the past 5 years on understanding the role of monocytes in innate immunity to malaria.
The COVID-19 pandemic has resulted in millions of infections, hundreds of thousands of deaths and major societal disruption due to lockdowns and other restrictions introduced to limit disease spread. ...Relatively little attention has been paid to understanding how the pandemic has affected treatment, prevention and control of malaria, which is a major cause of death and disease and predominantly affects people in less well-resourced settings.
Recent successes in malaria control and elimination have reduced the global malaria burden, but these gains are fragile and progress has stalled in the past 5 years. Withdrawing successful interventions often results in rapid malaria resurgence, primarily threatening vulnerable young children and pregnant women. Malaria programmes are being affected in many ways by COVID-19. For prevention of malaria, insecticide-treated nets need regular renewal, but distribution campaigns have been delayed or cancelled. For detection and treatment of malaria, individuals may stop attending health facilities, out of fear of exposure to COVID-19, or because they cannot afford transport, and health care workers require additional resources to protect themselves from COVID-19. Supplies of diagnostics and drugs are being interrupted, which is compounded by production of substandard and falsified medicines and diagnostics. These disruptions are predicted to double the number of young African children dying of malaria in the coming year and may impact efforts to control the spread of drug resistance. Using examples from successful malaria control and elimination campaigns, we propose strategies to re-establish malaria control activities and maintain elimination efforts in the context of the COVID-19 pandemic, which is likely to be a long-term challenge. All sectors of society, including governments, donors, private sector and civil society organisations, have crucial roles to play to prevent malaria resurgence. Sparse resources must be allocated efficiently to ensure integrated health care systems that can sustain control activities against COVID-19 as well as malaria and other priority infectious diseases.
As we deal with the COVID-19 pandemic, it is crucial that other major killers such as malaria are not ignored. History tells us that if we do, the consequences will be dire, particularly in vulnerable populations.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Infections with Plasmodium falciparum and Plasmodium vivax cause over 600,000 deaths each year, concentrated in Africa and in young children, but much of the world's population remain at risk of ...infection. In this article, we review the latest developments in the immunogenicity and pathogenesis of malaria, with a particular focus on P. falciparum, the leading malaria killer. Pathogenic factors include parasite-derived toxins and variant surface antigens on infected erythrocytes that mediate sequestration in the deep vasculature. Host response to parasite toxins and to variant antigens is an important determinant of disease severity. Understanding how parasites sequester, and how antibody to variant antigens could prevent sequestration, may lead to new approaches to treat and prevent disease. Difficulties in malaria diagnosis, drug resistance, and specific challenges of treating P. vivax pose challenges to malaria elimination, but vaccines and other preventive strategies may offer improved disease control.
Numerous efforts to understand the functional roles of antibodies demonstrated that they can protect against malaria. However, it is unclear which antibody responses are the best correlates of ...immunity, and which antibody functions are most important in protection from disease. Understanding the role of antibodies in protection against malaria is crucial for antimalarial vaccine design. In this review, the specific functional properties of naturally acquired and vaccine-induced antibodies that correlate to protection from the blood stages of Plasmodium falciparum malaria are re-examined and the gaps in knowledge related to antibody function in malarial immunity are highlighted.
Management of malaria in pregnancy Rogerson, Stephen
Indian journal of medical research (New Delhi, India : 1994),
09/2017, Letnik:
146, Številka:
3
Journal Article
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Pregnant women are especially susceptible to malaria infection. Without existing immunity, severe malaria can develop requiring emergency treatment, and pregnancy loss is common. In semi-immune ...women, consequences of malaria for the mother include anaemia while stillbirth, premature delivery and foetal growth restriction affect the developing foetus. Preventive measures include insecticide-treated nets and (in some African settings) intermittent preventive treatment. Prompt management of maternal infection is key, using parenteral artemisinins for severe malaria, and artemisinin combination treatments (ACTs) in the second and third trimesters of pregnancy. ACTs may soon also be recommended as an alternative to quinine as a treatment in the first trimester of pregnancy. Monitoring the safety of antimalarials and understanding their pharmacokinetics is particularly important in pregnancy with the altered maternal physiology and the risks to the developing foetus. As increasing numbers of countries embrace malaria elimination as a goal, the special needs of the vulnerable group of pregnant women and their infants should not be overlooked.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
9.
Neutrophils and Malaria Aitken, Elizabeth H; Alemu, Agersew; Rogerson, Stephen J
Frontiers in immunology,
12/2018, Letnik:
9
Journal Article
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Neutrophils are abundant in the circulation and are one of the immune system's first lines of defense against infection. There has been substantial work carried out investigating the role of ...neutrophils in malaria and it is clear that during infection neutrophils are activated and are capable of clearing malaria parasites by a number of mechanisms. This review focuses on neutrophil responses to human malarias, summarizing evidence which helps us understand where neutrophils are, what they are doing, how they interact with parasites as well as their potential role in vaccine mediated immunity. We also outline future research priorities for these, the most abundant of leukocytes.
Resistance of Plasmodium falciparum to sulfadoxine-pyrimethamine threatens the antimalarial effectiveness of intermittent preventive treatment during pregnancy (IPTp) in sub-Saharan Africa. We aimed ...to assess the associations between markers of sulfadoxine-pyrimethamine resistance in P falciparum and the effectiveness of sulfadoxine-pyrimethamine IPTp for malaria-associated outcomes.
For this systematic review and meta-analysis, we searched databases (from Jan 1, 1990 to March 1, 2018) for clinical studies (aggregated data) or surveys (individual participant data) that reported data on low birthweight (primary outcome) and malaria by sulfadoxine-pyrimethamine IPTp dose, and for studies that reported on molecular markers of sulfadoxine-pyrimethamine resistance. Studies that involved only HIV-infected women or combined interventions were excluded. We did a random-effects meta-analysis (clinical studies) or multivariate log-binomial regression (surveys) to obtain summarised dose-response data (relative risk reduction RRR) and multivariate meta-regression to explore the modifying effects of sulfadoxine-pyrimethamine resistance (as indicated by Ala437Gly, Lys540Glu, and Ala581Gly substitutions in the dhps gene). This study is registered with PROSPERO, number 42016035540.
Of 1097 records screened, 57 studies were included in the aggregated-data meta-analysis (including 59 457 births). The RRR for low birthweight declined with increasing prevalence of dhps Lys540Glu (ptrend=0·0060) but not Ala437Gly (ptrend=0·35). The RRR was 7% (95% CI 0 to 13) in areas of high resistance to sulfadoxine-pyrimethamine (Lys540Glu ≥90% in east and southern Africa; n=11), 21% (14 to 29) in moderate-resistance areas (Ala437Gly ≥90% central and west Africa, or Lys540Glu ≥30% to <90% east and southern Africa; n=16), and 27% (21 to 33) in low-resistance areas (Ala437Gly <90% central and west Africa, or Lys540Glu <30% east and southern Africa; n=30; ptrend=0·0054 univariate, I2=69·5%). The overall RRR in all resistance strata was 21% (17 to 25). In the analysis of individual participant data from 13 surveys (42 394 births), sulfadoxine-pyrimethamine IPTp was associated with reduced prevalence of low birthweight in areas with a Lys540Glu prevalence of more than 90% and Ala581Gly prevalence of less than 10% (RRR 10% 7 to 12), but not in those with an Ala581Gly prevalence of 10% or higher (pooled Ala581Gly prevalence 37% range 29 to 46; RRR 0·5% –16 to 14; 2326 births).
The effectiveness of sulfadoxine-pyrimethamine IPTp is reduced in areas with high resistance to sulfadoxine-pyrimethamine among P falciparum parasites, but remains associated with reductions in low birthweight even in areas where dhps Lys540Glu prevalence exceeds 90% but where the sextuple-mutant parasite (harbouring the additional dhps Ala581Gly mutation) is uncommon. Therapeutic alternatives to sulfadoxine-pyrimethamine IPTp are needed in areas where the prevalence of the sextuple-mutant parasite exceeds 37%.
US Centers for Disease Control and Prevention, the Malaria in Pregnancy Consortium (funded through a grant from the Bill & Melinda Gates Foundation to the Liverpool School of Tropical Medicine), Worldwide Antimalarial Resistance Network, European and Developing Countries Clinical Trials Partnership.
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