Follicular helper T cells recruit eosinophils into host liver by producing CXCL12 during Schistosoma japonicum infection

Schistosomiasis affects at least 200 million people in tropical and subtropical areas. The major pathology of schistosomiasis is egg‐induced liver granuloma characterized by an eosinophil‐rich inflammatory infiltration around the eggs, which subsequently leads to hepatic fibrosis and circulatory impairment in host. However, the mechanisms how eosinophils are recruited into the liver, which are crucial for the better understanding of the mechanisms underlying granuloma formation and control of schistosomiasis, remain unclear. In this study, we showed that follicular helper T (Tfh) cells participate in recruitment of eosinophils into liver partially by producing CXCL12 during schistosome infection. Our findings uncovered a previously unappreciated role of Tfh cells in promotion of the development of liver granuloma in schistosomiasis, making Tfh‐CXCL12‐eosinophil axis a potential target for intervention of schistosomiasis.     

Immunopathology of granuloma formation and fibrosis in schistosomiasis

In schistosomiasis the deposition of parasite ova within host tissues is the initial event in a complex pathophysiological cascade which is characterized by granuloma formation, and may terminate in fibrosis and related sequelae (Fig. 1). In spite of intensive study, the complex relationship between infection and morbidity remains poorly understood. In this article, Michael Phillips and Patrick Lammie review current concepts of the mechanisms of granuloma formation and its regulation in schistosome infections.     

Examining the relationship between urogenital schistosomiasis and HIV infection

Background

Urogenital schistosomiasis, caused by infection with Schistosoma haematobium, is widespread and causes substantial morbidity on the African continent. The infection has been suggested as an unrecognized risk factor for incident HIV infection. Current guidelines recommend preventive chemotherapy, using praziquantel as a public health tool, to avert morbidity due to schistosomiasis. In individuals of reproductive age, urogenital schistosomiasis remains highly prevalent and, likely, underdiagnosed. This comprehensive literature review was undertaken to examine the evidence for a cause-effect relationship between urogenital schistosomiasis and HIV/AIDS. The review aims to support discussions of urogenital schistosomiasis as a neglected yet urgent public health challenge.

Methodology/Principal Findings

We conducted a systematic search of the literature including online databases, clinical guidelines, and current medical textbooks. We describe plausible local and systemic mechanisms by which Schistosoma haematobium infection could increase the risk of HIV acquisition in both women and men. We also detail the effects of S. haematobium infection on the progression and transmissibility of HIV in co-infected individuals. We briefly summarize available evidence on the immunomodulatory effects of chronic schistosomiasis and the implications this might have for populations at high risk of both schistosomiasis and HIV.

Conclusions/Significance

Studies support the hypothesis that urogenital schistosomiasis in women and men constitutes a significant risk factor for HIV acquisition due both to local genital tract and global immunological effects. In those who become HIV-infected, schistosomal co-infection may accelerate HIV disease progression and facilitate viral transmission to sexual partners. Establishing effective prevention strategies using praziquantel, including better definition of treatment age, duration, and frequency of treatment for urogenital schistosomiasis, is an important public health priority. Our findings call attention to this pressing yet neglected public health issue and the potential added benefit of scaling up coverage of schistosomal treatment for populations in whom HIV infection is prevalent.     

Physiology of the seasonal relationship between the photochemical reflectance index and photosynthetic light use efficiency

The photochemical reflectance index (PRI) is regarded as a promising proxy to track the dynamics of photosynthetic light use efficiency (LUE) via remote sensing. The implementation of this approach requires the relationship between PRI and LUE to scale not only in space but also in time. The short-term relationship between PRI and LUE is well known and is based on the regulative process of non-photochemical quenching (NPQ), but at the seasonal timescale the mechanisms behind the relationship remain unclear. We examined to what extent sustained forms of NPQ, photoinhibition of reaction centres, seasonal changes in leaf pigment concentrations, or adjustments in the capacity of alternative energy sinks affect the seasonal relationship between PRI and LUE during the year in needles of boreal Scots pine. PRI and NPQ were highly correlated during most of the year but decoupled in early spring when the foliage was deeply downregulated. This phenomenon was attributed to differences in the physiological mechanisms controlling the seasonal dynamics of PRI and NPQ. Seasonal adjustments in the pool size of the xanthophyll cycle pigments, on a chlorophyll basis, controlled the dynamics of PRI, whereas the xanthophyll de-epoxidation status and other xanthophyll-independent mechanisms controlled the dynamics of NPQ at the seasonal timescale. We conclude that the PRI leads to an underestimation of NPQ, and consequently overestimation of LUE, under conditions of severe stress in overwintering Scots pine, and most likely also in species experiencing severe drought. This severe stress-induced decoupling may challenge the implementation of the PRI approach.     

Damage control and its costs: BM failure in Fanconi anemia stems from overactive p53/p21

Despite having well-characterized disease-associated mutations, the mechanisms underlying the progressive bone marrow failure and cancer susceptibility of Fanconi anemia have been unclear. In this issue of Cell Stem Cell, Ceccaldi et?al. identify an overactive p53/p21 stress response and cell cycle arrest as an underlying cause that starts during fetal development.     

Vitamin D and Risk of Multiple Sclerosis: A Mendelian Randomization Study

BackgroundObservational studies have demonstrated an association between decreased vitamin D level and risk of multiple sclerosis (MS); however, it remains unclear whether this relationship is causal. We undertook a Mendelian randomization (MR) study to evaluate whether genetically lowered vitamin D level influences the risk of MS.ConclusionsA genetically lowered 25OHD level is strongly associated with increased susceptibility to MS. Whether vitamin D sufficiency can delay, or prevent, MS onset merits further investigation in long-term randomized controlled trials.     

Mutagenicity evaluation of Schistosoma spp. extracts by the umu-test and V79/HGPRT gene mutation assay

Schistosomiasis has been suspected of being a risk factor for various types of cancers for sometime, e.g., bladder cancer, colorectal cancer and hepatic cancer. Among them, the etiological relationship between urinary schistosomiasis and bladder cancer is now widely accepted. However, mechanisms of the carcinogenesis are still unclear. Here, we tested the mutagenicity of the parasite extracts by the umu-test and hypoxanthine guanine phosphoribosyltransferase (HGPRT) gene mutation assay, which both overcome disadvantages of the Ames plate assay. Adult worm extracts and egg extracts of Schistosoma haematobium and Schistosoma mansoni were tested. Under our experimental conditions, neither worm nor egg extracts were shown to have any mutagenicity in both tests even in the presence of S9 mix. Our results suggest that there is very little possibility of immediate gene mutation due to the parasite-derived substances in schistosomiasis-related carcinogenesis.     

集落刺激因子治疗重型再生障碍性贫血疗效和安全性的Meta 分析

目的:通过Meta分析评价粒系或粒单系集落刺激因子(G-CSF或GM-CSF)对接受免疫抑制治疗(IST)的重型再生障碍性贫血(SAA)患者的疗效和安全性。方法:使用相关检索词检索MEDLINE、Cochrane Library、EMBASE、CNKI及CBM数据库,检索时间1990年1月～2011年12月。纳入G-CSF或GM-CSF治疗SAA的随机对照研究。用Review Manager4.2统计软件对数据进行Meta分析。结果:共纳入4篇文献,共466例SAA患者。Meta分析结果显示:①IST疗效:G-CSF/GM-CSF组与对照组的SAA患者对比,近远期疗效与生存率均无显著差异:总体生存率[OR=1.15,95%C(I0.73,1.82),P=0.54]、完全缓解率[OR=1.20,95%CI(0.71,2.02),P=0.50]、早期总体有效率[OR=1.61,95%CI(0.85,3.03),P=0.14]、远期总体有效率[OR=1.17,95%CI(0.78,1.74),P=0.45];②IST相关感染:IST治疗早期感染发生率、严重感染发生率、感染相关死亡率方面均未优于对照组;③G-CSF/GM-CSF组的复发率低于对照组,差异显著[OR=0.57,95%C(I0.35,0.93),P=0.02];④G-CSF/GM-CSF组远期随访发生克隆性病变的发生率与对照组无统计学差异,恶性肿瘤(MDS/AML)发生率[OR=0.90,95%CI(0.41,1.99),P=0.79]、PNH发生率[OR=1.48,95%CI(0.65,3.33),P=0.35]。结论:G-CSF/GM-CSF应用于接受IST治疗的SAA患者,尚不能证明具有提高总体生存率、完全缓解率、总体有效率、减少感染和感染相关死亡率等优势。虽然有可能降低复发率,也不增加远期克隆性病变发生率,但还需要更严格设计的大样本双盲随机对照试验,并进行更为长期的随访研究。     

UBE2W interacts with FANCL and regulates the monoubiquitination of fanconi anemia protein FANCD2

Fanconi anemia (FA) is a rare cancer-predisposing genetic disease mostly caused by improper regulation of the monoubiquitination of Fanconi anemia complementation group D2 (FANCD2). Genetic studies have indicated that ubiquitin conjugating enzyme UBE2T and HHR6 could regulate FANCD2 monoubiquitination through distinct mechanisms. However, the exact regulation mechanisms of FANCD2 monoubiquitination in response to different DNA damages remain unclear. Here we report that UBE2W, a new ubiquitin conjugating enzyme, could regulate FANCD2 monoubiquitination by mechanisms different from UBE2T or HHR6. Indeed, UBE2W exhibits ubiquitin conjugating enzyme activity and catalyzes the monoubiquitination of PHD domain of Fanconi anemia complementation group L (FANCL) in vitro. UBE2W binds to FANCL, and the PHD domain is both necessary and sufficient for this interaction in mammalian cells. In addition, over-expression of UBE2W in cells promotes the monoubiquitination of FANCD2 and down-regulated UBE2W markedly reduces the UV irradiation-induced but not MMC-induced FANCD2 monoubiquitination. These results indicate that UBE2W regulates FANCD2 monoubiquitination by mechanisms different from UBE2T and HRR6. It may provide an additional regulatory step in the activation of the FA pathway.     

Progress in the molecular biology of malaria and the immunology of nematode infections

Japan is one of a small number of countries to have successfully controlled or eliminated major parasitic diseases, including malaria, filariasis, schistosomiasis and enteric parasitoses. Of particular importance in this success was a close collaboration between primary research and public health efforts. Many Japanese researchers continue to study malaria, particularly the areas of genetics and immunology, and this should contribute to global parasite eradication strategies. Furthermore, studies of immunoregulation of nematode infection using the interleukin-18 pathway, most of which have been conducted in Japan, are helping to improve researchers' understanding of human immune mechanisms and host-parasite interactions.     

Schistosomiasis messaging in endemic communities: Lessons and implications for interventions from rural Uganda,a rapid ethnographic assessment study

BackgroundOver 240 million people are infected with schistosomiasis, the majority in sub-Saharan Africa. In Uganda, high infection rates exist in communities on the shores of Lake Victoria. Praziquantel mass drug administration (MDA) delivered by village health teams is the mainstay of schistosomiasis control. However, treatment uptake remains suboptimal, with many people unaware of treatment or thinking it is only for children. Furthermore, people are often rapidly reinfected post-treatment due to continued exposure. In three Schistosoma mansoni high endemicity lake-shore communities in Mayuge district, Eastern Uganda, we investigated the sources of schistosomiasis information, remembered content of information, and the perception of information and related practices towards the control of schistosomiasis.Methods and principal findingsData were collected from September 2017 to March 2018 using a rapid ethnographic assessment that included transect walks, observations, individual in-depth interviews and focus group discussions. Data were analysed thematically using iterative categorisation. We found that the main sources of schistosomiasis information included health workers at government facilities, village health teams, teachers, and radio programmes produced by the Ministry of Health. These messages described the symptoms of schistosomiasis, but did not mention the side effects of praziquantel treatment. Despite this messaging, the main cause of the disease and transmission was unclear to most participants. The translation of schistosomiasis on the radio into the local language ‘ekidada’—meaning swollen stomach—increased, rather than reduced, confusion about the cause(s) of schistosomiasis, due to believed links between ekidada and witchcraft, and prompted a reluctance to engage with treatment or preventative efforts.Conclusion and significanceThis study highlights gaps in schistosomiasis messaging. We recommend MDA is complemented by effective, evidence-based messaging on schistosomiasis transmission, prevention, and treatment, that is sensitive to local language and context issues, resulting in clear, concise, and consistent messages, to increase effectiveness.     

Epitopic and paratopically directed anti-idiotypic factors in the regulation of resistance to murine schistosomiasis mansoni

In this study we investigated aspects of targets and regulatory mechanisms of immunologically mediated resistance to schistosomiasis. The interactions of antigen, monoclonal antibodies (MAb), and anti-idiotypic antibodies were studied by using competitive inhibition ELISA, radioimmunoprecipitation, and direct-binding ELISA techniques. MAb, either protective or nonprotective against challenge with Schistosoma mansoni, recognize either discrete or shared epitopes. MAb that recognize the same specific epitope may or may not express the ability to adoptively transfer resistance to syngeneic recipients. These results suggest that the functional as well as the epitopic specificity must be considered in an evaluation of protective mechanisms. The antibodies also can be characterized by both unique and cross-reacting idiotypic determinants. In addition, a relationship between antigen and anti-idiotypic antibody activity has been demonstrated. The immunologic analogy between antigenic epitopes and anti-idiotypic antibodies has been demonstrated by the ability of these two moieties to reciprocally inhibit the recognition of paratope-associated idiotypes, expressed by the protective MAb. This anti-idiotypic activity can be demonstrated in serum of infected animals. In this study we have identified two specific epitopes related to protection, and we illustrate here the steric relationship between antigen and anti-idiotypic antibody. The presence of idiotypically directed regulatory pathways within actively infected animals suggests that the immune response can be differentially regulated at the clonal level.     

Analysis and estimative of schistosomiasis prevalence for the state of Minas Gerais, Brazil, using multiple regression with social and environmental spatial data

The aim of this work is to establish a relationship between schistosomiasis prevalence and social-environmental variables, in the state of Minas Gerais, Brazil, through multiple linear regression. The final regression model was established, after a variables selection phase, with a set of spatial variables which contains the summer minimum temperature, human development index, and vegetation type variables. Based on this model, a schistosomiasis risk map was built for Minas Gerais.     

Chronic lymphocytic leukemia cells bind and present the erythrocyte protein band 3: possible role as initiators of autoimmune hemolytic anemia

The mechanisms underlying the frequent association between chronic lymphocytic leukemia (CLL) and autoimmune hemolytic anemia are currently unclear. The erythrocyte protein band 3 (B3) is one of the most frequently targeted Ags in autoimmune hemolytic anemia. In this study, we show that CLL cells specifically recognize B3 through a still unidentified receptor. B3 interaction with CLL cells involves the recognition of its N-terminal domain and leads to its internalization. Interestingly, when binding of erythrocyte-derived vesicles as found physiologically in blood was assessed, we observed that CLL cells could only interact with inside-out vesicles, being this interaction strongly dependent on the recognition of the N-terminal portion of B3. We then examined T cell responses to B3 using circulating CLL cells as APCs. Resting B3-pulsed CLL cells were unable to induce T cell proliferation. However, when deficient costimulation was overcome by CD40 engagement, B3-pulsed CLL cells were capable of activating CD4(+) T cells in a HLA-DR-dependent fashion. Therefore, our work shows that CLL cells can specifically bind, capture, and present B3 to T cells when in an activated state, an ability that could allow the neoplastic clone to trigger the autoaggressive process against erythrocytes.     

Histocompatibilty-linked susceptibility for hepatospleenomegaly in human schistosomiasis mansoni.

In schistosomiasis mansoni, the pathogenesis of hepatosplenic disease has been shown to be due primarily to immune mechanisms. The present study was designed to examine the relationship between the development of schistosomal hepatosplenomegaly in Egyptian school children and the HLA antigens. Two groups of schistosome-infected children with similar fecal egg counts were examined: one group (23 children) had no clinically demonstrable hepatosplenomegaly whereas all the children (28) in the second group suffered from liver enlargement. Furthermore, 13 of the 28 individuals in the latter group had splenomegaly as well. Our results show that hepatosplenomegaly was related to the presence of two HLA antigens: HLA AI and B5. The average relative risk of developing hepatomegaly is 29 for HLA AI and 18.9 for 55.6. Furthermore, the severity of hepatomegaly was correlated with the presence of these two HLA antigens. These findings represent a step toward elucidating the factors controlling the pathogenic mechanisms in human schistosomiasis mansoni.     

A Review of the Adverse Effects of Peripheral Alpha-1 Antagonists in Hypertension Therapy

Background  

Doxazosin and its role as an antihypertensive agent have come under recent scrutiny as a result of the early termination of that treatment arm in ALLHAT. It is unclear why the cardiovascular (CV) event rate in this randomized, controlled trial (RCT), especially heart failure, is higher in those treated with a doxazosin-based regimen than with a chlorthalidone based-regimen. There has been little work in the past to summarize information on peripheral alpha-1 antagonists that may be helpful in evaluating the results of this randomized controlled trial.     

MCPIP1 Deficiency in Mice Results in Severe Anemia Related to Autoimmune Mechanisms

Autoimmune gastritis is an organ-specific autoimmune disease of the stomach associated with pernicious anemia. The previous work from us and other groups identified MCPIP1 as an essential factor controlling inflammation and immune homeostasis. MCPIP1^-/- developed severe anemia. However, the mechanisms underlying this phenotype remain unclear. In the present study, we found that MCPIP1 deficiency in mice resulted in severe anemia related to autoimmune mechanisms. Although MCPIP1 deficiency did not affect erythropoiesis per se, the erythropoiesis in MCPIP1^-/- bone marrow erythroblasts was significantly attenuated due to iron and vitamin B₁₂ (VB₁₂) deficiency, which was mainly resulted from autoimmunity-associated gastritis and parietal cell loss. Consistently, exogenous supplement of iron and VB₁₂ greatly improved the anemia phenotype of MCPIP1^-/- mice. Finally, we have evidence suggesting that autoimmune hemolysis may also contribute to anemia phenotype of MCPIP1^-/- mice. Taken together, our study suggests that MCPIP1 deficiency in mice leads to the development of autoimmune gastritis and pernicious anemia. Thus, MCPIP1^-/- mice may be a good mouse model for investigating the pathogenesis of pernicious anemia and testing the efficacy of some potential drugs for treatment of this disease.     

Periodontal Disease and Risk of Preeclampsia: A Meta-Analysis of Observational Studies

Background

Many epidemiological studies have found a positive association between periodontal disease (PD) and the risk of preeclampsia, but the magnitude of this association varies and independent studies have reported conflicting findings. We performed a meta-analysis to ascertain the relationship between PD and preeclampsia.

Methods

The PubMed database was searched up to January 12, 2013, for relevant observational studies on an association between PD and the risk of preeclampsia. Data were extracted and analyzed independently by two authors. The meta-analysis was performed using comprehensive meta-analysis software.

Results

Thirteen observational case-control studies and two cohort studies, involving 1089 preeclampsia patients, were identified. Based on a random-effects meta-analysis, a significant association between PD and preeclampsia was identified (odds ratio = 2.79, 95% confidence interval CI, 2.01–3.01, P<0.0001).

Conclusions

Although the causality remains unclear, the association between PD and preeclampsia may reflect the induction of PD by the preeclamptic state, or it may be part of an overall exaggerated inflammatory response to pregnancy. Larger randomized controlled trials with preeclampsia as the primary outcome and pathophysiological studies are required to explore causality and to dissect the biological mechanisms involved.     

Schistosoma mansoni egg glycoproteins and C-type lectins of host immune cells: molecular partners that shape immune responses

Schistosome eggs and egg-derived molecules are potent immunomodulatory agents. There is increasing evidence that the interplay between egg glycoproteins and host C-type lectins plays an important role in shaping immune responses during schistosomiasis. As most experiments in this field so far have been performed using complex protein/glycoprotein mixtures or synthetic model glycoconjugates, it is still largely unclear which individual moieties of schistosome eggs are immunologically active. In this review we will discuss molecular aspects of Schistosoma mansoni egg glycoproteins, their interactions with C-type lectins, and the relevance to schistosome egg immunobiology.     

Impact of placental Plasmodium falciparum malaria on pregnancy and perinatal outcome in sub-Saharan Africa: part III: placental malaria, maternal health, and public health

Plasmodium falciparum infections of the placenta remain a major medical challenge among pregnant women in sub-Saharan Africa. A number of factors influence the prevalence of placental malaria in pregnant women, including maternal age, gravidity, use of prophylaxis, nutrition, host genetics, and level of anti-parasite immunity, as well as parasite genetics and transmission rates [1]. Maternal anemia has been shown to be one of the major complications of placental malaria in sub-Saharan Africa. The mechanisms by which malaria causes anemia are fairly well understood. The pathophysiology of malaria-associated anemia is multifactorial. The most likely mechanisms include (i) hemolysis or the direct destruction of parasitized red blood cells that occurs both intravascularly and by sequestration in the microcirculation, mainly in the spleen; (ii) specific/nonspecific immune responses, whereby red cell survival is shortened; (iii) nonspecific, defective, red cell production, which depresses erythropoiesis, inhibits reticulocyte release, and prematurely destructs red cells during maturation in the bone marrow; and (iv) hypersplenism associated with a reduction in all three blood cell series, that is, causing not only anemia but also thrombocytopenia and leucopenia [2,3]. The relationship between maternal anemia with obstetric factors, however, is not fully understood, and, thus, evaluating the link between malaria, obstetric disorders, and maternal death has been recommended [4]. There have been efforts to quantify the contribution of malaria to maternal morbidity and mortality with the expectation that this would provide the evidence necessary to improve the effectiveness of advocacy to incorporate malaria prevention strategies in Safe Motherhood Programs [5,6]. The effects of placental malaria on maternal health can better be understood when considered in relation with various maternal parameters, including maternal age, parity, peripheral malaria infection, anemia, and HIV infection.