Role of Th1 and Th2 cytokines in immune response to uncomplicated Plasmodium falciparum malaria

The relative balance between Th1 and Th2 cytokines appears crucial, since the role of cytokines has been evaluated in several studies by comparison of clinically heterogeneous groups of patients. The aim of this study is to determine the role of proinflammatory Th1 cytokines, interleukin-12 (IL-12) and gamma interferon (IFN-gamma), and anti-inflammatory Th2 cytokines, IL-4 and IL-10, in a homogeneous group of patients with uncomplicated Plasmodium falciparum malaria. Levels of IL-12, IFN-gamma, Il-4, and IL-10 in serum for 20 adult patients and 15 healthy control subjects were determined by an immunoenzymatic assay. Serum levels of Th1 cytokines, IL-12 (8.6 +/- 2.8 pg/ml; controls, 3.2 +/- 0.7 pg/ml) and IFN-gamma (39.2 +/- 67.6 pg/ml; controls, 8.4 +/- 6.3 pg/ml), were significantly increased at admission; 3 days later, levels of IL-12 in serum remained significantly high (8.8 +/- 2.6 pg/ml), whereas IFN-gamma levels returned to control values. The anti-inflammatory response of Th2 cytokines (IL-10 and IL-4) was distinct. Levels of IL-10 in serum were not significantly increased at day 0 and day 3 (306.6 +/- 200.4 pg/ml and 56.6 +/- 38.4 pg/ml, respectively; controls, 17.4 +/- 9.0 pg/ml). In contrast, levels of IL-4 in serum were not increased on admission (3.4 +/- 1.2 pg/ml; controls, 2.4 +/- 0.8 pg/ml), but at day 3 a moderate and significant increase of IL-4 levels was observed (4.5 +/- 1.7 pg/ml). In conclusion, the increase of Th1 cytokine IL-12 and IFN-gamma levels during the acute phase of uncomplicated P. falciparum malaria may reflect an early and effective immune response regulated by proinflammatory Th1 cytokines, and in particular IFN-gamma may play a role in limiting progression from uncomplicated malaria to severe and life-threatening complications.     

Reciprocal Regulation of Th1- and Th2-Cytokine-Producing T Cells during Clearance of Parasitemia in Plasmodium falciparum Malaria

Flow cytometry for the intracellular detection of T-cell cytokines was performed for 15 Gabonese patients during acute uncomplicated Plasmodium falciparum malaria. A striking expansion of CD4⁺ and CD8⁺ T cells producing gamma interferon (IFN-γ) was found during drug-induced clearance of parasitemia, paralleled by a decrease of interleukin-2 (IL-2) production. The frequency of IL-4- and IL-13-producing CD4⁺ cells gradually decreased, whereas the frequency of T cells producing IL-2⁺–IFN-γ⁺, IL-4⁻–IL-5⁺, and IL-4⁺–IL-5⁺ cytokines as well as IL-4⁺–IFN-γ⁺ and IL-13⁺–IFN-γ⁺ cytokines was not significantly altered. The capacity for IL-10 production within the CD4⁺ subset increased due to an expansion of both IL-10⁺–IFN-γ⁻ and IL-10⁺–IFN-γ⁺ cytokine-expressing cells. Thus, a more pronounced Th2-driven immune response during acute untreated P. falciparum infection with a shift towards Th1 responsiveness induced by parasite clearance is suggested.     

Acquired Antibodies to Merozoite Antigens in Children from Uganda with Uncomplicated or Severe Plasmodium falciparum Malaria

Malaria can present itself as an uncomplicated or severe disease. We have here studied the quantity and quality of antibody responses against merozoite antigens, as well as multiplicity of infection (MOI), in children from Uganda. We found higher levels of IgG antibodies toward erythrocyte-binding antigen EBA181, MSP2 of Plasmodium falciparum 3D7 and FC27 (MSP2-3D7/FC27), and apical membrane antigen 1 (AMA1) in patients with uncomplicated malaria by enzyme-linked immunosorbent assay (ELISA) but no differences against EBA140, EBA175, MSP1, and reticulocyte-binding protein homologues Rh2 and Rh4 or for IgM against MSP2-3D7/FC27.Patients with uncomplicated malaria were also shown to have higher antibody affinities for AMA1 by surface plasmon resonance (SPR). Decreased invasion of two clinical P. falciparum isolates in the presence of patient plasma correlated with lower initial parasitemia in the patients, in contrast to comparisons of parasitemia to ELISA values or antibody affinities, which did not show any correlations. Analysis of the heterogeneity of the infections revealed a higher MOI in patients with uncomplicated disease, with the P. falciparum K1 MSP1 (MSP1-K1) and MSP2-3D7 being the most discriminative allelic markers. Higher MOIs also correlated positively with higher antibody levels in several of the ELISAs. In conclusion, certain antibody responses and MOIs were associated with differences between uncomplicated and severe malaria. When different assays were combined, some antibodies, like those against AMA1, seemed particularly discriminative. However, only decreased invasion correlated with initial parasitemia in the patient, signaling the importance of functional assays in understanding development of immunity against malaria and in evaluating vaccine candidates.     

The Th1 Immune Response to Plasmodium falciparum Circumsporozoite Protein Is Boosted by Adenovirus Vectors 35 and 26 with a Homologous Insert

The most advanced malaria vaccine, RTS,S, is comprised of an adjuvant portion of the Plasmodium falciparum circumsporozoite (CS) protein fused to and admixed with the hepatitis B virus surface antigen. This vaccine confers short-term protection against malaria infection, with an efficacy of about 50%, and induces particularly B-cell and CD4⁺ T-cell responses. In the present study, we tested by the hypothesis that the Th1 immune response to CS protein, in particular the CD8⁺ T-cell response, which is needed for strong and lasting malaria immunity, is boosted to sustainable levels vectors adenovirus and 26 with an homologous insert 35 (Ad35.CS/Ad26.CS). In this study, we evaluated immune responses induced with vaccination regimens based on an adjuvant-containing, yeast-produced complete CS protein followed by two recombinant low-seroprevalence adenoviruses expressing P. falciparum CS antigen, Ad35.CS (subgroup B) and Ad26.CS (subgroup D). Our results show that (i) the yeast (Hansenula polymorpha)produced, adjuvanted full-length CS protein is highly potent in inducing high CS-specific humoral responses in mice but produces poor T-cell responses, (ii) the Ad35.CS vector boosts the gamma interferon-positive (IFN-γ⁺) CD8⁺ T-cell response induced by the CS protein immunization and shifts the immune response toward the Th1 type, and (iii) a three-component heterologous vaccination comprised of a CS protein prime followed by boosts with Ad35.CS and Ad26.CS elicits an even more robust and sustainable IFN-γ⁺ CD8⁺ T-cell response than one- or two-component regimens. The Ad35.CS/Ad26.CS combination boosted particularly the IFN-γ⁺ and tumor necrosis factor alpha-positive (TNF-α⁺) T cells, confirming the shift of the immune response from the Th2 type to the Th1 type. These results support the notion of first immunizations of infants with an adjuvanted CS protein vaccine, followed by a booster Ad35.CS/Ad26.CS vaccine at a later age, to induce lasting protection against malaria for which the Th1 response and immune memory is required.Almost 40 years after the feasibility of vaccination against malaria was first demonstrated by means of irradiated sporozoites (9), a vaccine modality that efficiently induces long-lived protective immunity remains elusive. The most advanced circumsporozoite (CS)-based malaria vaccine candidate to date is RTS,S, a vaccine based on a fragment of Plasmodium falciparum circumsporozoite (CS) protein fused to and admixed with hepatitis B virus surface protein. In adults, RTS,S with the adjuvant AS02 has consistently conferred 40% protection against malaria infection upon sporozoite challenge (54). Even though RTS,S/AS02 induces high-level CS-specific antibody responses, the induced T-cell responses are weak (21). As the Th1 response, particularly gamma interferon (IFN-γ) and CD8⁺ T cells, is associated with protection, novel adjuvant systems were developed with the aim of improving the induced T-cell response while maintaining potent levels of CS-specific antibody responses. One of these novel adjuvant systems, AS01, demonstrated its suitability in mice, as it improved CS-specific CD4⁺ T-cell responses and led to induction of CD8⁺ T cells (32). Nonhuman primate studies also demonstrated that RTS,S with AS01 adjuvant induces strong CS-specific antibody responses as well as mean higher frequencies of IFN-γ- and tumor necrosis factor alpha (TNF-α)-producing CD4⁺ T cells than those generated by RTS,S with AS02 adjuvant. However, the induction of CD8⁺ T cells was not confirmed in this nonhuman primate study (32). In humans, RTS,S/AS01 has been shown to induce high titers of CS-specific antibodies and higher numbers of Th1 CD4⁺ T cells than those generated by RTS,S/AS02 but no CS-specific CD8⁺ T cells (22). However, RTS,S/AS01 was able to afford 50% protection against malaria infection in adults upon sporozoite challenge (22) and 53% efficacy against disease in children between the ages of 5 and 17 months (5). These results, albeit far from being optimal, supported the progress of RTS,S/AS01 to phase III clinical trial testing in early 2009, and these trials enrolled children at the age of 6 weeks to 17 months at multiple sites in sub-Saharan Africa. It is anticipated that RTS,S/AS01 will be the first licensed malaria vaccine, provided its efficacy is confirmed in the phase III trial.Although our understanding about the correlate(s) of protection for malaria is limited, there is ample evidence that CS protein-specific antibodies, CD8⁺ T cells, and Th1 cytokines, particularly IFN-γ, play a central role in controlling the preerythrocytic and early liver stages of malaria (19, 20, 35, 47, 57). Adenovirus (Ad) vectors are particularly suited for induction of IFN-γ-producing CD8⁺ T cells required to combat malaria infection (33, 43), due to intracellular expression of a transgene inserted in the vector genome and efficient routing of expressed protein toward the class I presentation pathway. Recently, we demonstrated the advantage of utilizing two recombinant adenoviral vectors derived from distinct serotypes, Ad type 35 CS (Ad35.CS) and Ad5.CS, in a heterologous prime-boost regimen in mice and nonhuman primates (46). This heterologous prime-boost regimen elicited a high-level CS-specific IFN-γ⁺ T-cell response as well CS-specific Th1-type antibodies able to bind malaria parasites. Though the Ad5-based vectors are very potent vaccines, the high prevalence of preexisting immunity toward Ad5 in the human population hampers their immunogenicity and clinical utility (8, 38). The low seroprevalence of Ad5-neutralizing antibodies in infants of 6 months to 1.5 years of age offers an opportunity to administer Ad5-based vaccines to this population without antibodies interfering and neutralizing the vaccine efficacy (42); however, acceptance of this approach by regulatory agencies may remain difficult to obtain. Novel vaccine vectors based on rare low-seroprevalence Ad serotypes have an advantage of not being hampered by anti-Ad5 immunity while inducing a strong immune response (1, 4, 28, 33, 41).Within this study, we evaluated whether vaccination with Ad35.CS and Ad26.CS can enhance the CS-specific immune response induced by a yeast-produced full-length CS protein vaccine and, in particular, whether the combined vaccination sustainably potentiates the Th1 responses necessary for protection against malaria. The Ad35.CS vaccine candidate is currently being evaluated in a phase 1 clinical study, in partnership with the National Institute of Allergy and Infectious Diseases, and so far, it has been shown to be safe. Candidate Ad35-based vaccines against other infectious diseases, i.e., tuberculosis and HIV infection, have also been clinically evaluated and demonstrated to be safe and immunogenic. Recently, an Ad26 vector vaccine against HIV was also clinically assessed in a phase I study, which showed that a 3-dose regimen of this HIV candidate vaccine is safe and immunogenic. Based upon encouraging results, the clinical testing of the combination of Ad35- and Ad26-based vaccines against malaria and HIV is in preparation.     

Distinct Th1- and Th2-Type prenatal cytokine responses to Plasmodium falciparum erythrocyte invasion ligands

Prenatal immunity to Plasmodium falciparum merozoite proteins involved in erythrocyte invasion may contribute to the partial protection against malaria that is acquired during infancy in areas of stable malaria transmission. We examined newborn and maternal cytokine and antibody responses to merozoite surface protein-1 (MSP-1), ribosomal phosphoprotein P0 (PfP0), and region II of erythrocyte binding antigen-175 (EBA-175) in infant-mother pairs in Kenya. Overall, 82 of 167 (50%), 106 of 176 (60%), and 38 of 84 (45%) cord blood lymphocytes (CBL) from newborns produced one or more cytokines in response to MSP-1, PfP0, and EBA-175, respectively. Newborns of primigravid and/or malaria-infected women were more likely to have antigen-responsive CBL than were newborns of multigravid and/or uninfected women at delivery. Newborn cytokine responses did not match those of their mothers and fell into three distinct categories, Th1 (21 of 55 CBL donors produced only gamma interferon and/or interleukin 2 [IL-2]), Th2 (21 of 55 produced only IL-5 and/or IL-13), and mixed Th1/Th2 (13 of 55). Newborns produced more IL-10 than adults. High and low levels of cord blood IL-12 p70 production induced by anti-CD40 activation were associated with malaria-specific Th1 and Th2 responses, respectively. Antigen-responsive CBL in some newborns were detected only after depletion of IL-10-secreting CD8 cells with enrichment for CD4 cells. These data indicate that prenatal sensitization to blood-stage Plasmodium falciparum occurs frequently in areas where malaria is holoendemic. Modulation of this immunity, possibly by maternal parity and malaria, may affect the acquisition of protective immunity against malaria during infancy.     

NKT细胞在CFA促进的Th1型免疫应答中的作用

为探索CFA促进小鼠对蛋白质抗原产生Th1介导的特异性免疫应答的机制 ,我们用OVA +CFA和OVA +IFA免疫C5 7BL/6小鼠 ,并于第 3天、第 8天后用MACS +FACS法分离引流淋巴结中NKT细胞 ,在体外经CD3单抗刺激 2d后测定其分泌的细胞因子数量及格局。同时于免疫后第 8天分离引流淋巴结抗原特异性T细胞 ,测定其分泌细胞因子的格局 ;并于再次免疫后 2周检测小鼠血清抗体类型。ELISA结果显示 ,与OVA +IFA组相比 ,OVA +CFA免疫小鼠引流淋巴结NKT细胞和抗原特异性T细胞分泌IFN γ的能力均显著升高 (P <0 0 5 ) ,且血清抗体类型以IgG2a为主。表明CFA促进抗原特异性Th0细胞极化为Th1细胞可能是通过激活NKT细胞使之在免疫应答局部产生大量的IFN γ而实现的     

Role of Macrophage Migration Inhibitory Factor in the Th2 Immune Response to Epicutaneous Sensitization

We examined the role of macrophage migration inhibitory factor (MIF) in the generation of the Th2 response using MIF-deficient mice in a model of epicutaneous sensitization to ovalbumin. Lymph node cells from sensitized MIF-deficient mice produce lower levels of Th2 cytokines after antigen challenge when compared to their wild-type counterparts. Sensitized mice lacking MIF show less pulmonary inflammation after intranasal antigen exposure. Mice deficient in CD74, the MIF receptor, also are unable to generate an inflammatory response to epicutaneous sensitization. Examination of the elicitation phase of the atopic response using DO11.10 OVA TCR transgenic animals shows that T cell proliferation and IL-2 production are strongly impaired in MIF-deficient T cells. This defect is most profound when both T cells and antigen-presenting cells are lacking MIF. These data suggest that MIF is crucial both for the sensitization and the elicitation phases of a Th2-type immune response in allergic disease.     

Th1/Th2类细胞因子在被动型Heymann肾炎发病中的作用

本文动态观测了被动型Ｈｅｙｍａｎｎ肾炎（ＰＨＮ）发病各期的Ｔｈ１类细胞因子（ＩＬ ２,ＩＦＮ γ）和Ｔｈ２类细胞因子（ＩＬ ４）的变化。结果表明在注射兔抗肾近曲小管刷状缘抗体（Ｔｕｂ Ａｂ）７ｄ后即开始出现蛋白尿,同时ＩＬ ２,ＩＦＮ γ较正常对照诱生水平降低（Ｐ＜００５）,而ＩＬ ４诱生水平开始升高;在注射Ｔｕｂ Ａｂ第１４天时,出现大量蛋白尿,此时ＩＬ ４进一步升高,与正常对照及注射第７天时ＩＬ ４水平均存在统计学差异,ＩＬ ４与蛋白尿定量之间并有一定相关性;第２８天时蛋白尿开始降低,ＩＬ ２,ＩＦＮ γ比第７天和第１４天时略有升高,此时ＩＬ ４水平与正常对照无差异。表明ＩＬ ２,ＩＦＮ γ的降低和ＩＬ ４升高（即Ｔｈ１／Ｔｈ２的失衡）与本病存在一定关系。     

Antibodies to a Single,Conserved Epitope in Anopheles APN1 Inhibit Universal Transmission of Plasmodium falciparum and Plasmodium vivax Malaria

Malaria transmission-blocking vaccines (TBVs) represent a promising approach for the elimination and eradication of this disease. AnAPN1 is a lead TBV candidate that targets a surface antigen on the midgut of the obligate vector of the Plasmodium parasite, the Anopheles mosquito. In this study, we demonstrated that antibodies targeting AnAPN1 block transmission of Plasmodium falciparum and Plasmodium vivax across distantly related anopheline species in countries to which malaria is endemic. Using a biochemical and immunological approach, we determined that the mechanism of action for this phenomenon stems from antibody recognition of a single protective epitope on AnAPN1, which we found to be immunogenic in murine and nonhuman primate models and highly conserved among anophelines. These data indicate that AnAPN1 meets the established target product profile for TBVs and suggest a potential key role for an AnAPN1-based panmalaria TBV in the effort to eradicate malaria.     

Malaria caused by multi-resistant Plasmodium falciparum contracted in Tanzania

In a severe case of malaria, the chemosensitivity of a Plasmodium falciparum strain from a traveller to Tanzania who underwent chemoprophylaxis treatment with chloroquine (600 mg weekly) was evaluated in vitro. In the 28 hours maturation assay and a 72 hours proliferation assay, the strain proved to be highly resistant to chloroquine and to have a reduced sensibility to the sulfadoxin - pyrimethamin association.     

Infective Dose Modulates the Balance between Th1- and Th2-Regulated Immune Responses during Blood-Stage Malaria Infection

Plasmodium chabaudi infection of mice provides an excellent model for examining acquired immunity to the blood-borne stage of malaria infection. CD4⁺ T-cell receptor (TCR) αβ-bearing T lymphocytes play a critical role in mediating protection, ascribed to both T helper (Th) 1 and Th2 subsets. One factor that may influence the Th1/Th2 cell balance is infective dose. In this study, we found that the size of the infective dose of P. chabaudi , and thus the level of antigen presented to the immune system, correlated with the balance of responder CD4⁺ T-cell phenotypes. Increasing the infective dose in a resistant mouse strain enhanced the Th1 cytokine (interferon-γ; IFN-γ) response and reduced the Th2 cytokine (interleukin-4; IL-4) response. In contrast, increasing the infective dose in a susceptible mouse strain led to a prominent and accelerated up-regulation of IL-4 production. These data show that the dose of antigen can significantly affect the balance between Th1- and Th2-mediated immune functions during infection of the mammalian host with blood-stage malaria parasites. This demonstration that parasite numbers may modulate CD4⁺ T-cell regulation has novel implications for the successful implementation of antimalarial vaccination and chemotherapeutic strategies.     

The Role of Innate Cells Is Coupled to a Th1-Polarized Immune Response in Pediatric Nonalcoholic Steatohepatitis

Background

Nonalcoholic steatohepatitis (NASH) is a chronic inflammatory liver disease influenced by risk factors for the metabolic syndrome. In adult patients, NASH is associated with an altered phenotype and functionality of peripheral immune cells, the recruitment of leukocytes and intrahepatic activation, and an exacerbated production of reactive oxygen species (ROS) and cytokines. It remains unclear if the previously described differences between pediatric and adult nonalcoholic fatty liver diseases also reflect differences in their pathogenesis.

Aims

We aimed to investigate the phenotype and functionality of circulating immune cells and the potential contribution of liver infiltrating leukocytes to the immunological imbalance in pediatric NASH.

Results

By a real-time PCR-based analysis of cytokines and immunohistochemical staining of liver biopsies, we demonstrated that the hepatic microenvironment is dominated by interferon-gamma (IFN-γ) but not interleukin-4 and is infiltrated by a higher number of CD8⁺ cells in pediatric NASH. The number of infiltrating neutrophils positively correlated with ROS generation by peripheral polymorphonuclear cells. By a flow cytometric analysis of peripheral blood lymphocytes, a distinctive increase in CD8⁺ CD45RO and CD8⁺ CD45RA subpopulations and an increased production of IFN-γ by CD4⁺ and CD8⁺ cells were shown. The production of ROS following PMA stimulation was augmented in circulating neutrophils but not in monocytes.

Conclusion

In sum, the distinctive phenotype and functionality of infiltrating and circulating cells suggest that the role of innate cells is coupled to a Th1-polarized immune response in pediatric NASH.     

Relationship between the Degree of Cardiovascular Adaptation and Th1/Th2 Polarization of Immune Response

The main parameters of humoral immunity during medium intensity exercise were studied in oarsmen with high and low cardiovascular adaptation. A relationship between high cardiovascular adaptation to exercise and immune response polarization by the Th2 mechanism was demonstrated. Increased production of IL-10 in response to physical stress plays a key role in this relationship. Translated from Byulleten’ Eksperimental’noi Biologii i Meditsiny, Vol. 146, No. 10, pp. 442–445, October, 2008     

Anemia and Interleukin-10, Tumor Necrosis Factor Alpha, and Erythropoietin Levels among Children with Acute, Uncomplicated Plasmodium falciparum Malaria

Anemia is an important complication of malaria, and its pathogenesis is not well understood. To gain insight into potential age-related relationships between tumor necrosis factor alpha (TNF-α), interleukin 10 (IL-10), erythropoietin, and anemia during acute malaria, 273 children of ages 12 to 120 months presenting with acute, uncomplicated malaria in Kampala, Uganda, were monitored at enrollment and 3 and 7 days later. Younger children had higher geometric mean erythropoietin, TNF-α, and α₁-acid glycoprotein (AGP) concentrations than older children. Univariate regression analysis revealed that age, log₁₀ erythropoietin levels, IL-10/TNF-α ratio, and AGP levels were each significantly associated with hemoglobin levels at baseline. Hemoglobin concentrations were inversely correlated with the log₁₀ erythropoietin level at all three visits. For the older age groups, higher levels of TNF-α were significantly associated with higher IL-10 levels at all three visits, but this relationship was significant only at baseline for younger children. These data suggest that younger children do not maintain IL-10 production in response to the inflammatory process, and this mechanism may contribute to the more severe anemia found in younger children. Acute malaria is an illness whose incidence and severity are largely age dependent. Further studies are needed to understand the relationships between age-related immune responses to malaria and their role in the pathogenesis of malarial anemia.     

Th1、Th2、Th17型细胞因子与糖尿病肾病相关性的研究

糖尿病肾病(diabetic Nephropathy,DN)是导致终末期肾脏病(end-stage renal disease,ESRD)的最主要病因,因此,早期诊断和治疗是糖尿病肾病的诊治要点。但目前糖尿病肾病的确切发病机制尚未完全明确,糖尿病肾病的发生发展与血流动力学改变和代谢的紊乱、氧化应激和炎症等多种因素有关,而细胞因子在2型糖尿病及其相关肾脏并发症的病因、发病机制中也起着重要的作用,各种细胞因子的识别将为糖尿病肾病的诊治提供新的潜在治疗靶点。文章就Th1、Th2、Th17型细胞因子与DN相关性的研究作了综述。     

Multiple Adhesive Phenotypes Linked to Rosetting Binding of Erythrocytes in Plasmodium falciparum Malaria

The cerebral form of severe malaria is associated with excessive intravascular sequestration of Plasmodium falciparum-infected erythrocytes (PRBC). Retention and accumulation of PRBC may lead to occlusion of brain microvessels and direct the triggering of acute pathologic changes. Here we report that by selection, cloning, and subcloning, we have identified rare P. falciparum parasites expressing a pan-adhesive phenotype linked to erythrocyte rosetting, a previously identified correlate of cerebral malaria. Rosetting PRBC not only bound uninfected erythrocytes but also formed autoagglutinates, adhered to endothelial cells, and bound to CD36, immunoglobulins, and the blood group A antigen. The linkage of rosetting, autoagglutination, and cytoadherence involved the coexpression on a single PRBC of ligands with multiple specificities and the binding to two or more receptors on erythrocytes and to at least two other cell adhesion molecules, including a new endothelial cell receptor for P. falciparum-infected erythrocytes. Limited proteolysis that differentially cleaved the rosetting ligand PfEMP1 from the PRBC surface abrogated all the binding phenotypes of these parasites, implicating the variant antigen PfEMP1 as a carrier of multiple ligand specificities. The results encourage the further study of pan-adhesion as a potentially important parasite phenotype in the pathogenesis of severe P. falciparum malaria.     

Evaluation of the Sensitivity of a pLDH-Based and an Aldolase-Based Rapid Diagnostic Test for Diagnosis of Uncomplicated and Severe Malaria Caused by PCR-Confirmed Plasmodium knowlesi,Plasmodium falciparum,and Plasmodium vivax

Plasmodium knowlesi can cause severe and fatal human malaria in Southeast Asia. Rapid diagnosis of all Plasmodium species is essential for initiation of effective treatment. Rapid diagnostic tests (RDTs) are sensitive for detection of uncomplicated and severe falciparum malaria but have not been systematically evaluated in knowlesi malaria. At a tertiary referral hospital in Sabah, Malaysia, we prospectively evaluated the sensitivity of two combination RDTs for the diagnosis of uncomplicated and severe malaria from all three potentially fatal Plasmodium species, using a pan-Plasmodium lactate dehydrogenase (pLDH)-P. falciparum histidine-rich protein 2 (PfHRP2) RDT (First Response) and a pan-Plasmodium aldolase-PfHRP2 RDT (ParaHIT). Among 293 hospitalized adults with PCR-confirmed Plasmodium monoinfection, the sensitivity of the pLDH component of the pLDH-PfHRP2 RDT was 74% (95/129; 95% confidence interval [CI], 65 to 80%), 91% (110/121; 95% CI, 84 to 95%), and 95% (41/43; 95% CI, 85 to 99%) for PCR-confirmed P. knowlesi, P. falciparum, and P. vivax infections, respectively, and 88% (30/34; 95% CI, 73 to 95%), 90% (38/42; 95% CI, 78 to 96%), and 100% (12/12; 95% CI, 76 to 100%) among patients tested before antimalarial treatment was begun. Sensitivity in severe malaria was 95% (36/38; 95% CI, 83 to 99), 100% (13/13; 95% CI, 77 to 100), and 100% (7/7; 95% CI, 65 to 100%), respectively. The aldolase component of the aldolase-PfHRP2 RDT performed poorly in all Plasmodium species. The pLDH-based RDT was highly sensitive for the diagnosis of severe malaria from all species; however, neither the pLDH- nor aldolase-based RDT demonstrated sufficiently high overall sensitivity for P. knowlesi. More sensitive RDTs are needed in regions of P. knowlesi endemicity.     

催乳素与系统性红斑狼疮Th1/Th2型细胞因子分泌异常

系统性红斑狼疮(SLE)是多种因素相互作用引起的自身免疫性疾病,其发病机制复杂。近年来,随着对神经内分泌免疫网络的研究和认识日渐增多加深,发现催乳素(PRL)与多种自身免疫性疾病相关,如SLE、类风湿性关节炎、干燥综合征等,其中与SLE的关系最引人注目,但具体作用机制还未明确。PRL作为一个自分泌/旁分泌的细胞因子,在细胞因子网络中起着重要的作用,影响其他细胞因子的产生。分别从SLE与Th1/Th2型细胞因子分泌异常、PRL与Th1/Th2细胞因子分泌异常、SLE与PRL的关系等作简要的分析非常重要。