Despite inducing a strong host cellular and humoral immune response, the helminth Echinococcus granulosus is a highly successful parasite that develops, progresses, and ultimately causes chronic disease. Although surgery remains the preferred therapeutic option, pharmacological research now envisages antihelminthic strategies. To understand the mechanisms that E. granulosus uses to escape host immunosurveillance and promote chronic infection, we investigated how two hydatid cyst components, purified antigen B (AgB) and sheep hydatid fluid (SHF), act on host dendritic cell (DC) differentiation from monocyte precursors and how they influence maturation of DC that have already differentiated. We evaluated the immunomodulatory potential of these antigens by performing immunochemical and cytofluorimetric analyses of monocyte-derived DCs from healthy human donors. During monocyte differentiation, AgB and SHF downmodulated CD1a expression and upregulated CD86 expression. Compared with immature DCs differentiated in medium alone (iDCs), AgB-and SHF-differentiated cells stimulated with lipopolysaccharide included a significantly lower percentage of CD83؉ cells (P < 10 ؊4 ) and had weaker costimulatory molecule expression. When stimulated with AgB and SHF, iDCs matured and primed lymphocytes towards the Th2 response typical of E. granulosus infection. SHF and particularly AgB reduced the production of interleukin-12p70 (IL-12p70) and tumor necrosis factor alpha in lipopolysaccharide-stimulated iDCs. Anti-IL-10 antibodies increased the levels of IL-12p70 secretion in AgB-and SHF-matured DCs. AgB and SHF induced interleukin-1 receptor-associated kinase phosphorylation and activated nuclear factor-B, suggesting that Toll-like receptors could participate in E. granulosus-stimulated DC maturation. These results suggest that E. granulosus escapes host immunosurveillance in two ways: by interfering with monocyte differentiation and by modulating DC maturation.

The larval stage of Echinococcus granulosus causes cystic echinococcosis, a neglected infectious disease that constitutes a major public health problem in developing countries. Despite being under constant barrage by the immune system, E. granulosus modulates antiparasite immune responses and persists in the human hosts with detectable humoral and cellular responses against the parasite. In vitro and in vivo immunological approaches, together with molecular biology and immunoproteomic technologies, provided us exciting insights into the mechanisms involved in the initiation of E. granulosus infection and the consequent induction and regulation of the immune response. Although the last decade has clarified many aspects of host-parasite relationship in human cystic echinococcosis, establishing the full mechanisms that cause the disease requires more studies. Here, we review some of the recent developments and discuss new avenues in this evolving story of E. granulosus infection in man.

No abstract

The human plasma protein ␤ 2 -glycoprotein I (␤ 2 -GPI) is the most common target for antiphospholipid antibodies associated with thrombotic events in chronic disorders related to endothelial cell dysfunction. Crucial information is needed to clarify why this self-abundant protein is targeted by autoimmune responses. In this study, we investigated whether oxidative modification of ␤ 2 -GPI, either spontaneous in culture wells or induced by treatment with H 2 O 2 , renders this selfprotein able to activate immature monocyte-derived dendritic cells (DCs) from healthy human donors. Oxidized ␤ 2 -GPI caused DCs to mature so that CD83 appeared and CD80, CD86, human leukocyte antigen-D region related (HLA-DR), and CD40 increased. The interaction between oxidized ␤ 2 -GPI and DCs specifically stimulated these cells to secrete interleukin 12 (IL-12), IL-1␤, IL-6, IL-8, tumor necrosis factor ␣ (TNF-␣), and IL-10. Oxidized ␤ 2 -GPI-stimulated DCs had increased allostimulatory ability and primed naive T lymphocytes, thus inducing T helper 1 (Th1) polarization. The interaction between oxidized ␤ 2 -GPI and DCs involved interleukin-1 receptor associated kinase (IRAK) phosphorylation and nuclear factor B (NFB) activation. Pretreatment of ␤ 2 -GPI with the antioxidant ␣-tocopherol prevented DC maturation. These findings show that human oxidized ␤ 2 -GPI, probably by interacting with a member of the Toll-like receptor (TLR) family, causes DCs to mature. Because this key ␤ 2 -GPI function requires oxidative modification, in several chronic disorders related to endothelial cell dysfunction oxidative stress might trigger the "autoimmune spiral. Introduction␤ 2 -glycoprotein I (␤ 2 -GPI), a human plasma protein that binds to negatively charged phospholipids, is the most common target for antiphospholipid antibodies (aPLs). These autoantibodies are associated with thrombotic events in systemic lupus erythematosus 1 and primary antiphospholipid antibody syndrome 2,3 and are proatherogenic. 4 ␤ 2 -GPI also activates lipoprotein lipase, 5 lowers the triglyceride level, 6 and binds to oxidized low-density lipoprotein (LDL) 7 and to nonself particles or apoptotic bodies to allow their clearance. [8][9][10] Another property of ␤ 2 -GPI is its ability to bind at the monocyte surface, thus promoting tissue factor and thereby increasing the risk of thrombotic events. 11 ␤ 2 -GPI can also be expressed on the endothelial cell membrane 12 and on macrophages. 13 Among the several candidate ␤ 2 -GPI cell receptors, annexin II, megaline, and apolipoprotein E receptor 2Ј (apoER2Ј) are involved in activating endothelial cells and platelets. [14][15][16] Recent findings demonstrate that anti-␤ 2 -GPI antibodies react with their antigen probably in association with a member of the Toll-like receptor (TLR)/interleukin 1 (IL-1) receptor family on the endothelial cell surface and directly induce activation. 17,18 Once bound to endothelial cells, ␤ 2 -GPI offers suitable epitopes targeting circulating anti-␤ 2 -GPI antibodies that affect cell functions a...

Cystic echinococcosis (CE) is a widespread chronic endemic helminthic disease caused by infection with metacestodes of the tapeworm Echinococcus granulosus. CE affects humans and has a worldwide prevalence of approximately six million. In this review, we discuss current findings in diagnosis and clinical management of CE and new concepts relating to E. granulosus molecules that directly modulate the host immune responses favouring a strong anti-inflammatory response and perpetuating parasite survival in the host. New insights into the molecular biology of E. granulosus will improve considerably our knowledge of the disease and will provide new potential therapeutic applications to treat or prevent inflammatory immune-mediated disease.

No abstract

To evaluate the diagnostic sensitivity and specificity of immunoelectrophoresis (IEP), indirect haemagglutination (IHA), enzyme-linked immunosorbent assay (ELISA) and immunoblotting (IB), we compared their ability in detecting IgG antibodies to a hydatid fluid fraction (HFF) and to native and recombinant antigen B of Echinococcus granulosus. We tested sera from patients who had cystic echinococcosis (CE) grouped according to their type of cysts (n = 204), from patients with other parasitic diseases (n = 21), lung or liver carcinomas (n = 6) or serous cysts (n = 26) and from healthy controls (n = 90). HFF-IB gave the highest sensitivity (80%) followed by ELISA (72%), IHA (54%) and IEP (31%), respectively. The diagnostic sensitivity significantly (P < 0.01) decreased as cysts matured from type I-II to type VII. Recombinant and native antigen B-IB yielded similar sensitivity (74%). A large number of clinically or surgically confirmed CE patients (20%) resulted negative. In these patients' sera, IB to assess the usefulness of the recombinant E. granulosus elongation factor-1 beta/delta in detecting IgE antibodies yielded 33% of positivity. Our findings underline the need to standardize techniques and antigenic preparations and to improve the performance of immunodiagnosis by characterizing new antigens and detecting distinct immunoglobulin classes.

SUMMARY The relation of interferon‐gamma (IFN‐γ), IL‐4, IL‐10 production and specific IgE, total IgG, IgG subclass expression to the effectiveness of pharmacological treatment in human hydatid disease (Echinococcus granulosus infection) was evaluated in 27 hydatid patients divided into four clinical groups according to their response to albendazole/mebendazole therapy (full, partial, low and non‐responders). After parasite antigen stimulation, peripheral blood mononuclear cells (PBMC) from full responders produced significantly more IFN‐γ (P= 0·038), significantly less IL‐4 (P= 0·001) and less IL‐10 than PBMC from non‐responders. PBMC from partial and low responders produced intermediate cytokine concentrations. ELISA determining immunoglobulin production showed that sera from all non‐responders had IgE and IgG4 antibodies, both regulated by IL‐4. In contrast to IgG4, IgE decreased rapidly in full responders. Full responders also showed the highest percentage of IgG3 reactions. Qualitative analysis of total IgG responses in hydatid patients’ sera determined by immunoblotting showed that binding profiles to hydatid cyst fluid antigen differed in the four groups of treated patients. Non‐responders had the highest percentage of reactions to all subunits of antigens 5 and B, and full responders had the highest percentage of reactions to antigen 5 alone. The high IFN‐γ production associated with a lack of IL‐4 and low IL‐10 production in the full responders, and vice versa the high IL‐4 and IL‐10 production associated with lack of or low IFN‐γ production in the non‐responders implies Th1 cell activation in protective immunity and Th2 cell activation in susceptibility to hydatid disease. IgE may be a useful marker of therapeutic success in hydatid patients with pretreatment specific IgE antibodies. IgG subclass responses and differential immunoglobulin subclass binding pattern to hydatid antigens may also be useful in the immunosurveillance of hydatid disease.