Browsing by Subject "complement"

Sort by: Order: Results:

Now showing items 1-10 of 10
  • Lokki, A. Inkeri; Kaartokallio, Tea; Holmberg, Ville; Onkamo, Paivi; Koskinen, Lotta L. E.; Saavalainen, Paivi; Heinonen, Seppo; Kajantie, Eero; Kere, Juha; Kivinen, Katja; Pouta, Anneli; Villa, Pia M.; Hiltunen, Leena; Laivuori, Hannele; Meri, Seppo (2017)
    Preeclampsia (PE) is a common vascular disease of pregnancy with genetic predisposition. Dysregulation of the complement system has been implicated, but molecular mechanisms are incompletely understood. In this study, we determined the potential linkage of severe PE to the most central complement gene, C3. Three cohorts of Finnish patients and controls were recruited for a genetic case-control study. Participants were genotyped using Sequenom genotyping and Sanger sequencing. Initially, we studied 259 Finnish patients with severe PE and 426 controls from the Southern Finland PE and the Finnish population-based PE cohorts. We used a custom-made single nucleotide polymorphism (SNP) genotyping assay consisting of 98 SNPs in 18 genes that encode components of the complement system. Following the primary screening, C3 was selected as the candidate gene and consequently Sanger sequenced. Fourteen SNPs from C3 were also genotyped by a Sequenom panel in 960 patients with severe PE and 705 controls, including already sequenced individuals. Three of the 43 SNPs observed within C3 were associated with severe PE: rs2287845 (p = 0.038, OR = 1.158), rs366510 (p = 0.039, OR = 1.158), and rs2287848 (p = 0.041, OR = 1.155). We also discovered 16 SNP haplotypes with extreme linkage disequilibrium in the middle of the gene with a protective (p = 0.044, OR = 0.628) or a predisposing (p = 0.011, OR = 2.110) effect to severe PE depending on the allele combination. Genetic variants associated with PE are located in key domains of C3 and could thereby influence the function of C3. This is, as far as we are aware, the first candidate gene in the complement system with an association to a clinically relevant PE subphenotype, severe PE. The result highlights a potential role for the complement system in the pathogenesis of PE and may help in defining prognostic and therapeutic subgroups of preeclamptic women.
  • Holopainen, Saila (Helsingfors universitet, 2008)
    Malaria remains one of the major health problems in many tropical countries, especially in sub-Saharan Africa. Among the most characteristic features of the malaria pathogens, protozoan parasites of the genus Plasmodium, is their ability to evade the immune defences of the host for extended periods of time. The complement system (C) is an essential part of the innate system in the first line of defense. It consists of over 30 soluble or membrane-bound components. C can be activated through three different (the classical, the lectin and the alternative) pathways, and the activation is tightly regulated. All three pathways converge at the C3 level and activation continues through the terminal pathway. C functions include lysis of microbes, opsonization, attraction and activation of leucocytes and enhancement of the inflammatory response. In the present study the aim was to look into whether Plasmodium falciparum (Pf) interferes with the complement at the level of C3 by accelerating C3b inactivation and thus inhibit the amplification of the C cascade. Considering the characteristics of Pf infection it is obvious that the plasmodia must somehow avoid complement attack. Flow cytometric analysis (FACS), enzyme-linked immunosorbent assays (ELISA), immunoblotting assays and matrix assisted laser desorption/ionization (MALDI) were used to determine if Pf evade C attack by acquisition of the host C inhibitors, factor H (FH) and C4b binding protein (C4bp), from serum. FH is the major regulator of the alternative-pathway while C4bp is an inhibitor of the classical-pathway. We also studied binding of complement components, especially C3, to Pf cells. In our studies, there appeared to be an elevated binding of FH to Pf parasitized erythrocytes in FACS. In immunoblotting assays, a putative C3-binding merozoite-stage Pf protein was observed. Previously, it has been suggested that Plasmodium spp. merozoites adsorb C3 fragments to their surface to gain entry into erythrocytes via CR1-receptor. No binding of C4bp was detected. Further studies are required to reveal the complement resistance mechanisms of Pf. Elucidation of Pf-C interactions will be of great importance for our understanding of the principles of Plasmodium immunoevasion that affect directly the virulence of the microbe. By identifying factors whereby Pf evades C, it is possible to understand better how the microbe causes disease and, ultimately, how this could be prevented.
  • Nissilä, Eija; Hakala, Pipsa; Leskinen, Katarzyna; Roig, Angela; Syed, Shahan; Van Kessel, Kok P. M.; Metso, Jari; De Haas, Carla J. C.; Saavalainen, Päivi; Meri, Seppo; Chroni, Angeliki; Van Strijp, Jos A. G.; Öörni, Katariina; Jauhiainen, Matti; Jokiranta, T. Sakari; Haapasalo, Karita (2018)
    The alternative pathway (AP) of complement is constantly active in plasma and can easily be activated on self surfaces and trigger local inflammation. Host cells are protected from AP attack by Factor H (FH), the main AP regulator in plasma. Although complement is known to play a role in atherosclerosis, the mechanisms of its contribution are not fully understood. Since FH via its domains 5-7 binds apoliporotein E (apoE) and macrophages produce apoE we examined how FH could be involved in the antiatherogenic effects of apoE. We used blood peripheral monocytes and THP-1 monocyte/macrophage cells which were also loaded with acetylated low-density lipoprotein (LDL) to form foam cells. Binding of FH and apoE on these cells was analyzed by flow cytometry. High-density lipoprotein (HDL)-mediated cholesterol efflux of activated THP-1 cells was measured and transcriptomes of THP-1 cells using mRNA sequencing were determined. We found that binding of FH to human blood monocytes and cholesterol-loaded THP-1 macrophages increased apoE binding to these cells. Preincubation of fluorescent cholesterol labeled THP-1 macrophages in the presence of FH increased cholesterol efflux and cholesterol-loaded macrophages displayed reduced transcription of proinflammatory/proatherogenic factors and increased transcription of anti-inflammatory/anti-atherogenic factors. Further incubation of THP-1 cells with serum reduced C3b/iC3b deposition. Overall, our data indicate that apoE and FH interact with monocytic cells in a concerted action and this interaction reduces complement activation and inflammation in the atherosclerotic lesions. By this way FH may participate in mediating the beneficial effects of apoE in suppressing atherosclerotic lesion progression.
  • Reichhardt, Martin P.; Lundin, Karolina; Lokki, A. Inkeri; Recher, Gaëlle; Vuoristo, Sanna; Katayama, Shintaro; Tapanainen, Juha S.; Kere, Juha; Meri, Seppo; Tuuri, Timo (2019)
    It is essential for early human life that mucosal immunological responses to developing embryos are tightly regulated. An imbalance of the complement system is a common feature of pregnancy complications. We hereby present the first full analysis of the expression and deposition of complement molecules in human pre-implantation embryos. Thus, far, immunological imbalance has been considered in stages of pregnancy following implantation. We here show that complement activation against developing human embryos takes place already at the pre-implantation stage. Using confocal microscopy, we observed deposition of activation products on healthy developing embryos, which highlights the need for strict complement regulation. We show that embryos express complement membrane inhibitors and bind soluble regulators. These findings show that mucosal complement targets human embryos, and indicate potential adverse pregnancy outcomes, if regulation of activation fails. In addition, single-cell RNA sequencing revealed cellular expression of complement activators. This shows that the embryonic cells themselves have the capacity to express and activate C3 and C5. The specific local embryonic expression of complement components, regulators, and deposition of activation products on the surface of embryos suggests that complement has immunoregulatory functions and furthermore may impact cellular homeostasis and differentiation at the earliest stages of life.
  • Kiyuka, Patience Kerubo; Meri, Seppo; Khattab, Ayman (2020)
    The malaria parasite has for long been thought to escape host complement attack as a survival strategy. However, it was only recently that complement evasion mechanisms of the parasite were described. Simultaneously, the role of complement in antibody-mediated naturally acquired and vaccine-induced protection against malaria has also been reported. Such findings should be considered in future vaccine design, given the current need to develop more efficacious vaccines against malaria. Parasite antigens derived from molecules mediating functions crucial for parasite survival, such as complement evasion, or parasite antigens against which antibody responses lead to an efficient complement attack could present new candidates for vaccines. In this review, we discuss recent findings on complement evasion by the malaria parasites and the emerging role of complement in antibody-mediated protection against malaria. We emphasize that immune responses to vaccines based on complement inhibitors should not only induce complement-activating antibodies but also neutralize the escape mechanisms of the parasite.
  • Burwick, Richard M.; Lokki, A. Inkeri; Fleming, Sherry D.; Regal, Jean F. (2021)
  • Sironen, Tarja; Sane, Jussi; Lokki, Marja-Liisa; Meri, Seppo; Andersson, Leif C.; Hautala, Timo; Kauma, Heikki; Vuorinen, Sakari; Rasmuson, Johan; Evander, Magnus; Ahlm, Clas; Vaheri, Antti (2017)
    The case-fatality rate of hantavirus disease depends strongly on the causative hantavirus, ranging from 0.1% to 40%. However, the pathogenesis is not fully understood, and at present no licensed therapies exist. We describe fatal cases caused by Puumala hantavirus indicating involvement of complement activation and vascular leakage.
  • O'Flynn, Joseph; Kotimaa, Juha; Faber-Krol, Ria; Koekkoek, Karin; Klar-Mohamad, Ngaisah; Koudijs, Angela; Schwaeble, Wilhelm J.; Stover, Cordula; Daha, Mohamed R.; van Kooten, Cees (2018)
    Properdin is the only known positive regulator of complement activation by stabilizing the alternative pathway convertase through C3 binding, thus prolonging its half-life. Recent in vitro studies suggest that properdin may act as a specific pattern recognition molecule. To better understand the role of properdin in vivo, we used an experimental model of acute anti-glomerular basement membrane disease with wild-type, C3-and properdin knockout mice. The model exhibited severe proteinuria, acute neutrophil infiltration and activation, classical and alternative pathway activation, and progressive glomerular deposition of properdin, C3 and C9. Although the acute renal injury was likely due to acute neutrophil activation, we found properdin deposition in C3-knockout mice that was not associated with IgG. Thus, properdin may deposit in injured tissues in vivo independent of its main ligand C3.
  • Lokki, A. Inkeri; Heikkinen-Eloranta, Jenni K.; Laivuori, Hannele (2018)
    Pregnancy is an immunological challenge to the mother. The fetal tissues including the placenta must be protected from activation of the maternal immune system. On the other hand, the placental tissue sheds into the maternal circulation and must be adequately identified and phagocytized by the maternal immune system. During a healthy pregnancy, numerous immunosuppressive processes take place that allow the allograft fetus to thrive under exposure to humoral and cellular components of the maternal immune system. Breakdown of immune tolerance may result in sterile inflammation and cause adverse pregnancy outcomes such as preeclampsia, a vascular disease of the pregnancy with unpredictable course and symptoms from several organs. Immunological incompatibility between mother and fetus is strongly indicated in preeclampsia. Recently, genetic factors linking immunological pathways to predisposition to preeclampsia have been identified. In this mini-review genetic variation in immunological factors are discussed in the context of preeclampsia. Specifically, we explore immunogenetic and immunomodulary mechanisms contributing to loss of tolerance, inflammation, and autoimmunity in preeclampsia.