SUMMARY Intravascular Schistosoma mansoni worms seem to take up immunoglobulins from blood by surface Fc‐receptors, but the process whereby bound immunoglobulins are processed by the parasite is poorly understood. We here present morphological data suggesting that two distinct main processes are involved: Host immunoglobulins were seen at two distinct locations in the parasite: in the frontal part of the enteric tube, the oesophagus, and as a fine granular staining at the surface and in the subtegumental region. The latter staining pattern corresponds to host immunoglobulin localization in discrete organelle‐like aggregates tentatively identified as ‘discoid or elongate bodies’ at the ultrastructural level using immunogold staining. Immunoglobulin uptake by intravascular worms was also demonstrated in vivo after passive administration of 125 I‐labelled rabbit and mouse immunoglobulins. Radiolabelled immunoglobulins were taken up by the worms and shown to localize as fine strands running perpendicular to the parasite surface. Our results suggest that intravascular schistosomes take up host immunoglobulins both as part of their enteric digestion and by a surface Fc‐receptor‐mediated mechanism, involving transport and processing within organelles, ‘elongate bodies’. Immunoglobulins taken up by intravascular schistosomes form a distinct organelle‐like granules, which seem to be processed within the excretory system of the parasite.
The most frequent form of hemolytic-uremic syndrome (HUS) is associated with infections caused by Shiga-like toxin-producing Enterohaemorrhagic Escherichia coli (STEC). In rarer cases HUS can be triggered by Streptococcus pneumoniae. While production of Shiga-like toxins explains STEC-HUS, the mechanisms of pneumococcal HUS are less well known. S. pneumoniae produces neuraminidases with activity against cell surface sialic acids that are critical for factor H-mediated complement regulation on cells and platelets. The aim of this study was to find out whether S. pneumoniae neuraminidase NanA could trigger complement activation and hemolysis in whole blood. We studied clinical S. pneumoniae isolates and two laboratory strains, a wild-type strain expressing NanA, and a NanA deletion mutant for their ability to remove sialic acids from various human cells and platelets. Red blood cell lysis and activation of complement was measured ex vivo by incubating whole blood with bacterial culture supernatants. We show here that NanA expressing S. pneumoniae strains and isolates are able to remove sialic acids from cells, and platelets. Removal of sialic acids by NanA increased complement activity in whole blood, while absence of NanA blocked complement triggering and hemolytic activity indicating that removal of sialic acids by NanA could potentially trigger pHUS.
The alternative pathway of complement is an important part of the innate immunity response against foreign particles invading the human body. To avoid damage to host cells, it needs to be efficiently down-regulated by plasma factor H (FH) as exemplified by various diseases caused by mutations in its domains 19-20 (FH19-20) and 5-7 (FH5-7). These regions are also the main interaction sites for microbial pathogens that bind host FH to evade complement attack. We previously showed that inhibition of FH binding by a recombinant FH5-7 construct impairs survival of FH binding pathogens in human blood. In this study we found that upon exposure to full blood, the addition of FH5-7 reduces survival of, surprisingly, also those microbes that are not able to bind FH. This effect was mediated by inhibition of complement regulation and subsequently enhanced neutrophil phagocytosis by FH5-7. We found that although FH5-7 does not reduce complement regulation in the actual fluid phase of plasma, it reduces regulation on HDL particles in plasma. Using affinity chromatography and mass spectrometry we revealed that FH interacts with serum apolipoprotein E (apoE) via FH5-7 domains. Furthermore, binding of FH5-7 to HDL was dependent on the concentration of apoE on the HDL particles. These findings explain why the addition of FH5-7 to plasma leads to excessive complement activation and phagocytosis of microbes in full anticoagulated blood. In conclusion, our data show how FH interacts with apoE molecules via domains 5-7 and regulates alternative pathway activation on plasma HDL particles.
Staphylococcus aureus is a major human pathogen causing more than a tenth of all septicemia cases and often superficial and deep infections in various tissues. One of the immune evasion strategies of S. aureus is to secrete proteins that bind to the central complement opsonin C3b. One of these, extracellular complement binding protein (Ecb), is known to interfere directly with functions of C3b. Because C3b is also the target of the physiological plasma complement regulator, factor H (FH), we studied the effect of Ecb on the complement regulatory functions of FH. We show that Ecb enhances acquisition of FH from serum onto staphylococcal surfaces. Ecb and FH enhance mutual binding to C3b and also the function of each other in downregulating complement activation. Both Ecb and the C-terminal domains 19-20 of FH bind to the C3d part of C3b. We show that the mutual enhancing effect of Ecb and FH on binding to C3b depends on binding of the FH domain 19 to the C3d part of C3b next to the binding site of Ecb on C3d. Our results show that Ecb, FH, and C3b form a tripartite complex. Upon exposure of serum-sensitive Haemophilus influenzae to human serum, Ecb protected the bacteria, and this effect was enhanced by the addition of the C-terminal domains 19-20 of FH. This finding indicates that the tripartite complex formation could give additional protection to bacteria and that S. aureus is thereby able to use host FH and bacterial Ecb in a concerted action to eliminate C3b at the site of infection.
Background: Etanercept (ETN) is the most used TNF blocker in children with JIA. There is still limited real-life data of etanercept concentrations in children, especially in association with dosing. Objectives: The aim of the study was to investigate association between ETN dosing and serum trough concentration in children with non-systemic JIA. Methods: We conducted a multicenter retrospective study of 180 Finnish JIA patients (Table 1) receiving ETN either as monotherapy or in combination with one or more DMARDs (Table 2). Prior biologicals were used by 17 % of the patients. Patients were divided into two groups, ETN started before or after one year of diagnosis (Figure 1). ETN concentration samples (collected 2014-2017) were analyzed using validated enzyme-linked immunosorbent assay (ELISA) in Sanquin Diagnostics, Amsterdam, the Netherlands. Results: Demographics at etanercept start and diagnoses are shown in Table 1. Duration of the treatment with ETN, ETN doses, concentrations and concomitant medications at the time of concentration measurement are shown in Table 2. Association between ETN dose and concentration is shown in Figure 1. Those who started medication early (< 1 year from diagnosis) were younger than those who started later (Table 1) and association between ETN dose and concentration was more obvious (Figure 1). Conclusion: There was an association between etanercept dose used and serum trough concentration and it was more evident when medication was started early after diagnosis, when the patients were younger and BSA lower. References: [1]Kneepkens EL et al. Lower etanercept levels are associated with high disease activity in ankylosing spondylitis patients at 24 weeks of follow-up. Ann Rheum Dis 2015;74(10):1825-9. [2]Bader-Meunier B et al. Etanercept concentration and immunogenicity do not influence the response to Etanercept in patients with juvenile idiopathic arthritis. Semin Arthritis Rheum 2019;48(6):1014-1018. Disclosure of Interests: None declared
