LPS-induced platelet response and rapid shock in mice: contribution of O-antigen region of LPS and involvement of the lectin pathway of the complement system

Blood ◽  
2002 ◽  
Vol 100 (9) ◽  
pp. 3233-3239 ◽  
Author(s):  
Lijuan Zhao ◽  
Yuko Ohtaki ◽  
Kouji Yamaguchi ◽  
Misao Matsushita ◽  
Teizo Fujita ◽  
...  
Keyword(s):  
Complement System ◽  
Serine Proteases ◽  
Lectin Pathway ◽  
Platelet Response ◽  
O Antigen ◽  
Mannose Binding ◽  
Anaphylactoid Shock ◽  
K 12 ◽  
The Complement System ◽  
Binding Lectin

AbstractIntravenous injection of a lipopolysaccharide (LPS) into mice induces a rapid accumulation of platelets in the lung and liver. When degradation of the accumulated platelets occurs, anaphylactoid shock follows rapidly, the severity of the shock paralleling the quantity of platelets accumulated in the lung. Here we examined the contributions made by LPS structure and the complement system to the platelet response to LPS. BALB/c mice were injected with an LPS fromEscherichia coli O8, O9, O111, or K-12, or from recombinant mutants of K-12. The O-regions of the O8 and O9 LPSs consist of a mannose homopolysaccharide (MHP), while that of O111 consists of a heteropolysaccharide (not including mannose), and K-12 LPS lacks an O-region. O111 LPS was devoid of the ability to induce the platelet response or shock, while the ability of K-12 LPS was weak. The 2 recombinant LPSs—each having an O-region (from O8 or O9) linked to K-12 LPS—exhibited activities similar to or stronger than those of their original LPSs. Mannose-binding lectin (MBL) complexed with MBL-associated serine proteases (MASPs) bound strongly to LPSs containing MHP and caused C4 activation. Moreover, the abilities of these LPSs to activate the complement system corresponded well with their abilities to induce the platelet response and rapid shock. These results suggest that the structure of the O-antigen region is important for the platelet response to LPS, and that activation of the lectin pathway of the complement system is involved in this response.

Reduced Mannose-Binding Lectin-Associated Serine Protease (MASP)-1 is Associated with Disturbed Coagulation in Septic Shock

2019 ◽  
Vol 119 (06) ◽  
pp. 952-961 ◽  
Author(s):  
Julie Brogaard Larsen ◽  
Mathies Appel Laursen ◽  
Christine Lodberg Hvas ◽  
Kim Michael Larsen ◽  
Steffen Thiel ◽  
...  
Keyword(s):  
Septic Shock ◽  
Complement System ◽  
Sofa Score ◽  
Thrombin Generation ◽  
Mannose Binding Lectin ◽  
Lectin Pathway ◽  
Complement Factor ◽  
Mannose Binding ◽  
The Complement System ◽  
Binding Lectin

Background Activation of the complement system is part of the dysregulated immune response in sepsis. The mannose-binding lectin-associated serine proteases (MASP)-1 and -2 activate the lectin pathway of the complement system. Besides, these proteins can activate coagulation in vitro. However, the role of the lectin pathway proteins in the development of sepsis-related disseminated intravascular coagulation (DIC) is only sparsely investigated. Aim This article investigates the association between lectin pathway proteins and coagulation disturbances in septic shock patients. Materials and Methods We included 36 septic shock patients from the intensive care unit, Aarhus University Hospital, Denmark. Blood samples were obtained within 24 hours after admission (day 1), and subsequently on day 2 and day 3. Plasma concentrations of mannose-binding lectin (MBL), H-ficolin, M-ficolin, CL-L1, CL-K1, MASP-1, -2 and -3, MBL-associated proteins of 19 and 44 kDa as well as complement factor C3dg were assessed. Standard coagulation parameters, thrombin generation, thrombin–anti-thrombin (TAT) complex and pro-thrombin fragment 1 + 2 were measured. Sequential Organ Failure Assessment (SOFA) score, DIC score and 30-day mortality were assessed. Results Reduced MASP-1 plasma concentration was associated with DIC score ≥5 (p = 0.02), impaired thrombin generation (p = 0.03) and lower plasma TAT complex levels (p = 0.03). No association was found between lectin pathway proteins and SOFA score or 30-day mortality. Conclusion Reduced MASP-1 concentrations were associated with impaired coagulation in septic shock patients. This indicates that increased MASP-1 activation and consumption is associated with the more severe coagulation disturbances in sepsis and points to a possible role for MASP-1 in sepsis-related DIC.

scholarly journals Investigation of Complement-activating Pattern Recognition Molecules and Associated Enzymes as Possible Inflammatory Markers in Oligoarticular and Systemic Juvenile Idiopathic Arthritis

2015 ◽  
Vol 42 (7) ◽  
pp. 1252-1258 ◽  
Author(s):  
Christine Petri ◽  
Steffen Thiel ◽  
Jens Christian Jensenius ◽  
Troels Herlin
Keyword(s):  
Pattern Recognition ◽  
Juvenile Idiopathic Arthritis ◽  
Complement System ◽  
Serine Proteases ◽  
Inflammatory Markers ◽  
Systemic Juvenile Idiopathic Arthritis ◽  
Lectin Pathway ◽  
Paired Samples ◽  
Systemic Jia ◽  
The Complement System

Objective.The complement system plays a crucial role in the pathogenesis of inflammatory processes. The lectin pathway of the complement system is activated through the recognition of pathogens by soluble pattern recognition molecules (PRM), i.e., mannan-binding lectin (MBL), collectin-LK, and the ficolins. PRM are reportedly correlated to disease activity in rheumatoid arthritis (RA). The aim was to evaluate the pathogenic role of PRM in juvenile idiopathic arthritis (JIA).Methods.We measured MBL, M-ficolin, H-ficolin, MBL-associated serine proteases (MASP) 1, MASP-2, MASP-3, and 2 alternative splice products, MBL-associated protein (MAp) 44 and MAp19, in plasma and synovial fluid (SF) of children with persistent oligoarticular (n = 109 in plasma, n = 38 in SF) and systemic JIA (n = 19 in plasma, n = 11 in SF). The concentrations of the proteins were measured by in-house time-resolved immunofluorometric assays.Results.We observed significantly higher levels of M-ficolin, MASP-1, MASP-2, and MASP-3 in plasma and SF from patients with systemic JIA compared with persistent oligoarticular JIA (p < 0.001). In paired samples of plasma and SF from 47 patients with oligoarticular and systemic JIA, we observed higher concentrations in plasma for both subtypes for 7 of the measured proteins while the reverse relationship was observed for MASP-3. M-ficolin and MASP-2 correlated to erythrocyte sedimentation rate, C-reactive protein, white blood cell count, and platelet count (p < 0.001). M-ficolin was in addition related to the number of active joints and inversely related to hemoglobin levels.Conclusion.Our results point to plasma M-ficolin and MASP-2 as inflammatory markers in JIA. The levels of all proteins are higher in plasma than in SF, except for MASP-3, indicating that MASP-3 may be produced locally in joints.

scholarly journals Changes in Mannose-Binding Lectin and Collectin Kidney 1 Levels in Sepsis Patients With and Without Disseminated Intravascular Coagulation

2019 ◽  
Vol 25 ◽  
pp. 107602961882118
Author(s):  
Mineji Hayakawa ◽  
Katsuki Ohtani ◽  
Nobutaka Wakamiya
Keyword(s):  
Disseminated Intravascular Coagulation ◽  
Complement System ◽  
Mannose Binding Lectin ◽  
Classical Type ◽  
Enzyme Linked Immunosorbent Assay ◽  
Intravascular Coagulation ◽  
Icu Admission ◽  
Mannose Binding ◽  
The Complement System ◽  
Binding Lectin

In sepsis, systemic coagulation activation frequently causes disseminated intravascular coagulation (DIC), and the uncontrolled activation of the complement system can induce multiple organ dysfunction and poor prognosis. This study aimed to examine the association of DIC with levels of collectin kidney 1 (CL-K1), a novel collectin of the complement system, and mannose-binding lectin (MBL), a classical-type collectin in patients with sepsis. We collected blood samples prospectively from adult patients with sepsis admitted to the intensive care unit (ICU) from day 1 (admission) to day 5. The CL-K1 and MBL levels were measured by enzyme-linked immunosorbent assay, and DIC was diagnosed by using a scoring algorithm. The correlation of CL-K1 and MBL levels with other coagulation markers was analyzed. There were 37 patients with DIC (DIC group) and 15 without DIC (non-DIC group). Compared to the non-DIC group, the DIC group had more severe conditions and higher mortality. During the 5 days after ICU admission, plasma CL-K1 levels were similar between the groups, but plasma MBL levels were significantly lower in the DIC group. Plasma CL-K1 levels were weakly correlated with prothrombin time, activated partial thromboplastin time, and antithrombin levels; plasma MBL levels were weakly correlated with fibrin/fibrinogen degradation product levels and DIC score. In conclusion, during the first 5 days of ICU admission, plasma CL-K1 levels were similar between the DIC and non-DIC groups. However, plasma MBL levels were lower in the DIC group compared to the non-DIC group, and the significance of this difference grew gradually over time.

scholarly journals Impact of Mannose-Binding Lectin Deficiency on Radiocontrast-Induced Renal Dysfunction

2013 ◽  
Vol 2013 ◽  
pp. 1-8 ◽  
Author(s):  
Michael Osthoff ◽  
Marten Trendelenburg
Keyword(s):  
Endothelial Dysfunction ◽  
Renal Dysfunction ◽  
Serine Proteases ◽  
Vascular Endothelial Cells ◽  
Ischemia Reperfusion ◽  
Mannose Binding Lectin ◽  
Lectin Pathway ◽  
Increased Risk ◽  
Mannose Binding ◽  
Binding Lectin

Contrast-induced nephropathy (CIN) is the third leading cause of acute renal failure in hospitalized patients. Endothelial dysfunction, renal medullary ischemia, and tubular toxicity are regarded as the most important factors in the pathogenesis of CIN. Mannose-binding lectin (MBL), a pattern recognition protein of the lectin pathway of complement, has been found to aggravate and mediate tissue damage during experimental renal ischemia/reperfusion (I/R) injury which was alleviated by inhibition with C1 inhibitor, a potent MBL, and lectin pathway inhibitor. In this paper, we highlight the potential role of MBL in the pathogenesis of human CIN. In experimental I/R models, MBL was previously found to induce tubular cell death independent of the complement system. In addition, after binding to vascular endothelial cells, MBL and its associated serine proteases were able to trigger a proinflammatory reaction and contribute to endothelial dysfunction. In humans, urinary MBL was increased after administration of contrast media and in individuals with CIN. Moreover, individuals with normal/high MBL levels were at increased risk to develop radiocontrast-induced renal dysfunction. Hence, MBL and the lectin pathway seem to be a promising target given that a licensed, powerful, human recombinant inhibitor exits to be added to the scarce armamentarium currently available for prophylaxis of CIN.

scholarly journals Diabetes Is Associated with Increased Autoreactivity of Mannan-Binding Lectin

2017 ◽  
Vol 2017 ◽  
pp. 1-12 ◽  
Author(s):  
Esben Axelgaard ◽  
Jakob Appel Østergaard ◽  
Steffen Thiel ◽  
Troels Krarup Hansen
Keyword(s):  
Diabetic Nephropathy ◽  
Complement System ◽  
Knockout Mice ◽  
Ex Vivo ◽  
Lectin Pathway ◽  
Urine Albumin ◽  
Mannan Binding Lectin ◽  
The Complement System ◽  
Binding Lectin

Mannan-binding lectin (MBL) has been reported to be involved in the pathophysiology of diabetic nephropathy. MBL is a pattern-recognition molecule of the innate immune system that initiates the lectin pathway of the complement system upon recognition of evolutionary conserved pathogen-associated molecular patterns or to altered self-tissue. Our group have previously shown direct effects of MBL on diabetes-induced kidney damage, and we hypothesized that MBL may cause autoactivation of the complement system via binding to neoepitopes induced by hyperglycemia. In the present study, we induced diabetes in MBL knockout mice and in wild type C57BL/6J mice by low-dose streptozotocin injection and measured blood glucose and urine albumin-to-creatinine ratio to monitor development of diabetes. After 24 weeks, fluorescently labelled recombinant MBL was injected intravenously in diabetic MBL knockout mice after which the distribution was investigated using in vivo fluorescence imaging. Mice were subjected to in vivo and ex vivo imaging 24 hours after injection. MBL was found to accumulate in the kidneys of diabetic mice as compared to healthy control mice (p<0.0001). These findings support the hypothesis of a significant role of MBL and the complement system in the pathophysiology of diabetic nephropathy.

scholarly journals Human IgA Activates the Complement System Via the Mannan-Binding Lectin Pathway

2001 ◽  
Vol 167 (5) ◽  
pp. 2861-2868 ◽  
Author(s):  
Anja Roos ◽  
Lee H. Bouwman ◽  
Daniëlle J. van Gijlswijk-Janssen ◽  
Maria C. Faber-Krol ◽  
Gregory L. Stahl ◽  
...  
Keyword(s):  
Complement System ◽  
Lectin Pathway ◽  
Mannan Binding Lectin ◽  
The Complement System ◽  
Binding Lectin

scholarly journals Increased Autoreactivity of the Complement-Activating Molecule Mannan-Binding Lectin in a Type 1 Diabetes Model

2016 ◽  
Vol 2016 ◽  
pp. 1-7 ◽  
Author(s):  
Jakob Appel Østergaard ◽  
Marieta Milkova Ruseva ◽  
Talat Habib Malik ◽  
Ingeborg Torp Hoffmann-Petersen ◽  
Matthew Caleb Pickering ◽  
...  
Keyword(s):  
Complement System ◽  
Drug Targets ◽  
Lectin Pathway ◽  
Diabetes Model ◽  
Healthy Control ◽  
End Stage ◽  
Mannan Binding Lectin ◽  
The Complement System ◽  
Binding Lectin ◽  
Immunofluorescence Intensity

Background. Diabetic kidney disease is the leading cause of end-stage renal failure despite intensive treatment of modifiable risk factors. Identification of new drug targets is therefore of paramount importance. The complement system is emerging as a potential new target. The lectin pathway of the complement system, initiated by the carbohydrate-recognition molecule mannan-binding lectin (MBL), is linked to poor kidney prognosis in diabetes. We hypothesized that MBL activates complement upon binding within the diabetic glomerulus.Methods. We investigated this by comparing complement deposition and activation in kidneys from streptozotocin-induced diabetic mice and healthy control mice.Results. After 20 weeks of diabetes, glomerular deposition of MBL was significantly increased. Diabetic animals had 2.0-fold higher (95% CI 1.6–2.5) immunofluorescence intensity from anti-MBL antibodies compared with controls (P<0.001). Diabetes and control groups did not differ in glomerular immunofluorescence intensity obtained by antibodies against complement factors C4, C3, and C9. However, the circulating complement activation product C3a was increased in diabetes as compared to control mice (P=0.04).Conclusion. 20 weeks of diabetes increased MBL autoreactivity in the kidney and circulating C3a concentration. Together with previous findings, these results indicate direct effects of MBL within the kidney in diabetes.

scholarly journals Fasciola hepatica is refractory to complement killing by preventing attachment of mannose binding lectin (MBL) and inhibiting MBL-associated serine proteases (MASPs) with serpins

2022 ◽  
Vol 18 (1) ◽  
pp. e1010226
Author(s):  
Carolina De Marco Verissimo ◽  
Heather L. Jewhurst ◽  
József Dobó ◽  
Péter Gál ◽  
John P. Dalton ◽  
...  
Keyword(s):  
Serine Proteases ◽  
Fasciola Hepatica ◽  
Membrane Attack Complex ◽  
Mannose Binding Lectin ◽  
Helminth Parasite ◽  
Lectin Pathway ◽  
Mannose Binding ◽  
Carbohydrate Arrays ◽  
Infectious Stage ◽  
Binding Lectin

The complement system is a first-line innate host immune defence against invading pathogens. It is activated via three pathways, termed Classical, Lectin and Alternative, which are mediated by antibodies, carbohydrate arrays or microbial liposaccharides, respectively. The three complement pathways converge in the formation of C3-convertase followed by the assembly of a lethal pore-like structure, the membrane attack complex (MAC), on the pathogen surface. We found that the infectious stage of the helminth parasite Fasciola hepatica, the newly excysted juvenile (NEJ), is resistant to the damaging effects of complement. Despite being coated with mannosylated proteins, the main initiator of the Lectin pathway, the mannose binding lectin (MBL), does not bind to the surface of live NEJ. In addition, we found that recombinantly expressed serine protease inhibitors secreted by NEJ (rFhSrp1 and rFhSrp2) selectively prevent activation of the complement via the Lectin pathway. Our experiments demonstrate that rFhSrp1 and rFhSrp2 inhibit native and recombinant MBL-associated serine proteases (MASPs), impairing the primary step that mediates C3b and C4b deposition on the NEJ surface. Indeed, immunofluorescence studies show that MBL, C3b, C4b or MAC are not deposited on the surface of NEJ incubated in normal human serum. Taken together, our findings uncover new means by which a helminth parasite prevents the activation of the Lectin complement pathway to become refractory to killing via this host response, in spite of presenting an assortment of glycans on their surface.

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