scholarly journals Novel evidence that the mannan-binding lectin pathway of complement activation plays a pivotal role in triggering mobilization of hematopoietic stem/progenitor cells by activation of both the complement and coagulation cascades

Leukemia ◽  
2016 ◽  
Vol 31 (1) ◽  
pp. 262-265 ◽  
Author(s):  
M Adamiak ◽  
A Abdelbaset-Ismail ◽  
M Suszynska ◽  
A Abdel-Latif ◽  
J Ratajczak ◽  
...  
Keyword(s):  
Progenitor Cells ◽  
Complement Activation ◽  
Pivotal Role ◽  
Lectin Pathway ◽  
Hematopoietic Stem ◽  
Mannan Binding Lectin ◽  
Binding Lectin

scholarly journals Novel Evidence That the Mannan-Binding Lectin (MBL) Pathway of Complement Activation Plays a Pivotal Role in Triggering Mobilization of Hematopoietic Stem/Progenitor Cells By Activation of Both the Complement and Coagulation Cascades

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3371-3371
Author(s):  
Mateusz Adamiak ◽  
Malwina Suszynska ◽  
Ahmed Abdel-Latif ◽  
Ahmed Abdelbaset-Ismail ◽  
Janina Ratajczak ◽  
...  
Keyword(s):  
Progenitor Cells ◽  
Complement Activation ◽  
Classical Pathway ◽  
Wild Type ◽  
Hematopoietic Stem ◽  
Mannan Binding Lectin ◽  
Binding Lectin ◽  
Poor Mobilizers ◽  
Mbl Deficiency

Abstract Background . The complement cascade (ComC), which is part of the innate immune system, exerts several pleiotropic effects, and, as we have demonstrated, it is required for mobilization of hematopoietic stem/progenitor cells (HSPCs) during infection or tissue/organ injury as well as in response to administration of pharmacological mobilizing agents, such as G-CSF or AMD3100 (Blood 2004, 103, 2071-2078). The ComC is activated by three pathways: the classical, mannan-binding lectin (MBL), and alternative pathways. Activation of the ComC and generation of cleavage fragments of the fifth component of the ComC (C5), such as C5a, desArgC5a, and C5b, by classical C5 convertase initiates events that are required for egress of HSPCs from bone marrow (BM) into peripheral blood (PB) (Leukemia 2009, 23, 2052-2062). Recent results indicate that the coagulation cascade (CoaC) is activated in parallel with activation of the ComC during the mobilization process and plays a supportive role, because thrombin has "C5 convertase-like activity" (Leukemia 2014, 28, 2148-2154). While a requirement for ComC activation and the pivotal roles of the distal part of complement activation and the generation of C5 cleavage fragments have been previously demonstrated (Leukemia 2009, 23, 2052-2062), mice with mutations in components of the classical pathway (C1q-/- mice), in which the distal pathway of C5 activation remained intact, do not show impairment of HSPC mobilization (Leukemia 2010, 24, 1667-1675). Aim of the study. Since no studies have yet been performed to address the role of the MBL pathway in triggering the mobilization of HSPCs, we became interested in its involvement in both ComC and CoaC activation after administration of G-CSF or AMD3100. The MBL pathway is homologous to the classical pathway but contains a soluble MBL receptor instead of C1q, and MBL functions as activator of the MBL-associated serine proteases, MASP-1 and MASP-2, which are activated downstream of both the ComC and the CoaC. Hypothesis. We hypothesized that the MBL-initiated ComC and CoaC activation pathways are involved in triggering mobilization of HSPCs and that MBL deficiency may result in poor mobilization efficiency.Materials and Methods. In our experiments, 2-month-old, MBL-deficient (MBL-/-) and MASP-1-deficient (MASP-1-/-) mice as well as their normal wild type (WT) littermates were mobilized with G-CSF or AMD3100. Following mobilization, we measured i) the total number of white blood cells (WBCs), ii) the number of circulating clonogenic colony-forming unit granulocyte/macrophage (CFU-GM) progenitors, and iii) the number of Sca-1+c-kit+lineage- (SKL) cells in PB. In parallel, we evaluated activation of the ComC after administration of G-CSF and AMD3100 in experimental animals by employing C5a ELISA. To address the role of the CoaC in MBL-MASP-1- and MBL-MASP-2-induced mobilization, MBL-/- mice were treated with inhibitors of the CoaC (refludan) in some of the experiments. Results. We found that the MBL-MASP ComC activation pathway is involved in pharmacological G-CSF- and AMD3100-induced mobilization of HSPCs. As predicted, MBL-/- and MASP-1-/- mice were found to be poor mobilizers. Furthermore, inhibition of the CoaC by refludan inhibited mobilization in wild type animals but did not generate the additional defects seen in MBL-/- mice. Conclusions. We identified a previously unrecognized role for the MBL-MASP-1 pathway in triggering ComC and CoaC activation in the HSPC mobilization process. This finding explains the pivotal role of the MBL pathway in triggering activation of the proximal part of the ComC and explains why, even with a deficiency in activation of classical pathway components (C1q), mobilization of HSPCs proceeds normally as long as the MBL pathway is intact. Taking into consideration that ~10% of normal people are poor activators of the MBL pathway and that this percentage corresponds with the ~10% of the normal healthy population that are poor mobilizers, we are currently investigating whether MBL deficiency correlates with poor mobilization status in patients. MBL could be an important predictive parameter for identifying poor mobilizers. Disclosures No relevant conflicts of interest to declare.

An assay for the mannan-binding lectin pathway of complement activation

2001 ◽  
Vol 257 (1-2) ◽  
pp. 107-116 ◽  
Author(s):  
S.V Petersen ◽  
S Thiel ◽  
L Jensen ◽  
R Steffensen ◽  
J.C Jensenius
Keyword(s):  
Complement Activation ◽  
Lectin Pathway ◽  
Mannan Binding Lectin ◽  
Binding Lectin

scholarly journals Global Autorecognition and Activation of Complement by Mannan-Binding Lectin in a Mouse Model of Type 1 Diabetes

2017 ◽  
Vol 2017 ◽  
pp. 1-13 ◽  
Author(s):  
Esben Axelgaard ◽  
Jakob Appel Østergaard ◽  
Saranda Haxha ◽  
Steffen Thiel ◽  
Troels Krarup Hansen
Keyword(s):  
Blood Glucose ◽  
Complement Activation ◽  
Ex Vivo ◽  
Vascular Complications ◽  
Lectin Pathway ◽  
Double Knockout ◽  
High Blood Glucose ◽  
New Findings ◽  
Mannan Binding Lectin ◽  
Binding Lectin

Increasing evidence links mannan-binding lectin (MBL) to late vascular complications of diabetes. MBL is a complement-activating pattern recognition molecule of the innate immune system that can mediate an inflammation response through activation of the lectin pathway. In two recent animal studies, we have shown that autoreactivity of MBL is increased in the kidney in diabetic nephropathy. We hypothesize that long-term exposure to uncontrolled high blood glucose in diabetes may mediate formation of neoepitopes in several tissues and that MBL is able to recognize these structures and thus activate the lectin pathway. To test this hypothesis, we induced diabetes by injection of low-dose streptozotocin in MBL double-knockout (MBL/DKO) mice. Development of diabetes was followed by measurements of blood glucose and urine albumin-to-creatinine ratio. Fluorophore-labelled recombinant MBL was injected intravenously in diabetic and nondiabetic mice followed by ex vivo imaging of several organs. We observed that MBL accumulated in the heart, liver, brain, lung, pancreas, and intestines of diabetic mice. We furthermore detected increased systemic complement activation after administration of MBL, thus indicating MBL-mediated systemic complement activation in these animals. These new findings indicate a global role of MBL during late diabetes-mediated vascular complications in various tissues.

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