High MW Kininogen Research Articles

COVID-19 triggers attacks in HAE patients without worsening disease outcome

COVID-19 triggers attacks in HAE patients without worsening disease outcome

A critical role for plasma kallikrein in the pathogenesis of autoantibody-induced arthritis.

The plasma kallikrein-kinin system (KKS) consists of serine proteases, prekallikrein (pKal) and factor XII (FXII), and a cofactor, high-MW kininogen (HK). Upon activation, activated pKal and FXII cleave HK to release bradykinin. Activation of this system has been noted in patients with rheumatoid arthritis, and its pathogenic role has been characterized in animal arthritic models. In this study, we generated 2 knockout mouse strains that lacked pKal and HK and determined the role of KKS in autoantibody-induced arthritis. In a K/BxN serum transfer-induced arthritis (STIA) model, mice that lacked HK, pKal, or bradykinin receptors displayed protective phenotypes in joint swelling, histologic changes in inflammation, and cytokine production; however, FXII-deficient mice developed normal arthritis. Inhibition of Kal ameliorated arthritis severity and incidence at early stage STIA and reduced the levels of major cytokines in joints. In addition to releasing bradykinin from HK, Kal directly activated monocytes to produce proinflammatory cytokines, up-regulated their C5aR and FcRIII expression, and released C5a. Immune complex increased pKal activity, which led to HK cleavage. The absence of HK is associated with a decrease in joint vasopermeability. Thus, we identify a critical role for Kal in autoantibody-induced arthritis with pleiotropic effects, which suggests that it is a new target for the inhibition of arthritis.-Yang, A., Zhou, J., Wang, B., Dai, J., Colman, R. W., Song, W., Wu, Y. A critical role for plasma kallikrein in the pathogenesis of autoantibody-induced arthritis.

Angiœdème héréditaire : diagnostic biologique

C1 inhibitor (C1 Inh) activity is an essential parameter for kinins angioedema (AE) diagnosis either hereditary or acquired or sporadic, it is analysed on plasma exclusively. Hereditary AE with C1 Inh functional deficiency is associated with alterations of the SERPING1 gene. Hereditary AE with normal C1 Inh (HAE nC1 Inh) is combined with F12 gene mutations, it is coding for Factor XII whose activity is controlled by C1 Inh, they are found in about 5% of HAE nC1 Inh cases. Every loss of C1 Inh activity must be taken as anormal by clinicians even for women with oral oestroprogestatives, it would be confirmed by the presence of cleaved C1 Inh. The kinins (primarily bradykinin) are the mediators responsible for local increase of vascular permeability. Bradykinin is released from high MW kininogen (HK) during the contact system activation. Plasma proteases mainly support this proteolytic activity controlled by C1 Inh. Family of a patient diagnosed with HAE must be studied, symptomatic as asymptomatic members indeed clinical symptoms regularly emerge very late in the life.

High Molecular Weight Kininogen Binds Phosphatidylserine and Opsonizes Urokinase Plasminogen Activator Receptor–Mediated Efferocytosis

Phagocytosis of apoptotic cells (efferocytosis) is essential for regulation of immune responses and tissue homeostasis and is mediated by phagocytic receptors. In this study, we found that urokinase plasminogen activator receptor (uPAR) plays an important role in internalization of apoptotic cells and also characterized the underlying mechanisms. In a flow cytometry-based phagocytic assay, uPAR-deficient macrophages displayed significant defect in internalization but not tethering of apoptotic cells. When uPAR-deficient mice were challenged with apoptotic cells, they exhibited pronounced splenomegaly resulting from accumulation of abundant apoptotic cells in spleen. Overexpression of uPAR in HEK-293 cells enhanced efferocytosis, which was inhibited by Annexin V and phosphatidylserine (PS) liposome, suggesting that uPAR-mediated efferocytosis is dependent on PS. In serum lacking high m.w. kininogen (HK), a uPAR ligand, uPAR-mediated efferocytosis was significantly attenuated, which was rescued by replenishment of HK. As detected by flow cytometry, HK selectively bound to apoptotic cells, but not viable cells. In purified systems, HK was specifically associated with PS liposome. HK binding to apoptotic cells induced its rapid cleavage to the two-chain form of HK (HKa) and bradykinin. Both the H chain and L chain of HKa were associated with PS liposome and apoptotic cells. HKa has higher binding affinity than HK to uPAR. Overexpression of Rac1/N17 cDNA inhibited uPAR-mediated efferocytosis. HK plus PS liposome stimulated a complex formation of CrkII with p130Cas and Dock-180 and Rac1 activation in uPAR-293 cells, but not in control HEK-293 cells. Thus, uPAR mediates efferocytosis through HK interaction with PS on apoptotic cells and activation of the Rac1 pathway.

The participation of high molecular weight kininogen in hypotensive shock and intravascular coagulation

Evidence for the participation of high MW kininogen (HMWK) was sought in the systemic circulation of rabbits undergoing severe hypotensive shock induced by bacterial lipopolysacchride or dextran sulfate. Despite severe injury in the animals by 5 hr, no consumption of the circulating HMWK was apparent. Evidence was discussed suggesting a local participation of HMWK during LPS-induced inflammatory injury of the lung without apparent consumption of the molecule in the systemic circulation.

Rabbit blood coagulation factor XI. Mechanism of activation by rabbit Hageman factor (factor XII)

Activation of rabbit blood coagulation Factor XI by purified rabbit Hageman factor, prekallikrein and high MW kininogen in the presence of kaolin was measured by clotting assay. Hageman factor and kaolin were absolute requirements for Factor XI activation. Prekallikrein and high MW kininogen enhanced the rate of Factor XI activation. Factor XI a generation was temporally associated with limited proteolytic cleavage of the molecule into disulfide-linked fragments of 50,000 and 33,000 molecular weight. Identical cleavage fragments were also seen when radiolabelled Factor XI was present in kaolin-activated rabbit plasma. The surface-binding and cleavage of rabbit 125I-Factor XI in normal human plasma and in plasmas deficient in high MW kininogen and Hageman factor were studied. The binding of Factor XI in plasma to kaolin was dependent upon the presence of high MW kininogen while the limited proteolysis of Factor XI during contact activation required the presence of both high MW kininogen and Hageman factor. These observations are consistent with the hypothesis that high MW kininogen links Factor XI to negatively charged surfaces where activated Hageman factor activates Factor XI by limited proteolysis.

Rabbit blood coagulation factor XI. Purification and properties

Rabbit blood coagulation Factor XI was purified in 30% yield from plasma by ion exchange chromatography. The purified Factor XI zymogen gave a single protein band on sodium dodecyl sulfate-polyacrylamide gel electrophoresis in the presence and absence of β-mercaptoethanol with an apparent molecular weight of 83,000. On alkaline disc gel electrophoresis Factor XI appeared either as a monomer or a dimer depending upon the conditions prior to electrophoresis. After dialysis against buffer at physiological pH and ionic strength Factor XI appeared as a monomer only. The apparent molecular weight of rabbit Factor XI in rabbit plasma on Sephadex G-200 chromatography was 200,000, probably reflecting a complex formed between high MW kininogen and Factor XI. The concentration of Factor XI in citrated normal rabbit plasma was 3.3 μg/ml.