Control of the classical and the MBL pathway of complement activation.
The activation of complement via the mannan-binding lectin (MBL) pathway is initiated by the MBL complex consisting of the carbohydrate binding molecule, MBL, two associated serine proteases, MASP-1 and MASP-2, and a third protein, MAp19. In the present report we used an assay of complement activation specifically reflecting the physiological activity of the MBL complex to identify biological and synthetic inhibitors. Inhibitor activity towards the MBL complex was compared to the inhibition of the classical pathway C1 complex and to a complex of MBL and recombinant MASP-2. A number of synthetic inhibitors were found to differ in their activities towards complement activation via the MBL pathway and the classical pathway. C1 inhibitor inhibited both pathways whereas alpha2-macroglobulin (alpha2M) inhibited neither. C1 inhibitor and alpha2M were found to be associated with the MBL complex. Upon incubation at 37 degrees C in physiological buffer, the associated inhibitors as well as MASP-1, MASP-2, and MAp19 dissociated from MBL, whereas only little dissociation of the complex occurred in buffer with high ionic strength (1 M NaCl). The difference in sensitivity to various inhibitors and the influence of high ionic strength on the complexes indicate that the activation and control of the MBL pathway differ from that of the classical pathway. MBL deficiency is linked to various clinical manifestations such as recurrent infections, severe diarrhoea, and recurrent miscarriage. On the other hand, impaired control of complement activation may lead to severe and often chronically disabling diseases. The results in the present report suggests the possibility of specifically inhibiting of the MBL pathway of complement activation.
Department of Medical Microbiology and Immunology, The Bartholin Building, University of Aarhus, DK-8000, Aarhus, Denmark. svp@microbiology.au.dk
S V
SV
Petersen
S
S
Thiel
L
L
Jensen
T
T
Vorup-Jensen
C
C
Koch
J C
JC
Jensenius
D000818:Animals; D002352:Carrier Proteins / Q000502:physiology*; D037222:Collectins; D003167:Complement Activation; D003169:Complement Inactivator Proteins / Q000502:physiology; D003171:Complement Pathway, Classical; D006041:Goats; D006801:Humans; D050606:Mannose-Binding Protein-Associated Serine Proteases; D012697:Serine Endopeptidases / Q000502:physiology
D002352:Carrier Proteins; D037222:Collectins; D003169:Complement Inactivator Proteins; D050606:Mannose-Binding Protein-Associated Serine Proteases; D012697:Serine Endopeptidases