TY - JOUR T1 - Controlling the anaphylatoxin C5a in diseases requires a specifically targeted inhibition. AU - Riedemann,Niels C, AU - Habel,Maria, AU - Ziereisen,Jana, AU - Hermann,Marlen, AU - Schneider,Conny, AU - Wehling,Cyrill, AU - Kirschfink,Michael, AU - Kentouche,Karim, AU - Guo,Renfeng, Y1 - 2017/03/30/ PY - 2017/03/10/received PY - 2017/03/27/revised PY - 2017/03/27/accepted PY - 2017/4/4/pubmed PY - 2017/8/30/medline PY - 2017/4/4/entrez KW - C5a blockade KW - Complement activation KW - Eculizumab KW - Thrombin KW - Trypsin SP - 25 EP - 32 JF - Clinical immunology (Orlando, Fla.) JO - Clin Immunol VL - 180 N2 - The terminal complement split product C5a has been described as an important mediator in inflammatory diseases. C5a is generated upon cleavage of C5 and earlier research suggests that, besides the known C5 convertases formed upon activation of the complement pathways, various enzymes could activate C5 directly. We demonstrate that eculizumab effectively blocks C5 activation when mediated by C5-convertase formation, but fails to block C5a generation resulting from direct enzymatic cleavage by trypsin and thrombin. C5a generated by these enzymes is shown to be fully biologically functional and can be blocked by IFX-1, a specific monoclonal anti-human C5a antibody. We further report clinical cases of atypical hemolytic uremic syndrome (aHUS) and C3 Glomerulonephritis (C3GN) patients under treatment with eculizumab presenting substantially elevated C5a levels. Thus, blocking the C5 convertase mediated activation of C5 may not be efficient to control C5a-mediated effects in human disease and that a targeted approach is warranted. SN - 1521-7035 UR - https://www.unboundmedicine.com/medline/citation/28366510/Controlling_the_anaphylatoxin_C5a_in_diseases_requires_a_specifically_targeted_inhibition_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S1521-6616(17)30172-9 DB - PRIME DP - Unbound Medicine ER -