How immune complexes from certain IgG NAbs and any F(ab')₂ can mediate excessive complement activation.
In sepsis death follows an excessive inflammatory response involving cytokines and complement that is activated primarily via the amplifying C3/C5 convertase. Excessive stimulation of complement amplification requires IgG-containing or F(ab')₂-containing immune complexes (IC) that capture dimeric C3b on one of their heavy chains or heavy chain fragments. The ability of IgG-IC to capture dimeric C3b by the Fab portion is dependent on an affinity for C3 within the Fab portion, but outside the antigen-binding region. This property is rare among IgG NAbs. In contrast to this, the lack of the Fc portion renders the Fab regions of any F(ab')(2)-IC accessible to nascent C3b, but dimeric C3b deposits only if F(ab')₂-IC form secondary IC with anti-hinge NAbs that rigidify the complex and thereby promote deposition of dimeric C3b. Both types of complexes, C3b₂-IgG-IC and C3b₂-F(ab')₂-IC/anti-hinge NAbs, are potent precursors of alternative C3 convertases and stimulate complement amplification along with properdin up to 750 times more effectively than C3b and properdin. F(ab')₂ fragments are not normally generated, but are formed from NAbs by enzymes from pathogens and neutrophils in sepsis. Unlike IgG-IC F(ab')₂-IC are not cleared by Fc-receptor dependent processes and circulate long enough to form secondary IC with anti-hinge NAbs that rigidify the complexes such that they capture dimeric C3b and gain the potency to stimulate complement amplification.
Institute of Biochemistry, Swiss Federal Institute of Technology, ETH Hönggerberg, Zurich, Switzerland. hans.lutz@bc.biol.ethz.ch
Hans U
HU
Lutz
D000936:Antigen-Antibody Complex; D001323:Autoantibodies / Q000276:immunology*; D003167:Complement Activation / Q000276:immunology*; D050577:Complement C3-C5 Convertases / Q000276:immunology; D003179:Complement C3b / Q000276:immunology; D016207:Cytokines / Q000276:immunology; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000276:immunology; D007074:Immunoglobulin G / Q000737:chemistry / Q000276:immunology*; D011414:Properdin / Q000276:immunology; D055503:Protein Multimerization; D018805:Sepsis / Q000276:immunology*
D000936:Antigen-Antibody Complex; D001323:Autoantibodies; D016207:Cytokines; D007140:Immunoglobulin Fab Fragments; D007074:Immunoglobulin G; D011414:Properdin; D003179:Complement C3b; D050577:Complement C3-C5 Convertases