C1q binding to surface-bound IgG is stabilized by C1r₂s₂proteases

Abstract

Complement is an important effector mechanism for antibody-mediated clearance of infections and tumor cells. Upon binding to target cells, the antibody's constant (Fc) domain recruits complement component C1 to initiate a proteolytic cascade that generates lytic pores and stimulates phagocytosis. The C1 complex (C1qr2s2) consists of the large recognition protein C1q and a heterotetramer of proteases C1r and C1s (C1r2s2). While interactions between C1 and IgG-Fc's are believed to be mediated by the globular heads of C1q, we here find that C1r2s2 proteases affect the capacity of C1q to form an avid complex with surface-bound IgG molecules (on various DNP-coated surfaces and pathogenic Staphylococcus aureus). The extent to which C1r2s2 contribute to C1q-IgG stability strongly differs between human IgG subclasses. Using antibody engineering of monoclonal IgG we reveal that hexamer-enhancing mutations improve C1q-IgG stability, both in absence and presence of C1r2s2. In addition, hexamer-enhanced IgGs targeting S. aureus mediate improved complement-dependent phagocytosis by human neutrophils. Altogether, these molecular insights into complement binding to surface-bound IgGs could be important for optimal design of antibody therapies.

Promoting Fc-Fc interactions between anti-capsular antibodies provides strong immune protection against Streptococcus pneumoniae

“…Like the pneumococcal capsule, WTA is an abundant and exposed glycopolymer on the cell wall of S. aureus (76). For mAbs targeting WTA, we recently observed that WT IgG1 and IgG3 mAbs could induce complement activation and downstream phagocytosis in the absence of Fc-Fc enhancing mutations (75). At present it is unclear why these WT anti-capsular antibodies showed a poor capacity to induce complement activation on S. pneumoniae.…”

“…For the anti-capsular antibodies included in this study, we showed that monoclonal IgGs had a poor capacity to activate complement when expressed with wild-type Fc domains. This in sharp contrast to monoclonal IgGs recognizing wall teichoic acid (WTA) on the surface of S. aureus (75). Like the pneumococcal capsule, WTA is an abundant and exposed glycopolymer on the cell wall of S. aureus (76).…”

Quantitative Visualization of the Interaction between Complement Component C1 and Immunoglobulin G: The Effect of CH1 Domain Deletion

“…The result indicated a significantly higher number of C1 accumulated on the IgG-covered membranes than C1q (Fig. 2), explaining the slower off rate of C1 than C1q on the IgG-immobilized surface shown by the previous surface plasmon resonance experiment [21]. It is supposed that the binding of the IgG hexameric ring suppresses motional freedom of the C1q globular heads.…”

Reference Intervals of Renal Function Set Established for Healthy Pregnant Women

“…Processing of test results. Results obtained by measurement of reference individuals were directly used for establishment of reference intervals, if the relative bias between the means of measured values of reference materials obtained by the analytical systems and the assigned target values of reference materials meet the desirable speci cation for inaccuracy of biologic variation [17] .…”

“…Complement C1q is an important component of complement C1. [17] Studies have shown that the absence of serum complement C1q (including lack of component and functional disorder) will cause the body's immune complex deposition in tissue, causing immune complex diseases, such as SLE, glomerulonephritis[18], etc. It is found that NGAL is closely related to the occurrence of chronic kidney disease and can be an important marker for early renal injury [13,19].…”