How Immune Complexes from Certain IgG NAbs and Any F(ab′)2 Can Mediate Excessive Complement Activation

Abstract

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.

Early Safety Indicators of COVID-19 Convalescent Plasma in 5,000 Patients

“…This theoretical concern is supported by reports of ADE in macaques given specific antibody administration prior to SARS-CoV-1 experimental infection (22) and ADE effects with other coronaviruses (23, 24). There is also the concern that antibody administration to individuals with significant viral loads may lead to the formation of antigen-antibody immune complexes, which may contribute to proinflammatory immune responses (25, 26). Although the specific signs and symptoms of ADE in humans with coronavirus infection are unknown, such an effect would presumably be associated with clinical deterioration and/or worse outcomes following convalescent plasma administration.…”

Convalescent Plasma: A Potential Treatment for COVID-19

“…27 There is also the concern that antibody administration to individuals with significant viral loads may lead to the formation of antigen-antibody immune complexes, which may contribute to proinflammatory immune responses. 28 But these are remote theoretical complications not reported with COVID-19 CP so far.…”

Convalescent serum therapy for COVID-19: A 19th century remedy for a 21st century disease

“…One theoretical complication that may arise is an antibodymediated proinflammatory disease enhancement known as antibody-dependent enhancement (ADE), whereby antibodies that developed during a prior infection exacerbate severity of the disease [12,28]. The transfer of these antibodies may aberrantly activate fragment crystallizable (Fc) or complement receptors, increasing recruitment of proinflammatory cytokines and chemokines to the site of infection and causing severe tissue damage [29][30][31]. Additionally, the presence of non-neutralizing antibodies may exacerbate viral endocytosis or phagocytosis into host cells via Fc receptors, potentializing viral replication [29,32].…”