In vivo handling of soluble complement fixing Ab/dsDNA immune complexes in chimpanzees.

Abstract

We used soluble, C-fixing antibody/dsDNA IC to investigate immune complex (IC) handling and erythrocyte (E)-to-phagocyte transfer in chimpanzees. IC bound efficiently to chimpanzee E in vitro and showed minimal release with further in vitro incubation in the presence of serum in EDTA (c 15% within 1 h). These IC also bound rapidly to E in vivo (70-80% binding within 1 min) and did not show detectable release from E in the peripheral circulation after infusion in vivo (< 2% within 1 h). Despite such slow C-mediated release of IC from E, IC were rapidly stripped from E by the mononuclear phagocyte system (T50 for E-IC1500 = 5 min) without sequestration of E.

A novel polymorphism of FcgammaRIIIa (CD16) alters receptor function and predisposes to autoimmune disease.

“…Fc␥RIIIa may also play a critical role in the first-dose cytokine-release syndrome seen with some therapeutic monoclonal antibodies (57). Furthermore, our earlier studies in a primate model of immune complex handling demonstrated an essential role for Fc␥RIIIa (58,59), and more recent observations in mice with targeted disruption of murine Fc␥RIII also support an important role in immune complex-mediated triggering of inflammatory reactions (60).…”

Use of heteropolymeric monoclonal antibodies to attach antigens to the C3b receptor of human erythrocytes: a potential therapeutic treatment.

“…The mechanism by which bona fide complement-fixing IC are cleared from the circulation after binding to CR1 on RBCs is controversial (6,9,11,26). If, as suggested, there is a proteolytic step or recognition and binding by fixed Fc receptors of the reticuloendothelial system, then safe and rapid clearance should occur.…”

“…It is unlikely the franked RBCs would be removed from the circulation. The maximum amount of mouse IgG bound to the RBCs (500-1000 IgG/ RBC) is less than is seen when IC are bound (14), and primate studies demonstrate that such RBCs containing IC are not cleared (5,6,9).…”

“…He provided intriguing evidence that this reaction plays an important role in the body's defense against microorganisms by facilitating their phagocytosis after adherence and immobilization on RBCs. Recent studies in the nonhuman primate by Hebert and coworkers (5,6) as well as reports from other laboratories (7)(8)(9) indicate that immune adherence of soluble complement-opsonized IC to RBCs via CR1 provides a vehicle for safe and rapid clearance of potentially pathogenic IC from the circulation. Defects in this RBC-based clearance reaction have been shown in a number ofdiseases (10)(11)(12) and are believed to presage disease activity, such as enhanced deposition of inflammatory IC in susceptible tissues and organs (13).…”

Preferential expression of human Fc gamma RIIIPMN (CD16) in paroxysmal nocturnal hemoglobinuria. Discordant expression of glycosyl phosphatidylinositol-linked proteins.

“…Patients with PNH have been shown to have normal levels of FcyRIIINK and FcyRIIIM,, (21)(22)(23) but are deficient in Fc~yRIIIPMN (18,19), consistent with the neutrophil isoform having a GPI anchor. Since CD 16 participates in the handling of immune complexes and certain bacteria (24)(25)(26)(27), a generalized deficiency in Fc-yRIIIPMN might lead to significant impairment of host defenses. However, the absence ofprominent immune complex-mediated disease, frequent bacterial infections, and recurrent viral infections (1, 28,29) suggests either that CD 16 is not essential for protection ofthe host or that it is not totally deficient on PNH PMN.…”