Abundant glomerular platelet deposition is a hallmark of certain animal models of immune complex (IC)-mediated glomerulonephritis (GN). By contrast, conspicuous platelet deposition is uncommon in the IC-GN seen in humans. This could result from intrinsic differences between human and animal platelets, which are known to be present. To assess whether abundant glomerular platelet deposition can occur in humans with IC-GN, the present studies were undertaken in nonhuman primates (cynomolgus monkeys, CYN), with active experimental IC-GN induced by 12 weeks of daily intravenous infusion of bovine gamma globulin (BGG). CYN are appropriate for these studies because, like humans, CYN platelets do not express the C3b receptor but do express receptors for the Fc region of IgG (FcRγII). Furthermore, in this model of IC-GN, which is indistinguishable from IC-GN seen in humans, it is possible to time the biopsy to coincide with a period of peak activity of the GN. The present studies proceeded as follows: ten CYN were studied before and after intravenous infusion of BGG sufficient to achieve conditions near antigen/antibody equivalence for circulating precipitating antibody to BGG. The infusion of BGG, which was given over 10 minutes, resulted in an acute reduction in circulating platelets (mean 43% ± 5 SE, P < 0.001). However, renal biopsies performed before and five minutes after the acute reduction in circulating platelets showed that relatively few of the platelets removed from the circulation lodged in glomeruli (platelets/ glomerular cross section: 0.2 ± 0.06 before BGG vs. 0.88 ± 0.31 after BGG, P = 0.035). In five of the CYN studied under the above protocol, autologous platelets were labeled with 111In and reinfused into the CYN just prior to the BGG infusion. These studies confirmed the paucity of platelet deposition in kidney but showed major uptake of the 111In-labeled platelets by liver and spleen (mean ± SE 111In CPM/mg of tissue: kidney cortex 18 ± 8, liver 132 ± 42, and spleen 808 ± 127, P = 0.038, comparing kidney to liver or spleen by paired t-test). Thus, the platelets removed from the circulation were taken up at the sites which are also the principal sites of IC uptake (liver and spleen), and over the time interval that coincides with the period of maximum uptake of IC by liver and spleen, after BGG infusion. In vitro studies, discussed herein, showed that BGG anti-BGG IC bind to CYN platelets via FcRγII. Thus, we suggest that, in vivo, circulating IC become bound to platelet FcRγII and the platelet-IC complex is cleared from the circulation, mainly by uptake by liver and spleen. Such a mechanism would divert platelets, activated by ligation of IC, from sites of IC-mediated injury such as the kidney. Such a mechanism would spare the kidney from platelet-induced injury. In primates with an active experimental IC-GN, which is comparable to GN seen in humans, platelets show little tendency to lodge in glomeruli. Instead, primate platelets appear to be primarily involved in the clearance of IC from the circulation. These observations suggest that, with respect to the pathogenesis of IC-GN, primate platelets may play a role that is different from that of rodent platelets.
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