This study tested the hypothesis that the rate of antigen entry into the circulation in systemic lupus erythematosus (SLE), a naturally occurring immune complex glomerulonephritis (IC-GN), is slow compared with that of traditional experimental models of IC-GN, in which the antigen is delivered rapidly as a daily iv bolus. This hypothesis was tested by comparing rates of decline of the third component of complement (C3) and of circulating neutrophils (PMN) in SLE patients with active disease with those of cynomolgus monkeys (CYN) undergoing induction of experimental IC-GN by means of a daily bolus infusion of antigen. It has previously been shown that, as antigen enters the circulation and forms circulating IC, C3 levels and circulating PMN decline acutely. Thus, acute changes in these parameters can be surrogates for the rate of antigen entry into the circulation. In the CYN undergoing induction of IC-GN (N = 11), infusion of the antigen (bovine gamma-globulin) over 10 min resulted in acute declines in C3 levels (25 +/- 6.6%; P = 0.0018 and PMN counts (59 +/- 9%; P < 0.0002). In addition, the CYN experienced the onset of acute respiratory distress and hypotension. By contrast, in patients with active SLE (N = 9), C3 and white blood cell counts measured at 24-h intervals did not change significantly, and episodes of acute hypotension or respiratory distress were not observed. In the CYN, the onset of visible vasculitic lesions in the omentum were also documented within minutes of the infusion of bovine gamma-globulin. The rapidity of onset of these vascular lesions suggests that the tempo at which lesions develop in experimental models of IC disease is faster than that of naturally occurring IC diseases. It was concluded that, in naturally occurring IC diseases, antigen probably enters the circulation slowly over prolonged periods of time, rather than as large boluses over short periods of time, as in traditional experimental models of IC-GN. Thus, models of IC-GN involving a daily bolus infusion of antigen may not be clinically relevant, particularly when IC clearing mechanisms are tested, because the efficiency of these mechanisms may be markedly influenced by the rate at which IC form in the circulation.