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The role of the complement system in nonspecific inflammation was investigated by depleting guinea pigs of serum complement with cobra venom factor (CoF). The progress of wound healing was compared in decomplemented and control animals which received buffer and no CoF. When wound tissue sections were assessed at 12 hours after wounding, no morphologic differences were observed between experimental and control wounds. Quantitation of 24-hour wound exudates by a point volumetric method revealed a 50% reduction in infiltrating polymorphonuclear neutrophilic leukocytes (PMN) in the absence of complement. A smaller decrease in mononuclear leukocytes (MNL) was seen. Red cells occupied four times as much space in the experimental wounds at 24 hours. In 48-hour wounds, PMN were still 50% of controls, but were near control levels at 72 hours. Despite the decreased influx of PMN, wound debridement and subsequent fibrogenesis proceeded as in the controls. No differences were seen in fibroblast proliferation, connective tissue formation or capillary regeneration. These results suggest that the complement system is not a primary mediator of inflammation following a nonimmunologic stimulus.

The serum disappearance, metabolic clearance and whole body catabolism of homologous immunoglobulin fragments were studied in rats. The rapid disappearance of Fab fragments from serum in normal animals was no longer present after nephrectomy. In contrast, the serum disappearance curve of Fc fragments was not altered by nephrectomy. The results of three different experiments, however, indicated that similar to Fab fragments, some Fc fragments underwent filtration and degradation in the kidneys. First, the amount of intact Fc fragments excreted in the first day after injection increased from 6% of the injected dose in normal rats to 17% in rats pretreated with sodium maleate. Secondly, nephrectomy eliminated the rapid phase of whole body catabolism of inected Fc fragments. Thirdly, auto-radiographic studies showed localization of Fc fragments in the renal proximal tubule cells in the first 3 hr after injection. An identical localization was seen with Fab fragments. These results support the conclusion that removal from circulation by glomerular filtration and subsequent reabsorption and degradation in proximal tubule cells represent the major mechanism for catabolism of Fab fragments. Although some Fc fragments undergo the same fate, most injected Fc fragments equilibrate with unknown sites where they are possibly bound and made unavailable for filtration in the kidneys.

The adherence of soluble immune complexes to stimulated alveolar macrophages was studied in vitro using HSA-anti-HSA complexes prepared in antigen excess. Those complexes containing more than two molecules of antibody preferentially adhered to macrophages in the absence of complement. Free gammaG in less than physiological concentrations inhibited the adherence of complexes, and the presence of complement did not significantly alter this inhibition. Complexes prepared with reduced and alkylated antibodies showed a decreased adherence. The strength of binding of soluble complexes to macrophages and their efficiency in fixing complement were greater than seen with small aggregates of homologous gammaG. These differences in biological properties were observed even though the immune complexes and aggregates contained comparable numbers of gammaG molecules. The gammaG receptor on rabbit macrophages exhibited species specificity. Pretreatment of macrophages with proteolytic enzymes led to adherence of larger amounts of soluble complexes. These observations suggest that the strength of binding of soluble immune complexes to macrophages and their efficiency in fixing complement are not determined solely by a random summation of individual binding sites. It is proposed that conformational changes in the gammaG antibodies or a specific molecular arrangement in the lattice work of complexes containing large protein antigens may influence the biological properties of the soluble complexes.

Preformed soluble immune complexes injected into rabbits or rhesus monkeys showed similar characteristics of disappearance from circulation. Complexes made with intact gammaG-antibodies and exceeding the Ag(2)Ab(2) lattice formation were rapidly removed by the hepatic RES. These complexes fixed complement effectively in vitro. Their hepatic uptake was not dependent upon circulating complement components, since their accumulation in the liver was unchanged in complement depleted rabbits. Similar antigen-antibody complexes made with reduced and alkylated gammaG-antibodies fixed complement ineffectively in vitro. These complexes possessed different disappearance characteristics and were not rapidly taken up by the liver, regardless of their degree of lattice formation. Both in vitro and in vivo studies failed to suggest any role for the immune adherence receptor on primate erythrocytes in the handling of circulating soluble immune complexes composed of BSA and gammaG-antibodies to this antigen.