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Intravenous injections of mice three times a day for 3 days with soluble complexes of 3 mg. of moderately avid rabbit antibody to chicken egg albumin prepared by dissolution of equivalence precipitates in 80 times the equivalence amount of antigen resulted in a combined mesangial and loop localization of immune complexes. With complexes formed from antibody of low avidity, injected four times a day for 3 days, a predominately subepithelial loop deposition of complexes was observed. Complexes formed from moderately avid antibody gave rise to a mainly mesangiopathic glomerulonephritis, whereas low avidity complexes were associated with a diffuse glomerulonephritis. These results, in combination with those of the previous paper, successfully reproduce the basic form of the lesions seen in active immune complex disease by passive means and suggest that antibody avidity is a major determinant of the site of localization of immune complexes and therefore of the morphologic form of the resulting glomerulonephritis. The importance of these observations for our understanding of the pathogenesis of human immune complex disease is considered.

Immunohistologic and electron microscipic studies were performed on the kidneys of rabbits given daily intravenous injections of porcine thyroglobulin in amounts adjusted to the immune response of the individual rabbits. Glomerular lesions were restricted to the mesangium, were characterized by varying degrees of proliferation of mesangial cells and increase of mesangial matrix, and were accompanied by accumulations of rabbit immunoglobulins, C3, and porcine thyroglobulin. Electron-dense deposits were localized to the mesangium and the adjacent subendothelial space. Less than 10 per cent of the animals with mesangila lesions developed obvious impairment of glomerular function. Thyroglobulin-containing immune complexes were found to be rapidly removed from the mesangium, so that overloading of the mesangium and consequent accumulation of complexes in the adjacent capillary loops could not occur. Thus, the results provide further evidence that when immune complex deposition is restricted to the mesangium, relatively little interference with glomerular function results. This situation is paralleled in man by the lesions of subclinical lupus nephritis, chance proteinuria and hematuria, and the early lesions of Berger's disease.

Rabbits were given injections of preformed complexes of purified goat antirabbit glomerular basement membrane antibody and rabbit antigoat immunoglobulin. When the animals were killed 24 hours later, examination of their kidneys revealed diffuse glomerulonephritis with widespread areas of localized loop necrosis, associated with extensive accumulations of polymorphonuclear leukocytes. By electron microscopy, accumulations of polymorphonuclear leukocytes in various degrees of disintegration were associated with areas of the basement membrane that appeared to be losing their structural integrity, suggesting that the damage to the membrane was brought about by the action of lysosomal enzymes. Reduction of the number of circulating polymorphonuclear leukocytes by pretreatment of the animals with nitrogen mustard completely prevented the lesions. Reduction of circulating complement levels by pretreatment of the animals with cobra venom factor prevented the occurrence of localized necrosis but allowed the development of the diffuse lesion.

Intravenous injection of mice with soluble complexes of highly avid rabbit antibody to egg albumin, prepared by dissolution of equivalence precipitates in large quantities of antigen, resulted in a purely mesangial localization of the complexes. When animals received three injections of complexes per day for 1 day it was noted that precipitates dissolved in 80 times the equivalence amount of antigen produced slight mesangial changes. When such complexes were injected for 2 or 3 days, outright mesangiopathic glomerulonephritis was observed in an increasing proportion of the animals. Equivalent amounts of antigen alone did not produce lesions.