Studies in Molecular Pathology

Abstract

In the studies of Germuth (1) dealing with serum sickness in the rabbit, the lesions of kidneys and other organs were observed to develop during the "immune" phase of antigen clearance from the blood and to regress after free antibody had appeared in the circulation. The pathogenic role of antigenantibody combination indicated by these temporal relations was further substantiated by the localizations of host gamma globulin (2, 3), presumably antibody, and antigen (3) at the lesion sites. Moreover, it has been shown that the lesions of serum sickness in normal rabbits can be produced by the passive transfer of antibody in the presence of antigen (4) and, more recently, that comparable lesions can be produced in normal mice by the passive transfer of soluble antigen-antibody complexes prepared in antigen excess (5, 6). In the latter experiments severe acute glomerulonephritis was observed in mice within 36 hours after the first injection of soluble immune complex. These observations, together with our experience in the preparation and the use of fluorescent immune complexes (7,8), prompted us to study the localizations of heterologous immune complexes in the tissues of mice. Materials and MethodsAntigens.--Bovine serum albumin (BSA), crystallized, and hen ovaibumin (OA), 5 times crystallized, were obtained from Pentex Inc., Kankakee, Illinois.Antiserums.--These were produced in New Zealand brown rabbits against BSA and OA.Each rabbit received an initial intramuscular injection of 10 mg of antigen incorporated in complete Freund's adjuvant (Difco Laboratories) followed by a similar injection I week later. 3 weeks after the second injection test bleedings were made. If the serum gave a strong precipitin reaction in agar gel with antigen at a concentration of 1 mg per ml, the rabbit was e~mnguinated. Weak reactors were given a booster injection of antigen and retested. Serums

Formation, Clearance, Deposition, Pathogenicity, and Identification of Biopharmaceutical-related Immune Complexes

“…After a single dose, the ICs initially localize to neutrophils, Kupffer cells, and sinusoidal lining cells in liver; neutrophils, macrophages, and sinusoidal lining cells in spleen; and neutrophils, macrophages, and endothelium in alveolar capillaries or larger vessels in lung. In kidney, ICs were found in glomerulus (capillary walls, intercapillary spaces, and basement membrane) but also were observed in walls of afferent arterioles, peritubular capillaries, tubular epithelium, and tubular lumens (Mellors and Brzosko 1962). After 48 hr, the ICs were found primarily associated with germinal center cells in spleen with limited glomerular deposition in kidney (Mellors and Brzosko 1962).…”

“…In kidney, ICs were found in glomerulus (capillary walls, intercapillary spaces, and basement membrane) but also were observed in walls of afferent arterioles, peritubular capillaries, tubular epithelium, and tubular lumens (Mellors and Brzosko 1962). After 48 hr, the ICs were found primarily associated with germinal center cells in spleen with limited glomerular deposition in kidney (Mellors and Brzosko 1962). If multiple doses of preformed ICs were infused and followed by hyperimmune serum, anaphylaxis was evident and IC deposits were observed to occlude glomerular or alveolar capillary lumens.…”

“…If multiple doses of preformed ICs were infused and followed by hyperimmune serum, anaphylaxis was evident and IC deposits were observed to occlude glomerular or alveolar capillary lumens. Microthrombi were present and associated with ICs phagocytosed by neutrophils and macrophages (Mellors and Brzosko 1962). Notably, studies in Fc receptor-deficient mice indicate that IC engagement of Fc receptors initiates the inflammatory cascade that results in a localized type 3 (Arthus-like) reaction (Sylvestre and Ravetch 1994).…”

Charge of circulating immune complexes as a factor in glomerular basement membrane localization in mice.

“…The factors that determine the sites of IC localization are poorly understood. Repeated studies in experimental animals given intravenous injections of preformed soluble IC (passive serum sickness) have shown that IC lodge predominantly in the glomerular mesangium and occasionally in subendothelial sites (12)(13)(14)(15)(16)(17)(18)(19)(20). Localization in subepithelial sites of the glomerular basement membrane is exceptional (21).…”

Disorganizing-fibrosing processes in alveolar walls of interstitial pneumonia, "alveolopneumonitis": A morphopathological study.

“…It was recognized that immune complex deposits were located not only in basement membrane along alveolar walls but also in epithelial as well as endothelial cytoplasms. It has been also clarified and well-known that antigen-antibody complexes are cleared from the blood by phagocytic activity of reticuloendothelial system (Benacerraf et al 1959;Mellors and Brzosko 1962;Cochrane and Koffier 1973).…”