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Systemic lupus erythematosus is a multifactorial systemic disease in which genetic, immunologic, hormonal, and environmental factors may contribute to disease pathogenesis. Bacterial products (eg, bacterial lipopolysaccharide [LPS]) induce a lupuslike disease in normal mice and trigger an early and accelerated form of lupus nephritis in NZB/W mice. To investigate whether the mechanism by which LPS accelerates nephritis in the NZB/W mice involves interference with processing of immune complexes (IC), we administered LPS to NZB/W mice for 5 weeks and probed the kinetics of removal, liver uptake, and organ localization of a subsaturating dose of radiolabeled IC (2.5 mg of bovine serum albumin-antibovine serum albumin). Control NZB/W mice received vehicle (saline) alone. In NZB/W exposed to LPS, features of polyclonal B-cell activation (PBA) were enhanced, anti-DNA antibodies were raised, and a proliferative glomerulonephritis developed that was associated with renal insufficiency and substantial proteinuria. This LPS-accelerated nephritis could not be attributed to altered complement concentration, to altered blood cell carrier function, to delayed removal of pathogenic (large-sized) ICs from the circulation, to impaired liver uptake of ICs, or to enhanced localization of ICs in kidney. The findings indicate that transformation of nephritis is probably the result of LPS-induced PBA, that defective processing of pathogenic IC is not a contributory factor to nephritis, and that mechanisms other than passive renal localization of circulating ICs must be operative.

Endothelial prolifertion was studied in sites of acute inflammation induced by necrotizing (60 C for 20 seconds) or mild (54 C for 20 seconds) thermal injury to the skin of rsts. DNA synthesis in endothelial cells was assayed 6 hours to 10 days following injury by quantitation of the (3)H-thymidine labeling indices on 2-mu Epon section autoradiographs. In lesions induced at 60 C for 20 seconds, increase in DNA synthesis in small vessels around the necrotic tissue began at 1 day and became significant at 2 and 3 days (10 to 12% for endothelial cells, 9% for perivascular cells). This increased endothelial replication resulted in the formation of new blood vessels by 5 to 7 days. Endothelial labeling diminished progressively after 3 days, as the epidermis regenerated. Foci completely covered by new epidermis consistently showed lower labeling indices than those which were not reepithelialized. Mild thermal injury (54 C for 20 seconds) also resulted in significant increases in endothelial labeling (6%), but the labeling was present mainly in superficial vessels and was not followed by neovascularization. The findings with mild injury are consistent with data that vascular leakage from superficial vessels is due to direct, albeit delayed, endothelial damage. Electron microscopic studies confirmed labeling in endothelial cells and indicated that ultrastructural alterations that were previously ascribed to activation, recovery, or regenerative transformation of endothelium represent, in the main, endothelial proliferation.

Detailed immunopathologic studies of early or silent renal alterations in systemic lupus erythematosus have been sparse. The renal biopsies of 16 lupus patients with normal renal function, including 8 with hematuria and/or proteinuria of recent onset, and 8 without clinically detectable renal disease were investigated by light, immunofluorescence, and electron microscopy. Immunoglobulins, complement components, and electron-dense deposits were detected in glomeruli of all patients, regardless of morphologic appearance or lack of clinical evidence of renal involvement. Features of membranous glomerulonepritis were observed in 4 patients with substantial proteinuria. In the remaining 12 patients, including 3 with hematuria and 4 with slight proteinuria, either minimal glomerular alterations or features of mesangial proliferative glomerulonephritis were seen. Transformation of the original disease was demonstrated in 3 of 3 patients rebiopsied within 2 years. The significance of these findings is discussed in relation to a) the spectrum of clinical and immunopathologic alterations in lupus nephritis and b) transformation of the original disease.

The pathogenesis of proteinuria associated with immune complex disease is incompletely understood. A quantitative electron-microscopic study was undertaken to determine the relative contribution of lesions in capillary loops and mesangial basement membrane areas and their possible correlations to urinary protein excretion data. Pathologic features including the loss of foot processes (and slit diaphragms), the formation of junctional complexes in visceral epithelium, and the distribution of immune complexes in basement membrane were assessed in glomeruli of mice with lupus nephritis. Swiss albino mice served as control animals. In control animals the distribution of split pores per unit length of basement membrane was approximately 60% higher in capillary loop compared to mesangial basement membrane areas. In mice with lupus nephritis, the reduction in the number of slit pores per unit length of basement membrane to 30% or less of normal, the formation of epithelial junctions, and the relative distribution of immune complexes were not statistically different in capillary versus mesangial basement membrane areas. Animals with murine lupus showed poorly selective proteinuria, but the correlation between features studied and extent of protein excretion was poor. The results of these studies 1) establish the relative distribution of slit pores in mesangial and peripheral loop basement membrane, 2) demonstrate that glomerular changes associated with immune complex deposition are comparable in capillary and mesangial basement membrane areas, and 3) are consistent with a focal and nonuniform alteration in glomerular permeability properties associated with immune complex disease.

Patients with progressive systemic sclerosis (PSS, scleroderma) exhibit a variety of immunologic abnormalities. To verify whether the renal vascular lesions of such patients might be mediated by an immunologic mechanism, kidney tissues of 16 patients with PSS were investigated by means of fluorescence, light, and electron microscopy; elution of tissue-bound antibody; and fixation of heterologous (guinea pig) complement. Controls consisted of 12 nonsclerodermatous patients with similar levels of hypertension with no evidence of associated immunologic abnormalities. Diffuse vascular deposits of immunoglobulins (predominantly IgM) and/or complement (predominantly Clq) were found in all 16 patients with PSS. These deposits were bound to the intima of intralobular and arcuate arteries which, by light microscopy, often exhibited typical fibromucinous alterations. Elution of antibody and heterologous complement fixation studies suggested that such reactants may represent the interaction of complement-fixing antibody and antigen. Electron microscopies studies demonstrated abundant fibrillar and ground substance material in the arterial intima but features of deposited (circulating) immune complexes were not found. By contrast, in the hypertensive (control) group, deposits of immunoglobulin (s) and/or complement were rare and, when present, were mostly confined to the arterioles. As judged by the results of elution and heterologous complement fixation, these arteriolar deposits appeared to represent trapped rather than specifically bound serum proteins. The possible signficance of these findings are discussed in relation to immunologic mechanisms which might be implicated in the pathogenesis of the renal vascular disease of PSS.

The glomerular lesions induced in 10 chimpanzees infected with variable numbers of Schistosoma japonicum cercariae were studied by means of light and electron microscopy and fluorescent antibody technic. Ten animals served as controls; 5 were uninfected and 5 were only lightly infected. The animals were observed for periods ranging from 3 to 17 months, and by the time of sacrifice, all had developed advanced liver fibrosis. In general, the degree of glomerular injury was related to infection intensity and degree and duration of portal liver fibrosis. Some animals had terminal BUN elevation and slight proteinuria. By light and electron microscopy, in the initial stages, only part of the glomeruli were involved and exhibited mesangial matrix expansion and mesangial cell proliferation with intracellular hyaline droplets. At later stages, a larger number of glomeruli were affected and exhibited diffuse hypercellularity, glomerular basement thickening, mesangial sclerosis and less often, focal necrosis, crescent formation, synechiae and global hyalinization. In addition, there were discrete electron-dense deposits localized in the mesangial area in some glomeruli. Immunofluorescent studies utilizing antisera to chimpanzee gamma-globulin and complement (C3) and to human properdin disclosed only faint deposits of C3, apparently in mesangial areas. The association of hepatosplenic schistosomiasis and nephropathy, the possible role of schistosomal antigen and the mechanism(s) of such glomerular injuries are reviewed and compared with the disease in humans and other host species infected with Schistosoma.

To verify whether an increase in glomerular permeability precedes the deposition of immune complexes in the capillary wall, the following were studied in mice with lupus nephritis: 1) urinary proteins; 2) glomerular transfer of IgG, albumin, and anionic ferritin (AF) (isoelectric point, 4.2-4.6); and 3) anionic groups of the capillary wall as detected by binding of cationized ferritin (CF) (isoelectric point, 7.5-8.6). The glomeruli were investigated by immunofluorescence, immunoelectron, and transmission electron-microscopic studies. Urinary proteins were quantitated and characterized by electrophoresis. When mice were 5 months of age, (the time at which pathologic proteinuria was first detected), immune deposits were few and were confined to the mesangium. Although AF molecules were largely retained at the level of the lamina rara interna, focal leakage of albumin and IgG was detected across capillary walls that were not found to contain immune deposits. Focal and irregular loss of anionic groups, reflected by decreased binding of CF molecules, occurred in the laminae rarae of the basement membrane. Foot processes of glomeruli incubated with CF showed no loss of polyanion. We conclude that the increase in glomerular permeability that precedes deposition of immune complexes is due, in part, to focal loss of anionic groups of the basement membrane.

A body of evidence suggests that in membranoproliferative glomerulonephritis (MPGN), complement is activated by the alternate pathway. Therefore, deposition of early components of complement should not be expected in glomeruli. The renal tissues of 16 patients--13 with classic MPGN and 3 with dense deposit disease, a variant of MPGN--were studied by light and electron microscopy and by means of elution and immunofluorescence for the localization of complement (C1q, C4, and C3), immunoglobulins (1gG, IgM, and 1gA), and other serum proteins. Variable amounts of C3, C4 and/or C1q, and IgM were detected in the glomeruli of all patients, whereas IgG and IgA were present, respectively, in 15 of 16 and 6 of 16 patients. Deposits were localized in mesangium and in peripheral capillary loops in a typical lobular distribution. The specificity of each antiserum was verified by immunodiffusion, immunoelectrophoresis, and blocking experiments utilizing unlabeled antibody. Glomerular-bound IgG was eluted with acid citrate buffer, suggesting that IgG might be complexed with antigen(s) in glomerular deposits. By light microscopy, lesions ranged from focal proliferation and lobulation to more severe involvement with typical splitting of glomerular basement membranes, sclerosis, and less frequently, crescent formation. Ultrastructurally, all patients with classic MPGN exhibited mesangial and subendothelial deposits, and in 5 of these patients, subepithelial deposits were demonstrated. With the exception of ultrastructural lesions, patients with the dense deposit variant lacked distinguishable features when compared with those with classic MPGN. The significance of these findings is discussed in relation to a) activation of complement and the possible role of an immune complex mechanism and b) the variability of the morphologic expression.

The early local vasoproliferative response induced by live tumor cells and an extract derived from such cells was studied in rat subcutaneous tissue by means of electron microscopy and ultrastructural autoradiography after local injections of tritium-labeled thymidine. DNA synthesis was localized in endothelial cells, pericytes, and perivascular cells 6 to 8 hours after exposure to 10(6) live Walker ascites tumor cells. At this time, DNA-synthesizing endothelial cells in parent vessels exhibited a continuous basement membrane and could not be readily differentiated, ultrastructurally, from control endothelium. At 48 to 50 hours, the number of labeled cells increased and there was ultrastructural evidence of regenerating endothelium: marked increase in ribosomes and endoplasmic reticulum, scarce or absent pinocytotic vesicles, attenuated or discontinuous basement membrane and marked irregularities in cytoplasmic surfaces. Labeled endothelial cells were present in parent vessels, as well as along newly formed sprouts. Autoradiographic and ultrastructural findings after tumor extract or live tumor cells at 48 hours were similar. Evidence was also presented that cells which were recognizable as pericytes, by ultrastructural criteria and by their localization within the basement membrane, were capable of DNA synthesis and mitosis.