Jimmy L. Roberts

Immunopathology of cardiac lesions in fatal systemic lupus erythematosus.

Immunopathologic studies were performed on cardiac tissue obtained at autopsy in 10 patients with severe systemic lupus erythematosus (SLE). The immunopathologic findings were correlated with histopathologic and clinical evidence of cardiac injury, and with clinical and serologic features of SLE. Immune reactants were demonstrated by direct immunofluorescence in nine patients in a granular deposition pattern suggesting immune complex aggregates. Histologic and gross anatomic findings of inflammation were generally more focal than was the distribution of immune reactants. Most of the immune deposits were present in the walls of the blood vessels of myocardium (eight of 10) or pericardium (two of three). In one patient with Libman-Sacks endocarditis, immunoglobulin and complement components were present in the valve stroma and the vegetations. The immune deposits around epicardial nerve fibers in two patients with severe neurologic manifestations contained immunoglobulin E(IgE). In general, the most intense and widespread immune deposits were observed in patients with persistently increased serologic and clinical evidence of activity of their systemic disease. These results suggest a role for immune complex deposition in the pathogenesis of the cardiac lesions of SLE.

Differential characteristics of immune-bound antibodies in diffuse proliferative and membranous forms of lupus glomerulonephritis

Diffuse proliferative (PGN) and membranous (MGN) glomerulonephritis represent contrasting histologic lesions in systemic lupus erythematosus (SLE). Serum, cryoglobulins, and renal biopsies in 8 SLE patients with PGN and 8 with MGN were studied in order to determine whether variations in the properties of immune-bound antibodies correlate with the pattern of glomerular involvement. Several immunologic parameters suggested differences in complement activation between the two groups. PGN cryoglobulins demonstrated immunoglobulin G (IgG) anti-native DNA (nDNA) subclass heterogeneity with highest titers of IgG3. These findings contrasted with the observation that MGN was characterized by a predominance of IgG4 in cryoglobulins. The major glomerular IgG subclasses in PGN were IgG3 and IgG1, while MGN biopsies demonstrated IgG4 in largest amount. Serum C1q was lower in PGN than in MGN. Serum anti-nDNA antibodies, solid-phase C1q-binding IgG immune complexes, and cryoglobulin protein concentrations were higher in PGN sera. Cryoglobulin complement component and control protein concentrations were greater in PGN than in MGN, while cryoglobulin Ig and immune-bound anti-nDNA were not different. In vitro C3 fixation by cryoglobulin anti-nDNA was greater in PGN than in MGN. Glomerular C1q, C4-binding protein (C4bp), and C3c were present in comparable amounts to IgG deposits in PGN biopsies, while in MGN IgG was demonstrable in greater quantities than C1q, C4bp, and C3c. In contrast, glomerular C3d (alpha 2d), C5, C6, P, and H were comparable in the two groups. It was concluded that immune-bound antibodies in cryoglobulins and in glomerular immune deposits in SLE PGN appear to activate complement via the classical and alternative pathways, while complement activation in MGN appears to occur predominantly via the alternative pathway. These differences in IgG subclass composition may account for the differential complement activation and may explain the contrasting histologic expression of immune aggregate localization in glomerular capillaries in these variants of lupus nephritis.

Necrotizing glomerulitis of systemic lupus erythematosus

The authors report four cases of systemic lupus erythematosus (SLE) with severe, active glomerulonephritis. Associated with histologic evidence of glomerular inflammation were focal, predominantly mesangial immune reactants. This finding contrasts with reports that massive subendothelial electron-dense deposits are the ultrastructural feature that correlates best with the severity of glomerular inflammation. The patients studied had significantly fewer subendothelial electron-dense deposits than did other patients with SLE with comparable glomerular lesions (8 +/- 3 per cent versus 42 +/- 14 per cent of glomerular capillaries involved, respectively; P less than 0.05). In addition, serologic evidence of disease activity, assessed by measurement of serum levels of C3, C4, circulating immune complexes (cryoglobulins), and serum antinative DNA activity, was either normal or only mildly abnormal. The lack of correlation between the severity of glomerular lesions on the one hand and the paucity of glomerular immune reactants and mild serologic abnormalities on the other may be interpreted as questionable evidence that these cases of glomerulonephritis were mediated by immune complexes. In the light of recent clinical and experimental studies that support a possible role for cell-mediated immunity in the pathogenesis of glomerulonephritis, the authors propose that a role for cell-mediated hypersensitivity be considered.

Clinical and Pathological Features of Membranous Glomerulonephritis of Systemic Lupus erythematosus

The prognostic significance of glomerular inflammation in patients with lupus membranous glomerulonephritis (MGN) was evaluated by classifying 100 renal biopsies from lupus patients according to World Health Organization (WHO) criteria and correlating the histology with clinical data. There were 22 cases of MGN: in 3 the lesion was pure MGN (Va); in the remainder, diffuse MGN was modified by superimposed mesangial proliferation in 6 (Vb), segmental glomerulonephritis (GN) or sclerosis in 10 (Vc), and diffuse GN in 3 (Vd). Patients in the four categories had similar clinical presentations. When the 4 patients with active proliferative glomerulonephritis (PGN) were grouped and compared to those without PGN, they had more active serologies. Quantitation of glomerular electrondense deposits in MGN showed variation in the percentage of basal lamina covered by subepithelial deposits, segmental subepithelial deposits in 4 cases, focal segmental subendothelial deposits in most cases and massive subendothelial deposits in 5 biopsies. 4 of the latter patients had active PGN, suggesting that only extensive subendothelial deposits are pathogenetically significant. The predicted 5-year survival for all MGN patients was 90%, and the only 2 deaths were not related to renal failure. Thus, it appears valid to include mixed lesions in the membranous category, but it is our impression that the immediate course and prognosis of SLE and associated PGN depends upon the extent and reversibility of the inflammatory lesions.

Membranous and vascular choroidopathy: Two patterns of immune deposits in systemic lupus erythematosus

Two patterns of immune aggregate localization were demonstrated by immunofluorescence and electron microscopy in the choroid plexus of four young women with fatal systemic lupus erythematosus. The two patients with granular immune aggregates localized to the basement membrane of the choroid epithelium (membranous choroidopathy) had subepithelial and intramembranous electron-dense deposits and membranous glomerulopathy in their kidneys. The two patients with immune aggregates in the walls of choroidal blood vessels (vascular choroidopathy) had subendothelial electron-dense deposits and proliferative glomerulonephritis. Vascular deposits in the choroid plexus were associated with capillary thrombi and extravasation of fibrinoid material, while isolated membranous choroidopathy had no histopathologic evidence of inflammation. The clinical presentation and serological studies of blood and cerebrospinal fluid were compared in an effort to discriminate between patients with membranous and vascular choroidopathy. All patients had variable neuropsychiatric symptoms and major motor seizures. While those with vascular choroidopathy had more evidence of disease activity in their sera, both groups demonstrated elevated titers of immune-complexed antinuclear antibodies in cerebrospinal fluid. Although both patterns of choroidal localization of immune aggregates were associated with neuropsychiatric dysfunction, we were unable to identify discrete clinical-symptom complexes which differentiated patients with membranous and vascular choroidopathy. These contrasting patterns of choroid plexus immunopathology suggest that factors responsible for differential localization of immune aggregates are not restricted to the renal glomerulus.

Subpithelial Electron-Dense Deposits in Proliferative Glomerulonephritis of Systemic Lupus Erythematosus

Subepithelial electron-dense deposits (SED) were found in the renal biopsies of 36 of 59 patients with systemic lupus erythematosus (SLE). The SED were divided into two groups based on their ultrastructural appearance and distribution within the glomeruli. Type I SED were regular in size and shape, had a homogeneous electron density and a diffuse distribution within the glomeruli, and involved all of the glomeruli in the biopsy. In contrast, the type II SED were irregular in size and shape, tended to be quite large, and had variable electron density. They were present in reduced numbers in involved capillary loops, and they were absent from other loops within the same glomerulus. Type I SED were seen in cases of membranous SLE glomerulonephritis (GN), and type II SED were associated with severe proliferative SLE GN. Although the patients with proliferative GN had more active urinary sediments at the time of biopsy than did the patients with membranous GN, the mean serum creatinine and urinary protein excr...

Low-molecular-weight plasma cryoprecipitable antinative DNA: polynucleotide complexes in lupus glomerulonephritis.

Abstract The DNA antigen:anti-DNA antibody system was studied in plasma cryoprecipitable-immune complexes (cryoglobulins) isolated from patients with systemic lupus erythematosus (SLE) glomerulonephritis in order to determine the molecular weight of DNA:anti-DNA and to characterize the DNA in these precipitates. Cryoglobulins from four patients were subjected to sucrose gradient ultracentrifugation. Gradient fractions with a molecular weight between 6.5 and 10 S demonstrated the greatest amount of immunoglobulin (Ig) G-immune complex reactivity in the Raji cell and solid-phase Clq assays. The highest titers of immune-bound IgG antinative DNA (nDNA) antibody were demonstrated in 6.5 to 10 S fractions in all samples. Immune-bound IgG and IgM anti-nDNA antibodies were identified less frequently in high (16 – 30 S)-molecular-weight fractions. Protease-digested fractions tested with ethidium bromide for double-stranded DNA revealed ethidium-reactive material at 6.5 to 10 S, as well as in heavier fractions, indicating that immune-bound, double-stranded DNA determinants are present in the same fractions that contain the largest quantities of IgG anti-nDNA. DNA was identified using counterimmunoelectrophoresis only in high-molecular-weight fractions in two of the samples. We conclude that low-molecular-weight anti-nDNA:polynucleotide complexes constitute the major portion of cryoprecipitable-circulating DNA:anti-nDNA in SLE patients with glomerulonephritis.

The quest for an intrinsic C3 activating factor in human glomerular disease

While there is a voluminous literature on the subject of in vitro mechanisms of complement activation, tittle is understood about the events which lead to complement activation in certain forms of glomerulonephritis. One of the most perplexing examples of our ignorance concerns the pathogenetic events leading to glomerular damage in membranoproliferative glomerulonephfitis (MPGN), a disease which is associated with evidence of abnormal complement activation in the plasma and glomeruti of effected individuals [1-4]. On the basis of ultrastructural morphologic and immunopathoMgic features, MPGN has been divided into several categories: type I, with subendothelial glomerular immune-reactant deposits; type II, characterized by immune deposits within the glomerular basement membrane; and type III, a variant of type I, which demonstrates both subendothelial and subepithelial deposits [5-7]. Type I lesions are associated with serum abnormalities suggesting activation of both the classical complement pathway (CCP) and the alternative complement pathway (ACP),

Circulating Immune Complexes and Systemic Lupus Erythematosus

The immunopathologic features of systemic lupus erythematosus appear analogous to the vascular lesions found in experimental serum sickness (1). Ultrastructural and immunopathologic studies reveal the deposition of immune aggregates not only in various renal structures, but also in the pulmonary alveolar capillary bed (2), myocardial vessels (3), choroid plexus (4) and the media of larger arteries (5). Because the development vascular lesions in experimental acute serum sickness appears at a time when there are circulating immune complexes, much attention has been centered around the role of these complexes in the pathogenesis of inflammatory diseases of small vessels.