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Polyclonal B cell activation (PBA) and autoimmune disease can be induced in immunologically normal mice, or enhanced in lupus-prone mice, by bacterial lipopolysaccharide (LPS). Because immune defects are common in autoimmune diseases and IgA deficiency is prevalent in patients with systemic lupus erythematosus, we investigated: (i) whether LPS might induce IgA deficiency in normal mice; (ii) whether IgA deficiency might be a feature in lupus-prone mice; (iii) whether, if present in lupus-prone mice, IgA deficiency could be further accentuated by LPS; and (iv) whether the effects of LPS on IgA concentrations of normal and lupus-prone mice might be reversible upon withdrawal of LPS. We injected normal (C57BL/6) and lupus-prone (NZB/W) mice with 50 μg of LPS from Salmonella minnesota Re595 twice a week for 5 weeks and then discontinued LPS for 6 weeks. We determined the concentrations of plasma immunoglobulins, DNA antibodies, and circulating immune complexes before, during, and after mice were exposed to LPS. Our results indicate that: (i) LPS induces IgA deficiency in normal mice concurrently with PBA; (ii) IgA deficiency is a feature of lupus-prone mice; (iii) LPS accentuates naturally occurring PBA and IgA deficiency in lupus-prone mice; and (iv) LPS induced, or LPS enhanced, IgA deficiency and PBA in normal and lupus-prone mice persist long after withdrawal of LPS. Thus, LPS triggers or enhances autoimmune disease by a mechanism that involves in part PBA with selective increase (IgG, IgM) and concurrent decrease (IgA) of specific isotypes. [ABSTRACT FROM AUTHOR]

To gain some insight into the pathogenesis of proliferative lupus nephritis in MRI-lpr mice we investigated the kinetics of removal of immune complexes from the circulation, the carrier state of blood cells, the uptake of complexes by the mononuclear phagocyte system, and the localization of complexes in kidneys. In nephritic MRL/lpr mice challenged with a subsaturating dose of radiolabelled complexes (25 mg bovine serum albumin-anti-bovine serum albumin) liver uptake was profoundly decreased., removal of circulating complexes was delayed, and 12-h kidney localization of complexes was enhanced 7-3-fold, in comparison to control mice. The findings were not encumbered by differences in complement concentration and most likely are attributable to various altered immune functions: spontaneous polyclonal activation of B cells, enhanced production of endogenous immune complexes, delayed removal of complexes from the circulation, and decreased uptake of complexes by the mononuclear phagocyte system. In concert, such altered functions contribute to prolonged circulation of complexes to result in their enhanced deposition in the mierocirculation. [ABSTRACT FROM AUTHOR]

We investigated the effects of cyclophosph amide (Cy) on immunoreactants of plasma and kidney of mice with lupus nephritis. Cy therapy decreased plasma concentrations of IgG. but not the concentrations of anti-DNA antibodies. C3. and Clq reactive materials; in glomeruli deposits of immunoreactants were mesangial in location and decreased overall. Although Cy arrested the nephritis of NZB/W mice, the anti-DNA activity in the renal eluates was very low and comparable in untreated and in treated mice. Immune complex systems other than, or in addition to. DNA anti-DNA are likely to play a role in the pathogenesis and course of murine lupus nephritis. [ABSTRACT FROM AUTHOR]

We investigated the effect of azathioprine on glomerular permeability and deposition of immunoreactants in NZB/W mice. Glomerular permeability, assessed by proteins excreted in the urine and by a molecular probe of anionic sites of the basement membrane, underwent negligible changes, in comparison to pre-treatment findings, and deposits of immunoreactants were largely mesangial and were decreased overall. Therapy with azathioprine preserved glomerular structure and function by decreasing the amount of immunoreactants, by inducing a preferential mesangial localization of immunoreactants, and, possibly, by interfering with factors that favor the deposition of immunoreactants in the glomerular capillary wall. [ABSTRACT FROM AUTHOR]

We investigated the effect of cyclophosphatnide on glomerular permeability and deposition of immunoreactants in NZB/W mice. Glomerular permeability, assessed by proteins excreted in the urine and by a molecular probe of anionic sites, remained unaltered, compared to pretreatment studies, and deposits of immunoreactants were mesangial and decreased overall, in comparison to untreated NZB/W mice. Therapy with cyclophosphamide may prevent deterioration of glomerular filtration characteristics by interfering with factors that favour the deposition of immunoreactants in the glomerular capillary wall. [ABSTRACT FROM AUTHOR]

Trypan blue has previously been shown to inhibit complement-mediated phagocytosis by inter- action with the C3 receptor but not with the Fc receptor. In studies reported here, trypan blue inhibited EAC3 rosette formation with human polymorphonuclear leucocytes (PMN) and mononuclear cells, rabbit alveolar macrophages (AM) and peritoneal PMN, and guinea-pig spleen cells. Trypan blue also inhibited C3-mediated bacterial adherence to the same receptor-bearing cells and to human glomerular cells. EAC3bi rosette formation was also inhibited, but BAC3d rosettes were not detected in our assay system. Although the precise molecular nature of C3b fragments deposited on antibody-sensitized erythrocytes has not been fully determined, trypan blue probably inhibits all C3 receptors from different species and may prove useful in vivo and in vitro for the definition of C3-receptor function in various aspects of the immune response. [ABSTRACT FROM AUTHOR]

Six patients with coexistent antiglomerular basement membrane disease and granular immunoreactants in the glomerular basement membrane and mesangium are discussed. These six patients represent 35% of all patients with antiglomerular basement membrane nephritis examined over 10 years. All patients presented with acute, oliguric renal failure, and rapid deterioration in renal function. In all patients the pathogenetic role of the antiglomerular basement membrane antibody was confirmed by the demonstration of linear deposits of IgG along the glomerular basement membrane and antiglomerular basement membrane antibody activity in the serum or renal eluates, or both. Evidence for the existence of concurrent immune aggregates was obtained by immunofluorescence studies and electron microscopy. Radioimmunoassays, which were performed in two patients to detect circulating immune complexes, however, yielded negative results. The possible mechanisms concerned in the evolution of this condition and their potential implications are reviewed. [ABSTRACT FROM PUBLISHER]

Circulating immune complexes (CIC) containing Treponema pallidum proteins have been preliminarily implicated as inducers of a neutrophilic vascular reaction in early human cutaneous lesions of secondary syphilis. To clarify the role of specific GIG in producing cutaneous and renal lesions, 12 rabbits were studied at the following intervals after induction of disseminated syphilis: 20 days (4 rabbits: biopsies of normal and lesional skin for direct immunofluorescence (IMF) for (IgG, IgM, IgA, Clq, C[sub3], C[sub4]), fibrin, and T. pallidum proteins; routine histology; and immunoblots of serum for CIC containing T. pallidum proteins); 21 days (4 rabbits: as at 20 days without IMF for T. pallidum protein); 23 days (4 rabbits: as at 20 days without IMF); 30 days (same 12 rabbits restudied with routine histology of normal and lesional skin; kidneys from 4 rabbits removed for routine, IMF, and electron microscopy (EM). Treponemal polypeptide antigen (MW-87kd) was demonstrated in CIC from rabbits. Routine cutaneous histology showed evolution of lesions from an early neutrophilic vascular reaction to the typical lymphoplasmacytic reaction. IMF showed vessel-based immunoreactants in 3 of the 4 rabbits tested at 20 days and 1of 4 at 21 days, and T. pallidum proteins in 3 of 4 rabbits at 20 days. Routine histology, IMF, and EM studies of glomeruli showed glomerular abnormalities, but no evidence of immune deposits containing specific T. pallidum protein. Skin and kidney studies of 4 controls were all negative. These data indicate a role for specific immune complexes in the pathogenesis of cutaneous lesions in this rabbit model. [ABSTRACT FROM AUTHOR]