The effect of sodium cromoglycate on the induction of experimental IgA nephropathy

Mesangial IgA nephropathy was experimentally induced in ddY mice by oral and parenteral administration of the poliomyelitis vaccine (POLIO), and we then tried to investigate if IgA deposition could be prevented by the concurrent use of sodium cromoglycate (SCG), which is known to inhibit the local mucosal immune reaction. Mucosal and systemic immunity could be induced by the administration of POLIO; proteinuria, increased serum IgA levels, mesangial cell proliferation, mesangial matrix widening, mesangial deposits of IgA, and large electron dense deposits in the mesangium were observed. Concurrent administration of SCG and POLIO resulted in a significant decrease in the serum IgA level and mesangial IgA deposits. The later addition or abstinence of SCG after the 70th day did not influence the glomerular mesangial IgA deposition. But the serum IgA level was still decreased by the continuous treatment of SCG even after the 70th day. Thus, mesangial IgA nephropathy simulating IgA nephropathy in humans could be induced in ddY mice using POLIO and its induction could largely be prevented by the concurrent use of SCG. However mesangial IgA deposits already present could not be cleared by the late administration of SCG.     

Glomerulopathic Light Chain-Mesangial Cell Interactions Modulate in Vitro Extracellular Matrix Remodeling and Reproduce Mesangiopathic Findings Documented in Vivo

Glomerulopathic light chains (LCs) are associated with two distinct mesangiopathies: AL (light-chain-related) amyloidosis and light-chain deposition disease (LCDD) with immunomorphologic features that are well documented in the literature. Even though both conditions are caused by monoclonal LCs, these entities differ dramatically in their morphologic expressions. In AL amyloidosis the mesangial matrix is replaced by amyloid fibrils, while in LCDD the matrix increases as a consequence of deposition of excess extracellular matrix (ECM). The immunomorphologic mesangial alterations observed in biopsy material are closely reproduced in vitro when mesangial cells grown on an artificial matrix are incubated with monoclonal light chains obtained from the urine of patients with either condition. This article summarizes previously reported data, reports new findings, and focuses on integrating all the available information on the subject. When mesangial cells are incubated with LCDD-LCs, production of ECM proteins (collagen IV, laminin, fibronectin, and tenascin) is increased, with maximum effect at 72 hours post LC treatment. A concomitant decrease in collagenase IV activity further accentuates the accumulation of mesangial matrix. These effects are mediated through transforming growth factor-beta (TGF-beta) activation. In contrast, when mesangial cells are incubated with Am-LCs, a decrease in ECM protein production and a stimulatory effect on collagenase IV is observed, which results in matrix degradation and facilitates amyloid deposition. The decreased TGF-beta documented in the literature in this setting precludes adequate matrix repair. These findings substantiate the morphologic alterations observed in renal biopsy specimens and in the in vitro model. Using this in vitro model, it is then possible to delineate the LC interactions with putative receptors at the mesangial cell surface that regulate mesangial cell pathobiologic responses and mesangial matrix homeostasis.     

Relationship between amyloid deposition and intracellular structural changes in familial amyloidotic polyneuropathy

Transthyretin-related familial amyloidotic polyneuropathy is a systemic amyloidosis caused by mutations in the transthyretin gene. Extracellular deposition of amyloid is the common pathologic hallmark of amyloidoses including Alzheimer disease, AL amyloidosis, AA amyloidosis, and familial amyloidotic polyneuropathy. However, the exact relationship between amyloid deposition and cell death has not yet been clarified. To elucidate this relationship, we studied the effect of transthyretin amyloid fibrils and prefibrillar aggregates on cells by using autopsy tissues obtained from 8 patients with familial amyloidotic polyneuropathy, as well as cultured cell lines. Ultrastructural studies of amyloid-laden cardiomyocytes showed that intracellular structural changes correlated with the degree of amyloid deposition and may reflect metabolic disturbances caused by physical limitations imposed by the amyloid deposits. Amyloid-laden vascular endothelial cells, mesangial cells, smooth muscle cells, Schwann cells, and cardiomyocytes, however, had well-preserved cell nuclei and showed no apoptotic changes, even when cells were completely surrounded by prefibrillar transthyretin aggregates and amyloid fibrils. Synthesized prefibrillar transthyretin aggregates, transthyretin fibrils, and amyloid fibrils obtained from patients with familial amyloidotic polyneuropathy evidenced no cytotoxicity in cell culture experiments. Our data thus indicate that neither transthyretin amyloid fibrils nor prefibrillar transthyretin aggregates directly induced apoptosis. However, cellular metabolic disturbances caused by cells' being physically confined by amyloid deposits may induce cell degeneration.     

Pathogenesis of glomerulosclerosis in light chain deposition disease. Role for transforming growth factor-beta.

The glomerulopathy of monoclonal immunoglobulin light chain deposition disease is a progressive disorder characterized by accumulation of monoclonal light chains and matrix proteins in the mesangium. To define the role of light chains in this process, cultured rat mesangial cells were exposed to different light chains and human albumin. Two light chains were purified from the urine of patients who had biopsy-proven light chain deposition disease. These proteins inhibited mesangial cell proliferation and increased production of matrix proteins, including type IV collagen, laminin, and fibronectin. By immunocytochemistry and bioassay, transforming growth factor-beta (TGF-beta) production and activity increased when mesangial cells were exposed to these proteins. Furthermore, anti-TGF-beta antibody abolished the inhibition of cell proliferation and the increase of extracellular matrix protein production caused by these light chains. These findings were not observed in mesangial cells exposed to human albumin and two other light chains previously characterized to be tubulopathic. We concluded that the glomerulopathic light chains increased TGF-beta, which inhibited mesangial cell proliferation and increased matrix protein production. Together with overexpression of TGF-beta in affected glomeruli of light chain deposition disease, light chain-mediated stimulation of mesangial cells to produce TGF-beta appears to be a key pathological mechanism of this disease.     

Participation of endothelial cells in the development of glomerulosclerosis: a study on murine serum sickness nephritis with mitomycin C

To investigate the participation of endothelial cells in glomerulosclerosis, the study was performed in serum sickness nephritis (SSN) with administration of mitomycin C (MMC). SSN was induced in 8 week male Fisher rats by sensitizing them with albumin, chicken egg (EA). Then MMC (0.5 mg/kg bodyweight) was injected daily for 3 days and they were killed at 1, 2, 4 and 6 week intervals. Significant mesangial expansion and sclerosis were observed in the experimental mixed SSN-MMC group in comparison to the SSN or MMC control group from 1 week to 6 weeks (P < 0.05). Moreover at 1 week, double contour appearance of the glomerular capillary wall, basement membrane splitting and disruption were observed light microscopically in the mixed SSN-MMC group. Electron microscopy revealed peripheral capillary basement membrane disruption with huge subepithelial, mesangial osmiophilic deposits and epithelial foot process effacement. At 6 weeks, disappearance of the endothelial cell fenestration and subepithelial basement membrane-like material formation were observed in the MMC group. Based on these results, it is suggested that MMC induced assault on the glomerular endothelial cell produces prominent glomerular capillary basement membrane disruption at the early phase of SSN, resulting in the accumulation of huge subepithelial and mesangial deposits, mesangial cell proliferation, production of the extracelluar matrix component and initiation of glomerulosclerosis.     

The mesangium and glomerulonephritis

Summary The mesangium of the glomerular capillary ultrafilter is a specialized pericapillary tissue. In adult mammals its location is limited to the axial portions of the loop, but it extends peripherally to encircle the capillary in the fetal state and in certain glomerular diseases. It contains predominantly intrinsic mesangial cells, which resemble contractile endocytic capillary pericytes, and which are embedded in the extracellular matrix. In addition, the mesangial space normally harbors few resident Ia-antigen bearing, immune-competent cells and rare transient monocyte-macrophages. Due to its unique location between the fenestrated endothelial lining of the capillary lumen and the glomerular basement membrane, constituting the filtration barrier, the mesangium is prone to deposition of potentially noxious plasma constituents and filtration residues, such as phlogogenic foreign proteins and immune complexes. The determinants of the mesangial entry, uptake and removal of such materials are presently incompletely understood but they are thought to include the amount and nature of the deposit, local hemodynamic factors and the ability of the mesangium to degrade or to eliminate the deposited agent. Histopathologic studies of various human and experimental glomerular diseases reveal that increased mesangial cell proliferation and matrix widening may occur either in direct response to deposits or induced by mediators released from inflammatory cells, such as monocyte-macrophages. While the functional damage to the glomerular filter is usually mild when the reaction is limited to the mesangial space, it is more pronounced when the mesangial abnormalities are secondary to subendothelial deposits of the peripheral capillary wall. Recent experimental data indicate that a mesangial inability in removing deposited material may develop in certain chronic glomerular disorders characterized by marked proteinuria, glomerular hypertension and hyperfiltration or accumulation of matrix material. Such states of mesangial dysfunction may play a critical role in the pathogenesis of progressive glomerular sclerosis. It is concluded that better understanding of the pathophysiology of the mesangium would be valuable for designing more effective diagnostic and therapeutic approaches to patients with glomerular disease.Supported by grants from the Veterans Administration, Washington, DC     

Interleukin-4 transgenic mice develop glomerulosclerosis independent of immunoglobulin deposition

Mice with constitutive transgenic (tg) expression of IL-4 develop autoimmune-type disorders resembling human lupus nephritis. The kidneys show progressive glomerulosclerosis with immunoglobulin (Ig) and complement deposition. This study investigated the roles of renal IL-4 expression and glomerular Ig deposition in the pathogenesis of glomerulosclerosis in IL-4 tg mice. Treatment of these mice with IL-4 neutralizing antibody prevented renal disease. IL-4 tg mice treated with methylprednisolone (MP) showed increased mesangial collagen deposition with only trace amounts of glomerular Ig. To analyze the relevance of Ig deposition in the development of the renal lesions, IL-4 tg mice were cross-bred with mu chain-deficient mice (muMT-/-), which are unable to produce Ig. IL-4 tg/muMT-/- mice developed progressive glomerulosclerosis with mesangial accumulation of collagen types I, IV and V despite complete absence of glomerular Ig deposits. Renal IL-4 expression was observed in both anti-IL-4- and MP-treated IL-4 tg mice as well as in IL-4 tg/muMT-/- mice. No statistical difference in the number of glomerular T cells and macrophages between any of the groups was evident. Our data demonstrate that in this model glomerulosclerosis can develop independently of and prior to Ig deposition, and suggest that the initial accumulation of glomerular extracellular matrix is due to renal IL-4 expression. Our results point to a novel mechanism for the development of glomerulosclerosis which may have implications for human disease.     

Effect of IgA deposits on the glomerular mesangium in Berger's disease

In mesangial IgA glomerulonephritis (Berger's disease), the immunoproteins appeared to gain access from the capillary lumen to the mesangium via endothelial fenestrae or via channels between the endothelial cells. The deposits are transported into the deeper mesangium by a process of inhibition or diffusion, with the matrix acting as the head. There are no true channels or grooves in the mesangial matrix for the transport of the immunoproteins. The contractility of the glomerular myoid fibrils may account for the movement of deposits to the hilus for possible removal. There was partial dissolution of the deposits in the mesangial matrix accompanied by loosening of the matrix. No evidence was found for any significant intracellular phagocytosis and digestion. The mesangial deposits directly or indirectly stimulated the cellular hypertrophy and hyperplasia and increased deposition of mesangial matrix. This was accompanied by formation of collagen fibrils within the thickened matrix and led to atrophy of the mesangial cells and sclerosis of the glomeruli.     

State of humoral and cellular immunity in experimental amyloidosis]

On a model of caseine amyloidosis in 52 rabbits it was shown that in the preamyloid phase the humoral immunity was stimulated, but as soon as the first deposits of amyloid appeared, it was inhibited. The cellular immunity was inhibited starting from the 20th day of the experiment. On the 40th day of the experiment the cellular immunity was found to be less inhibited in the animals with initial deposits of amyloid as compared with the animals with no amyloidosis; on the 60--80th day in progressing of amyloidosis differences in the degree of inhibition of the cellular immunity were obliterated. The degree of fixation of IgG in amyloid was directly dependent on its content in the blood serum and on the "age" of amyloid.     

SPARC is expressed by mesangial cells in experimental mesangial proliferative nephritis and inhibits platelet-derived-growth-factor-medicated mesangial cell proliferation in vitro.

Mesangial cell proliferation is a characteristic feature of many glomerular diseases and often precedes extracellular matrix expansion and glomerulosclerosis. This study provides the first evidence that SPARC (secreted protein acidic and rich in cysteine) could be an endogenous factor mediating resolution of experimental mesangial proliferative nephritis in the rat. SPARC is a platelet-derived-growth-factor-binding glycoprotein that inhibits proliferation of endothelial cells and fibroblasts. We now show that SPARC is synthesized by mesangial cells in culture and that SPARC mRNA levels are increased by platelet-derived growth factor and basic fibroblast growth factor. Recombinant SPARC or the synthetic SPARC peptide 2.1 inhibited platelet-derived-growth-factor-induced mesangial cell DNA synthesis in vitro. In a model of experimental mesangioproliferative glomerulonephritis, SPARC mRNA was increased 5-fold by day 7 and was identified in the mesangium by in situ hybridization. Similarly, SPARC was increased in glomerular mesangial cells and visceral epithelial cells by day 5 and reached maximal expression levels by day 7. Mesangial cell proliferation increased by 36-fold on day 5 and decreased abruptly on day 7. Maximal expression of SPARC was correlated with the resolution of mesangial cell proliferation. We propose that SPARC functions in part as an endogenous inhibitor of platelet-derived-growth-factor-mediated mesangial cell proliferation in glomerulonephritis and that it could account for the resolution of cellular proliferation in this disease.     

Mesangial proliferative glomerulonephritis.

Eleven cases of mesangial proliferative glomerulonephritis whose kidney biopsies were studied with light, immunofluorescent, and electron microscopy are described. Nine patients presented with nephrotic syndrome, one with proteinuria and hematuria, and one with proteinuria alone. Morphologically mesangial proliferative glomerulonephritis was characterized by diffuse mesangial cell proliferation and some increase in mesangial matrix. On immunofluorescence, mesangial IgM deposition was observed in all cases and was considered a distinct feature of mesangial proliferative glomerulonephritis. Electron microscopy showed electron-dense granular deposits within the mesangial matrix in four cases. The clinical course was variable. Of the eight cases with nephrotic syndrome, four treated with steroids alone and four treated with steroids and cytotoxic drugs, one in each group achieved remission while the remaining patients continued to have steroid dependency or resistance. Two of these latter patients manifested steroid responsiveness, steroid resistance, and spontaneous remission at different times in their courses. Renal function remained normal in all. These cases demonstrate that mesangial proliferative glomerulonephritis is an entity characterized by increased mesangial cellularity, deposition of IgM in a mesangial distribution, a relatively benign course, and variable response to treatment.     

The morphological heterogeneity of mesangioproliferative glomerulonephritis

Three variants of mesangioproliferative glomerulonephritis (MPGN) are distinguished on the basis of quantitative and qualitative morphological study of 172 kidney biopsies. The first variant is characterized by subendothelial and mesangial deposits of IgA and C3 in the glomeruli, the lack of fibroplastically transformed (FT) glomeruli and small tubulointerstitial component (TIC), the predominance of the phagocytizing mesangial cells; the second variant by the subendothelial deposits in the glomeruli of IgM or IgM and C3, the absence of FT glomeruli and TIC, the presence of an equal number of phagocytizing and synthetizing mesangial cells. Glomerular deposition of IgG or the absence in the glomeruli of all immunoglobulins and C3, the presence of FT glomeruli and TIC, pronounced accumulation of mesangial matrix and moderate proliferation of predominantly synthetizing and fibrosing mesangial cells are characteristic of the third variant. Recognition of the MPGN variants allows one to understand the variety of its clinical manifestations and differing prognosis.     

THE FINE STRUCTURE OF GLOMERULAR EPITHELIAL CELLS IN EXPERIMENTAL RENAL AMYLOIDOSIS

The fine structure of the three types of glomerular cells, especially glomerular epithelial cells was studied In experimental renal amyloidosis induced by both prolonged sensitization of focus antigens and casein.
The presence of cytoplasmic invaginations which contained a bundle of amyloid fibrils in almost parallel array and intracytoplasmlc membrane-surrounded amyloid fibrils were observed in the glomerular epithelial cells. They are quite comparable to those which were demonstrated in reticuloendothelial cells In other reports. The intracytoplasmlc invaginations opened at the plasma membrane either in the urinary space or in the basement membrane. By processing serial sections on the minimal deposition of amyloid, some of the Intracytoplasmlc membrane-surrounded amyloid fibrils were found to be connected with parallel arrayed extracellular amyloid fibrils.
Amyloid accumulated usually In large amount In mesangial matrix and along the basement membrane adjacent to the mesangium, but isolated depositions of amyloid, minimal though definite, were sometimes observed in the subepithelial and subendothelial areas, and in the epithelial cells far from the mesangium.     

Fibrillary renal deposits and nephritis.

Fibrillary renal deposits and nephritis. The authors have studied 8 patients whose glomeruli contain abundant fibrils in their mesangial matrix and basement membranes. Although the location of these fibrils is very similar to that of amyloid, they are about twice the size of amyloid fibrils, averaging 20 nm in width, and fail to react as amyloid does with special stains. Immunofluorescence-microscopic studies are usually positive with antiserums to IgG, often IgM, and in some cases IgA, and also kappa and lambda light chains, C3, and C4. The fibrils are associated with diffuse mesangial widening and increased mesangial matrix strands. Although peripheral glomerular capillary walls appear to be spared initially, their eventual involvement leads to glomerular capillary collapse and glomerular obsolescence. Crescent formation occurred in 5 cases, focally in 3 and diffusely in 2. Tubular basement membrane involvement was seen in 1 case. These patients exhibit hematuria, and proteinuria, and often hypertension and renal insufficiency. Proteinuria was in the nephrotic range in 3 patients in whom involvement of glomerular capillary basement membranes was extensive. Unless electron microscopy is applied to renal biopsies, these cases may be considered to represent mesangiocapillary or rapidly progressive glomerulonephritis, or amyloidosis. The nature of these fibrils is as yet not determined. It is likely that they have been called "atypical amyloidosis" in the past.     

Glomerulonephritis induced by monoclonal anti-Thy 1.1 antibodies. A sequential histological and ultrastructural study in the rat

The present report describes the natural history of an experimental acute glomerulonephritis with massive proteinuria induced by a single intravenous injection of a (mouse) monoclonal anti-rat Thy 1.1 antibody into the rat. The disease is characterized by direct although transient binding of this monoclonal antibody to glomerular basement membrane and mesangium after injection as demonstrated by immunofluorescence microscopy. Immediate activation of complement occurs as shown by glomerular deposition of C3 and C9. Concomitant activation of the coagulation cascade is reflected by the presence of fibrinogen deposits in the affected glomeruli. One hour after injection mesangial alterations are prominent including condensation of mesangial cell chromatin, and lysis of mesangial cells as shown by light- and electron- microscopy, leading to the formation of aneurysms in the capillary tuft. Commencing on day 4 mesangial cell proliferation can be observed, accompanied by glomerular crescent formation at day 14, which decreases gradually 3 weeks after antibody administration, whereas mesangial hypercellularity can be observed up week 10 after intravenous injection of the antibody. The disease is clinically characterized by a massive transient proteinuria starting immediately after antibody injection, reaching mean values of 300 mg/24 hours at days 2 to 4, gradually decreasing to normal levels after 3 weeks. It is concluded that in this unique model of glomerulonephritis induced by a monoclonal antibody, recognition of Thy 1.1 epitopes as well as activation of complement including the C5-C9 membrane attack complex may play a major role in the pathogenesis of this experimental disease.     

Alpha 1-antichymotrypsin is present together with the beta-protein in monkey brain amyloid deposits

The recent finding that the serine protease inhibitor, alpha 1-antichymotrypsin, is tightly associated with the amyloid deposits in brains of normal aged individuals and patients with Alzheimer's disease [Abraham C. R., Selkoe D. J. and Potter H. (1988) Cell 52, 487-501], suggests a role for this inhibitor in the progressive deposition of brain amyloid in humans. We have used immunocytochemistry to detect alpha 1-antichymotrypsin in the amyloid that accumulates in brains of aged monkeys, a naturally occurring animal model of Alzheimer-like neuropathology. In monkeys of increasing age, the earliest alpha 1-antichymotrypsin immunoreactivity was found in cortical perivascular cells, before the appearance of either Thioflavin S-detectable amyloid deposits or beta-protein reactivity in the vessel walls. Subsequently, amyloid deposits appeared in small meningeal blood vessels and cortical neuritic plaques. The oldest monkeys also showed microvascular amyloid in the cortical gray matter. Amyloid was never seen in white matter. The amyloid deposits in meningeal vessels were always positive for both beta-protein and alpha 1-antichymotrypsin, whereas in the cortex, alpha 1-antichymotrypsin immunoreactivity seemed to appear somewhat later than that of beta-protein. These findings demonstrate that two of the brain amyloid components of human senescence and Alzheimer's disease--the beta-protein and the protease inhibitor alpha 1-antichymotrypsin--are also present in the amyloid deposits of normal aged monkey brain. The extended molecular parallels between normal brain aging and Alzheimer's disease suggest that similar biochemical mechanisms may underlie progressive amyloid deposition in both situations.     

Experimental canine adenovirus glomerulonephritis: histological,immunofluorescence and ultrastructural features of the early glomerular changes.

Eighteen 16-week-old dogs were inoculated i.v. with a virulent strain of canine adenovirus and the renal glomeruli were examined by light, electron (transmission and scanning) and immunofluorescence microscopy at intervals from 24 h to 7 days after inoculation of virus. From 2 days onwards intranuclear inclusion bodies and cell-associated viral antigen were detected in mesangial, endothelial and circulating mononuclear cells. This was accompanied by swelling and, in some cases, necrosis of these cells with partial or complete occlusion of capillary loops. In 5 dogs examined on days 5-7 after inoculation of virus, granular deposition of IgG, C3 and viral antigen was observed in mesangial areas and electron dense deposits were found in the mesangial matrix.     

Nodular glomerulopathy associated with nonamyloidotic kappa light chain deposits and excess immunoglobulin light chain synthesis

A nodular glomerulopathy characterized by mesangial deposits of monoclonal kappa light chains was detected by immunofluorescence in a renal biopsy from a patient with proteinuria and hypertension. These nodules lacked the tinctorial and morphologic features of amyloid. Ultrastructurally, the nodules contained electron-dense granular deposits as well as fibrils in parallel arrangement. The fibrils measured 110-140 A in diameter. They were consistent in size with amyloid fibrils. However, they differed in lacking the randomly oriented network of typical amyloid fibrils and more closely resembled fibrils intrinsic to mesangial matrix. The patient had no bone marrow or X-ray evidence of myeloma and no evidence of free monoclonal light chains in serum or concentrated urines. Biosynthetic studies of the patient's bone marrow cells demonstrated unbalanced immunoglobulin synthesis with excess production of monoclonal kappa light chains. These observations suggest that the observed glomerulopathy results from direct deposition of monoclonal light chains. Deposits with kappa light chain determinants have been found in 7 other patients with similar nodular glomerulopathies, 4 of whom had diagnosed clinical myeloma. The lesion of nonamyloidotic nodular glomerulopathy previously described in 19 patients, nor examined by immunopathologic techniques or not shown to contain light chain determinants, may have a similar pathogenesis.     

Fate of immune complexes, glomerulonephritis, and cell-mediated vasculitis in lupus-prone MRL/Mp lpr/lpr mice

Immune complex formation was induced by the injection of (125)I-BSA into female MRL/Mp lpr/lpr mice, which develop spontaneous systemic lupus erythematosus (SLE)-like disease, and MRL/Mp +/+ mice, which do not. At designated intervals following the injection of 10 mg of (125)I-bovine serum albumin (BSA), the nonlupus mice developed sparse, small electron-dense deposits in mesangial areas and subepithelial immune deposits that underwent partial resolution. By contrast, glomeruli of the SLE-prone mouse kidneys revealed proliferation of mesangial cells and some increase in mesangial matrix material. Numerous subepithelial and mesangial electron-dense deposits were present. Some subendothelial and intramembranous deposits were also demonstrated. Capillary lumens contained massive electron-dense deposits. The resolving subepithelial deposits observed were fewer than half the number found in kidneys of the non-SLE mice. Whole body counts were also recorded daily following the injection of (125)I-BSA. Whereas, both lupus-prone and non-SLE control mice eliminated (125)I-BSA at equivalent rates through day 12 postinoculation, those with SLE-like disease showed a decreased (125)I-BSA elimination rate between days 6 and 12. Results suggest an impairment in the ability of SLE-prone mice to resolve immune complexes, whether they are nuclear-antinuclear or from an exogenous source, i.e., BSA-anti-BSA, compared to controls in this experimental model of the superimposition of exogenous immune complex formation on systemic lupus erythematosus-like disease.