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Henoch-Schönlein purpura (HSP) is a systemic disorder characterized by small vessel vasculitis with the deposition of IgA immune complexes. Renal involvement is the major cause of morbidity and mortality in patients with HSP. We report here a 37-year-old female patient with HSP nephritis (HSPN) associated with steroid-resistant nephrotic syndrome and renal dysfunction despite conventional therapy. The patient was successfully treated with intravenous cyclophosphamide following treatment with intravenous pulse methylprednisolone and oral prednisolone. The combination therapy resulted in a significant decrease in proteinuria, together with improvement of renal function. The patient finally reached a stage of clinical remission.

We report here two interesting cases of systemic lupus erythematosus(SLE) accompanied by antiphospholipid syndrome nephropathy(APSN). These cases satisfied the criteria for SLE established by the American College of Rheumatology 1997 and also satisfied the criteria for antiphospholipid syndrome (APS) established by the Sapporo International Workshop of APS 1998. Both cases had high blood pressure with elevated plasma renin activity, proteinuria and renal dysfunction. Their biopsied renal specimens showed the characteristic findings for APSN, such as mesangial proliferation, double contours, thickening of the capillary loops, and intimal hyperplasia, but there was no evidence for immune complexes in the glomeruli, which were examined by the indirect immunofluorescence methods and the electron microscopy method. These results indicated that their renal dysfunction was caused by APSN, but not by immune complex nephritis. In addition to treatment with prednisolone, they were administered anticoagulants(warfarin, or aspirin, or heparin) for APSN and an angiotensin II receptor blocker, candesartan, for the hypertension. Subsequently, their conditions recovered with the improvement of renal function and hypertension. Our experiences suggest that anticoagulant therapy in addition to corticosteroids offers advantages in the treatment of patients with SLE accompanied by APSN and renal dysfunction.

IgA nephropathy (IgAN), a common glomerular disease, is characterized by the presence of IgA deposits, predominantly in the glomerular mesangium, and by mesangial proliferative glomerulonephritis (GN). Concerning its pathogenesis, several investigators suggest that the deposited IgA is an antibody to viral, bacterial, or dietary antigens. Thus the antibody is probably produced as part of the specific host immune response to various environmental antigens. Such reports strengthen the possibility of a relationship between mucosal immunity and the pathogenesis of IgAN. Nevertheless, attempts to isolate a specific IgA-circulating immune complex associated antigen in patients with IgAN have been unsuccessful. We have showed that such mucosal infections as pharyngitis are often associated with the acute onset of IgAN. Then IgAN is an immune complex disease that is caused by a poor mucosal immune response to environmental antigens to which the patient has been chronically exposed. We observed that Haemophilus parainfluenzae (HP) is more commonly isolated from the pharynx of patients with IgAN than from those with other diseases. We have also identified the glomerular deposition of outer membranes of HP antigens (OMHP) and an increased serum concentration of IgA antibodies against OMHP in patients with IgAN. Further studies will be necessary to determine whether the association of OMHP antigens in the glomeruli and IgA antibody against OMHP antigens in the sera of patients with IgAN can be confirmed in other parts of the world and whether this association is important in the pathogenesis of IgAN. Nevertheless, the demonstration of glomerular deposition of OMHP antigens and of IgA antibody against OMHP in sera indicates a potential new avenue of investigation into the elusive cause of IgAN.

Complement activation products in pleural effusions were studied to clarify the causes of tuberculous and malignant pleuritis. Pleural SC5b-9, an activation product of complement common pathway, was significantly higher in tuberculous effusions than in malignant ones. In the tuberculous effusions, the levels of SC5b-9 and LDH (a marker of tissue damage) were significantly correlated, but in the malignant effusions these two values were not correlated. In the tuberculous effusions, SC5b-9 and Bb values were significantly correlated, but SC5b-9 and C4d were not, and nor were SC5b-9 and immune complex. In the malignant effusions, SC5b-9 and Bb values were low and were not significantly correlated. These results suggest that complement activation plays a significant role in tuberculous pleuritis, but not in malignant pleuritis.

Almost all of intractable vasculitis have been thought to develop mainly in immunological mechanisms, based on the data from several animal models previously established. Serum sickness models, microbe-induced models and others have contributed to supporting this idea. These models have furthermore indicated that vasculitis could be generated by exogenous factors in normal individuals, and that vasculitis might be explained in monism. However, recent studies in murine lupus suggest that intractable vasculitis requires endogenous factors involving retroviruses and/or genetic background under the control of polygene system. In this review, although not comprehensive, significance of background genes in vasculitis will be focused.

In the early 1900s, von Pirquet first introduced the concept that antigen antibody complexes might cause disease. Since that time, systemic necrotizing vasculitis is believed to be a typical form of immune complex-mediated vasculitis and it may be found in many disorders associated with immunological abnormalities. In 1866, Kusmaul and Maier reported a case with multilesions of necrotizing vasculitis named as periarteritis nodosa which is now nominated as polyarteritis nodosa characterized by the presence of focal inflammatory lesions in small and medium-sized arteries. Besides polyarteritis nodosa, necrotizing vasculitis is frequently found in connective tissue diseases, especially in SLE and RA. Granulomatous vasculitis is a definitely different type of vasculitis from necrotizing vasculitis and known to be found in Wegener's granulomatosis. Whether or not granulomatous vasculitis is an immune complex-mediated disease is unknown, but it can be produced experimentally in several settings. In a experimental model of serum sickness, animals who are hyperimmune responders have widespread granulomatous lesions similar to Wegener's granulomatosis in histology. Intravenous injection of complete Freund's adjuvant in rabbits followed by intravenous administration of human IgM rheumatoid factor is capable of inducing a marked pulmonary granulomatous reaction. The relation of these observations to human Wegener's granulomatosis is uncertain, but the histology and location of the lesions are strikingly similar to human disease. Vasculitis involved in large and medium-sized arteries is seen in two different types of diseases known as temporal arteritis and Takayasu's arteritis. Circulating and tissue-bound immune complexes have been found in both conditions. Most common vasculitis in childhood is Schonlein-Henoch purpura in North America and Kawasaki disease in Japan.(ABSTRACT TRUNCATED AT 250 WORDS)

Intractable vasculitis syndromes are reviewed in terms of pathways leading to the diseases. The III-type, IV-type, and II-type allergic reaction, as well as angiospasm and endothelial dysfunction pathways are important in the pathogenesis of vasculitis. Each pathway has been described, using appropriate animal models or experimental and clinical data. Antigens of microorganisms are, among others, important pathogenic factors, activating several pathways. Endogenous retroviral antigens in the mouse, and possibly in humans, cause vasculitis through the II-type and III-type hypersensitivity, and experiments on the intractable vasculitis remain to be focused on this point.

We reported an infant case of Guillain-Barré syndrome treated with high-dose gammaglobulin. Gammaglobulin was given at a dose of 1 g/kg/day for 2 consecutive days. Dyspnea disappeared six hours after the start of the infusion. The patient was able to sit 3 days and walk alone 25 days after the end of therapy. Circulating immune complexes were 48 micrograms/ml before the therapy, 95 micrograms/ml and 39 micrograms/ml 10 days and 37 days, respectively, after the therapy.

We have recently found that allogenic bone marrow transplantation (BMT) can be used to treat lupus nephritis in NZB x NZW F1 (B/W F1) and BXSB mice. To elucidate why and how glomerular damage is repaired, serial renal biopsies were carried out using B/W F1 mice before, and after BMT. Donor-derived B cells and macrophages with normal functions developed two weeks after BMT, whereas donor-derived functional T cells were generated after seven weeks of BMT. Visceral epithelial cells as well as macrophages in the glomeruli were activated (probably by T cell-derived lymphokines) at this time; they showed marked phagocytic activity, resulting in clearance of immune complexes (ICs) and repair of damaged basement membranes. These results suggest that normal T cell functions, which have the capacity to activate macrophages and epithelial cells, are essential in repairing IC-mediated glomerular damage.

Complement system was investigated in 7 patients with status asthmatics treated with large doses of methylprednisolone (MPS). Complement hemolytic activities, complement protein profile, complement fragments and circulating immune complexes were measured before, 3 and 8 hours after and 14 days after MPS administration. MPS normalized C4 and C1INH activities 6 hours after administration. MPS also decreased ACH50 6 hours after administration and D activity 3 and 6 hours after, but these activities recovered to their previous normal range within 14 days. P and H were decreased at each measurement time, and C1s was transiently decreased 6 hours after MPS administration. Complement fragment iC3b was increased at each measurement time, but fragment Bb tended to be decreased 14 days after MPS administration. The increment of anaphylatoxin C3a recovered to normal 14 days after MPS administration. In vitro experiments, MPS inhibited D and C1s activation directly, and decreased the decay of B and C4. Inhibition of C1s might also increase C1INH activity clinically. These results clarified that the alternative complement pathway was activated, and suggested that the C1 bypass pathway might be also activated in status asthmatics. It was further considered that these anti-complementary effects induced by MPS, brought about an improvement in asthmatic symptoms. Studies to identify the complement activators continued, and circulating immune complexes may possibly be one of those agents activating complement cascade.

One hundred hemophilia A and 30 hemophilia B patients who had been treated with non-heated and heated factor VIII or prothrombin complex concentrates were examined by immunological tests including Clq-bearing immune complexes assay. Antibodies to human immunodeficiency virus type 1 (HIV-1), hepatitis B virus (HBV), hepatitis C virus (HCV) and human parvovirus B19 (B19) were analyzed by Western blotting, enzyme immunoassay, passive hemagglutination or radio-immunoassay. Clq-bearing immune complexes were assayed by a monoclonal anti-Clq ELISA system (Immunomedics). Seropositivity to HIV-1, HBV, HCV, and B19 was 56.9%, 87.7%, 79.2% and 100% respectively. Clq-bearing immune complexes were positive in 109 of the 130 patients (83.8%). The positivity and the levels were extremely higher than those in normal individuals. Clq-bearing immune complex levels in patient positive for HIV-1, HCV, or HBV were higher than those in the negative group (HIV: P less than 0.001, HCV: P less than 0.005, HBV: P less than 0.05). When the patients were divided into four groups according to seropositivity to HIV-1 and/or HCV, Clq-bearing immune complex levels were the highest in the group positive for both antibodies, and the lowest in the group negative for both antibodies. These results suggested that each viral infection influences the formation of immune complexes and repeated viral infection increased the level of Clq-bearing immune complexes in these patients.

In order to evaluate the pathogenesis of proteinuria and the charge of immune deposits in lupus nephritis, anionic sites of periodate-lysin-paraformaldehyde (PLP) fixed renal tissue (5 patients with renal pelvic tumor as normal control and 17 patients with lupus nephritis), were stained with the critical electrolyte concentration method. Cuprolinic blue (CB) was used as a cationic probe. Ultra-structural study and semi-quantitative analysis were done. In the normal glomerular basement membrane (GBM), the CB stainable anionic sites appeared as filamentous structure with several short lateral branches. On the basis of electron microscopic observation of isolated proteoglycan, it is suggested that the central filaments are the protein core and the branches are the glycosaminoglycans of proteoglycan molecules. These filamentous anionic sites were located mainly in the laminae larae and lie close to each other forming a mesh-like network pattern. The semi-quantitative analysis of the normal GBM revealed that the number of anionic sites in the lamina rara externa (LRE) was 22.9 +/- 1.9-23.7 +/- 1.4/1000 nm GBM and in the lamina rara interna (LRI) 14.0 +/- 1.6-15.1 +/- 1.5/1000 nm GBM. These findings suggest that the anionic sites composed of heparan sulphate proteoglycan occupy large area of the laminae larae and prevent permeation of anionic molecules. In non-proteinuric 5 patients with class II lupus nephritis, the number of anionic sites of the GBM (LRE; 21.3 +/- 2.0-22.3 +/- 1.8/1000 nm GBM, LRI; 13.5 +/- 2.0-14.2 +/- 2.0/1000 nm GBM) showed no significant difference from that of the normal GBM. In contrast, the GBM of proteinuric patients with class IV (6 patients, LRE; 14.8 +/- 2.7-19.3 +/- 1.8/aooo nm GBM, LRI; 5.8 +/- 1.9-11.3 +/- 2.4/1000 nm GBM) and (V) (6 patients, LRE; 13.0 +/- 2.4-17.9 +/- 2.8/1000 nm GBM, LRI; 12.0 +/- 1.9-13.0 +/- 2.5/1000 nm GBM) exhibited loss of the anionic sites in association with the localization of the immune deposits (ID). From these findings, it is concluded that in severe and active lupus nephritis the failure of charge barrier of the GBM is responsible for the proteinuria. The ID observed in the patients with lupus nephritis were not stained with CB. This finding suggests that net charge of the ID could be cationic and that cationic immune complex and/or antibody could involve in the pathogenesis of lupus nephritis.

Using a murine acute serum sickness model caused by cationized bovine gamma-globulin (CBGG), the histological findings, accumulation of CBGG in the organs and the effect of decomplementation for the clearance of immune complex (IC) were investigated. The accumulation of CBGG increased in the lungs in the presence of anti-CBGG antibody 1 hour after injection of CBGG, but did not change in the kidneys. This suggests that CBGG forms IC in situ in the kidneys, and that circulating IC accumulates in the lungs. Decomplementation did not influence the uptake of CBGG immediately after challenge but delayed the clearance of CBGG in the kidneys, lungs, liver and spleen. A beneficial role of the complement system in the clearance of IC even for those formed in situ was recognized. Histological changes, cellular infiltration and microvascular destruction, evoked in the lungs in this experimental model immediately after challenge, were not seen in the kidney, suggesting the different modes of complement activation in these organs.

A 30-year-old SLE patient developed a xanthoma on her alopecia lesion. Histological examination showed typical lupus changes including immunofluorescence stainings. In addition, there were numerous xanthoma cells existed through the dermis, interlobular spaces of subcutaneous fat tissue, perivascular areas of small blood vessels, and subendothelial spaces and inside of intraluminal thrombosis of subcutaneous small arteries. These xanthoma cells contained granular materials in their cytoplasm. Histochemically, these materials are diastase resistant P.A.S. (+), immunoglobulin (+), Sudan BB (+), Sudan III (+), Nile blue (pinkish red), and yellowish orange autofluorescence suggesting that they are lipofuscin or lipid peroxidation products. Further histological findings showed destruction of sebaceus glands and peri-glandular++ infiltration of lymphocytes and histiocytes. These histiocytes contained phagocytic neutral lipid droplets in their cytoplasm. Very small lipid peroxides were also seen on surface and/or cytoplasm of infiltrating lymphocytes existing not only peri-lobular area but also intraluminal area of blood vessels. The marker profile of these infiltrating lymphocytes are B-cell predominant admixed with some CD8(+) T-cells. These data suggest that the mechanism of developing xanthoma is initiated by immune-complex deposition on basal lamina of sebaceus glands, followed by destruction of sebaceus glands by lympho-histiocytic cells infiltration with some antigen presenting and/or effector cells, and finally xanthoma cells were developed by phagocytosis of lipid peroxides caused by macrophage-derived oxygen radicals. Interestingly, our data suggest that the lipid peroxides, which may act as photosensitizer, may leave the skin and may enter the small vessels carried by lymphocytes. Furthermore the xanthoma cells may also enter the circulation through the small arteries.

In order to analyze the antigens (Ags) which cause Heymann nephritis (HN) and mechanisms of IC formation in the subepithelial site of GBM, we isolated two Ags from renal tubular epithelium (RTE) from Wistar rats and prepared rabbit antiserum against these Ags. Classical HN was induced by immunization with crude renal tissue suspension by the method of Heymann et al. Immunofluorescence method in normal rat kidney revealed that the Ag with MW of 65 KD (= beta) existed not only in RTE, but also in the glomerular capillary wall. On the other hand, the Ag with MW of 35 KD (= gamma) only existed in RTE. Circulating Abs and glomerular eluted Abs from the kidney of classical HN, reacted to RTE only by indirect immunofluorescence. Soluble Fx1A, beta and gamma were electrophoresed on SDS-PAGE gels and transblotted onto nitrocellulose membrane, anti beta Abs reacted to several bands including 330 KD band of Fx1A and beta Ag. However anti gamma Abs reacted to only 330 KD band of Fx1A and gamma Ags. On the other hand, Glomerular eluted Abs from the kidney of classical HN reacted to several bands of Fx1A and gamma Ag, but not to beta Ag. These facts suggest that beta and gamma are components of 330 KD protein of Fx1A. The gamma Ag is thought to be one of the major pathogenic Ag in HN.

This study was undertaken to analyze the mechanisms of immune complex formation in Heymann nephritis. We isolated two different RTE antigens by gel filtration and prepared rabbit antisera against these antigens. By the indirect immunofluorescence method using normal rat renal tissues, the 65,000 molecular weight antigen (= beta) was observed not only in RTE, but also in the glomerular epithelium, epithelium of the small intestine, liver and spleen. On the other hand, the 35,000 molecular weight antigen (= gamma) existed in RTE and epithelium of the small intestine. When rats were injected intravenously with rabbit antiserum against beta, glomerular depositions were observed within two hours. In rats injected with rabbit antiserum against gamma, no glomerular deposition was seen within 2 days, but fine granular depositions were observed after 6 days. When rat kidneys were perfused with rabbit antiserum against gamma in saline by a single pass method, no glomerular deposition was seen. However, in rat kidneys perfused with preformed soluble gamma-anti gamma IC, fine granular depositions along the capillary walls were seen soon after the perfusion. Further the antigen which was reacted with anti gamma antiserum was isolated from normal rat serum by immuno-affinity chromatography. These facts suggest that the mechanisms of IC formation may be due to not only in situ immune complex formation but also circulating immune complex deposition in Heymann nephritis.

In situ immune complex glomerulonephritis can be induced in the rat employing cationized antigen planted in the glomerular basement membrane (GBM) as a target for specific antibody. Another possible mechanism of in situ immune complex formation is antibody already present in the GBM to bind circulating antigen. Present study was performed in order to determine whether cationized antibodies planted in the GBM could react with anionic as well as cationic antigens to form immune deposits. Horse ferritin, rabbit antibody to horse native ferritin (f-Ab) and rabbit antibody to ovalbumin (o-Ab) were highly cationized as described by Danon et al. The ability of the cationized antibodies to precipitate antigens was estimated by Ouchterlony analysis. 500 micrograms/100 g body weight (b.w.) of cationized f-Ab or o-Ab was perfused into the left renal artery of male Wistar rats and 0.1-10.0 mg/100 g b.w. of either native or cationized ferritin or ovalbumin was injected respectively into the tail vein 1 hr later. Estimation of proteinuria was done and the kidneys were removed up to 5 days for immunohistological as well as electron microscopical examination. Cationized antibodies bound to anionic sites of the GBM and combined with subsequently injected cationized ferritin or native ovalbumin in situ, both leading to formation of subepithelial immune deposit with activation of C3 and caused mild proteinuria. Native ferritin, however, induced neither subepithelial immune deposit nor proteinuria, because it didn't permeate through the GBM. The presented model indicates that antibody molecules of high positive charge can bind to the GBM and react with specific antigens that are traversing the barrier to form immune deposits. This is independent of the charge of antigen provided that the antigen molecules are permeable into the GBM, as is the case with ovalbumin but not native ferritin.

The present report is a detailed, prospective analysis of 29 pregnancies in 19 patients with systemic lupus erythematosus (SLE). The clinical pregnant status was correlated with maternal serologic patterns. Poor obstetrical prognosis was associated with low or declining complement (C3 and C4) levels and rising antinuclear and anti-DNA antibody titers. Complement levels reflected clinical changes more accurately than either antinuclear factor. A smooth antepartum course and successful delivery occurred when complement values remained normal. Immunohistochemical studies showed granular or linear depositions of immunoglobulin and complement on syncytial trophoblast and stromal tissue in placenta with SLE. Slight deposits of IgG were observed on the stromal tissue in normal placenta. Immune complex deposition on the trophoblast correlated to both serologic evaluation and course of SLE pregnancy. Obstetrical prognosis can be evaluated by serial determinations of serologic status. These data suggest that declining levels of maternal complements in SLE may be partly due to immune complex deposition in the placenta, resulting in the increased placental dysfunction.

A case of myasthenia gravis accompanied with polymyositis and malignant thymoma, detected immune complexes in the sera and around the muscle fibers, was described. A 37-year-old woman was admitted to Shinshu University Hospital in September, 1987 because of dyspnea, dysphagia and muscle weakness. She first noticed her right blepharoptosis 3 weeks before admission. Weakness of all four limbs and myalgia of lower extremities were noticed one week later. These symptoms got worse and nocturnal dyspnea, dysphagia and easy fatigability at mastication appeared. On admission, she looked ill and neurological examination revealed left blepharoptosis, bilateral facial weakness, weakness of all four limbs, more prominent in proximal muscles and tenderness of lower extremities. Edrophonium test was positive, improving her muscle weakness. Laboratory examination revealed the elevated serum levels of CK, the increased titre of circulating immune complexes and high titres of acetylcholine receptor antibodies and anti-skeletal muscle antibodies. Electromyographic study showed myogenic pattern and Harvey-Masland test revealed waning at low frequency stimulation. Muscle biopsy showed marked perivascular infiltration of lymphocytes, accompanied by phagocytosis and interstitial fibrosis. IgG deposits were shown around the muscle fibers exclusively around the infiltrates of mononuclear cells. Granular deposits of C3 were also shown specifically around the muscle fibers exclusively around the infiltrates of mononuclear cells. Thymectomy was performed on September 21, 1987. Invasion of thymoma, predominantly lymphocytic type, to right lung and pericardium was observed histologically. After thymectomy, she got better. Immunological data and immunohistochemical examination of the present case suggest that in the case of myasthenia gravis accompanied with polymyositis and malignant thymoma, immune complexes may play a primary role on the pathogenesis of myositis.

In order to examine the ability of complement to solubilize the immune complexes (IC) in vivo, we made acute or chronic serum sickness nephritis in 10 rabbits or 12 rats with injection of BSA as antigen (Ag). Animals were divided into two groups. The 500 mu or 50 mu/week of cobra venom factor (CVF) for rabbits or rats was administered intraperitoneally in one group of animals to reduce the serum complement levels and complement-mediated solubilization of immune complex. On the other hand, the 2 ml or 0.2 ml/week of turpentine oil (TO) was injected intramuscularly in another group of animals to elevate the serum complement levels. The renal biopsy was performed with weekly intervals in each animals, and the specimens were stained for antigen (BSA), antibody (IgG) and C3 by immunofluorescence techniques. The result in this experiments showed the significant difference between TO-, and CVF-treated animals in the degree of disappearance of IC in the kidney lesions. The undetectable amount of IC (especially BSA) was remained in the renal tissue of TO-treated animals. This fact indicated that complement might act to solubilize the IC deposited in the tissue in vivo also.