Incidence of circulating immune complexes in patients with acute poststreptococcal glomerulonephritis and in patients with streptococcal impetigo

In an attempt to further study the possible contribution of circulating immune complexes (CIC) in the pathogenesis of acute poststreptococcal glomerulonephritis, 61 patients with APSGN were studied during the first three weeks of the disease, and 13 patients with noncomplicated streptococcal impetigo as a control group. C1q solid phase ELISA and Conglutinin (K) solid phase ELISA were used to measure the levels of immune complexes. The incidence of CIC in a single serum sample from patients with APSGN was 48%. Elevated levels of immune complexes were found in 46% of the patients with streptococcal impetigo. The absolute levels of CIC were comparable in both groups of patients. No correlation was found among the presence of CIC and the clinical, immunoserological or pathological findings of the disease. Our results do not support the hypothesis that trapping of the circulating immune complexes play an important role on the renal injury poststreptococcal infection. Instead, we suggest that CIC are an epiphenomena present in APSGN, and may represent rather a systemic inflammatory immune response in patients with group A streptococcal infection.     

Studies on circulating immune complexes. I: Circulating immune complexes in various types of glomerulonephritis and collagen disease: a comparative study employing conglutinin solid phase radioimmunoassay and raji cell radioimmunoassay

A study was undertaken to examine the differences in serum levels of circulating immune complexes (CIC) detected by different methods in various types of collagen disease and primary glomerulonephritis. The subjects used were 16 patients with SLE, 22 with IgA nephropathy, 8 with membranoproliferative glomerulonephritis, 8 with membranous nephropathy, 6 with minimal change nephrotic syndrome, and 2 each with RA, PSS, DM, Sj?gren syndrome, PN, MCTD and overlap syndrome, respectively. CIC were measured by two assays, namely, bovine conglutinin solid phase radioimmunoassay (C-assay) and Raji cell radioimmunoassay (R-assay). In SLE, the incidence and amounts of CIC detected were higher in R-assay than in C-assay. Similar results were obtained for the other types of collagen diseases. Furthermore, a discrepancy in the incidence of CIC detected by the two assays was found in 30% of patients with collagen diseases. Concerning the detection of CIC in primary glomerulonephritis, the sensitivity of C-assay was higher than that of R-assay. This discrepancy appears to reflect the different sensitivities of the two assays. No significant correlation was found between the CIC level and the intensity of IgG deposits in various types of glomerulonephritis. These results suggest that the R-assay was better for the detection of CIC in collagen diseases, and that the C-assay was suitable for that in primary glomerulonephritis.     

Humoral immunity to streptococcal antigen in acute and chronic glomerulonephritis

A study was carried out to verify the clinical usefulness of the elaborated method for the measurement of antistreptococcal antibody in revealing the streptococcal etiology of glomerulonephritis.In 158 patients with glomerulonephritis antistreptococcal antibody (ASA), circulating immune complexes (CIC) and haemolytic activity of the complement were measured.On the basis of immune complex formation it has been concluded that streptococcal infection may cause glomerulonephritis. Serial determinations of ASA and CIC are helpful in establishing the streptococcal etiology of glomerulonephritis and in monitoring the course of the disease.     

In situ formation of subepithelial glomerular immune complexes in passive serum sickness

Epimembranous glomerular deposition of circulating immune complexes in considered to be the pathogenesis of immune complex glomerulonephritis, based on experiments in serum sickness glomerulopathy. A subepithelial localization of immune aggregates, however, was never obtained after the intravenous injection of preformed immune complexes. Recent studies on heterologous immune complex glomerulonephritis provide evidence of in situ formation of subepithelial glomerular immune complex aggregates as a second pathogenetic mechanism. We investigated the existence of a comparable mechanism in a serum sickness model of glomerulonephritis. A passive immune complex glomerulopathy involving lysozyme/antilysozyme and bovine serum albumin (BSA)/anti-BSA was used to investigate this thesis. Alternating perfusion of a kidney with antigen and antibody resulted in a granular deposition of both components along the glomerular basement membrane (GBM). The deposits of immune aggregates were localized exclusively along the epithelial side of the GBM and were still present 3 days after the perfusion. Control perfusions with preformed immune complexes or with either BSA or anti-BSA alone did not result in subepithelial deposition. Conclusion. The alternating excess of antigen and antibody in the circulation might result in in situ formation of immune complexes localized at the epithelial side of the GBM.     

Hepatitis B virus-associated membraneous nephropathy: clinical features, immunological profiles and outcome

To evaluate the clinical features, immunological profiles and the prognosis of hepatitis B virus-associated membraneous nephropathy (HBVMN), 34 patients (25 boys and 9 girls) were studied from April 1981 to November 1987. With Fab fragments of monoclonal antibodies, hepatitis B e antigen (HBeAg) was detected in the glomerular deposits from 30 cases (88.2%) and in the sera from 32 cases (94.1%). These results suggest that HBeAg plays an important role in the development of HBVMN. In addition, clinical trials of 32 cases demonstrate a relatively poor response to the steroid therapy with persistent heavy proteinuria (32.4%) or a high frequent relapse rate (38.2%); only 1 case (3.1%) had early response. In 4 cases follow-up renal biopsy was performed, progressive sclerosis with interstitial fibrosis being noted in each instance. The stage of membraneous nephropathy examined under the light microscope, had progressed from stage I or II to stage III. One had impaired renal function. Therefore, HBVMN does not always take a benign course. In the immunological profiles, significant hypocomplementemia with low C3, C4 and properdin factor B levels were found during the initial 6 months after the onset of disease. Hepatitis B surface antigen (HBsAg) circulating immune complexes (CIC) were also significantly higher. However, the levels of HBsAg CIC did not correlate with the degree of proteinuria or hematuria. In patients with persistent HBaAg carriage, serum HBeAg status alone did not correlate with remission rate, and remission occurred usually before the HBeAg seroconversion to anti-HBe. These results suggest that factors other than HBeAg play important roles in HBVMN.     

Protective role of BCG in the rabbit model of mesangial proliferative glomerulonephritis

A study was designed to investigate whether BCG could play a protective role in a rabbit model of mesangial proliferative glomerulonephritis. Fifteen rabbits were immunised with multiple injections of bovine serum albumin and their mononuclear phagocytic system was depressed by endotoxin from E. coli. The rabbits were divided into two groups: Group 1 (n = 7) received intravenous BCG from 3 weeks prior to the pathogenic immunisation and until the end of this period; Group 2 (n = 8) acted as a control and received normal saline. In the BCG group circulating immune complex (CIC) titres were significantly reduced, rabbit IgG deposition in glomeruli was significantly less, and mean glomerular cell counts were significantly less than those in the control group. We conclude that BCG stimulates the mononuclear phagocytic system to remove CIC and reduce the deposition of immune complexes in glomeruli, thereby mitigating the inflammatory response.     

Circulating immune complexes in membranoproliferative glomerulonephritis

Circulating immune complexes (CIC), measured by the solid-phase Clq method, were found to be in abnormal concentration in about half of 39 patients with membranoproliferative glomerulonephritis (MPGN). In contrast, they were present, usually in higher concentration, in nearly all patients with active lupus nephritis. Correlations between clinical course and CIC levels in patients with MPGN showed that complexes were always present when the disease was mild or "silent," but when renal impairment developed or was incipient, complexes were nearly always absent. In patients with disease of intermediate severity, characterized by definite proteinuria but without renal impairment, 50% had complexes. The presence of complexes when glomerular abnormality is relatively slight could be interpreted as indicating that the complexes measured were not nephritogenic, or that they program subsequent events that augment glomerular injury in the absence of complexes. The measurement of CIC in MPGN appears to have minimal value both in diagnosis and in determining prognosis.     

The role of hepatitis B surface antigen in the pathogenesis of glomerulopathies.

The frequency of hepatitis B surface antigen (HBsAg) has been studied in the sera and renal biopsies of 276 patients with various forms of glomerulonephritis (GN), the nephrotic syndrome and other nephropathies. Using a modified Hepanosticon method, HBs antigenemia was detected in 32 of 196 patients (16.3%) with immune complex (IC) GN and the nephrotic syndrome. Indirect immunofluorescence revealed HBsAg in 33 renal biopsy tissue specimens (16.8%). HBsAg was found in the sera of four of the 80 remaining patients with other renal diseases (5%), and in the renal biopsy tissues of another four (5%). Antibody against HBsAg could only be demonstrated in the serum of one glomerulonephritic patient. The sera of 18,799 normal blood donors were used as controls; of these 186 (0.99%) had positive tests for HBsAg. It is concluded that, in some patients with GN and the nephrotic syndrome, HBsAg-containing IC may be implicated in the development and/or progression of the disease.     

Retroviral gp70 antigen in spontaneous mesangial glomerulonephritis of ddY mice

We examined whether the retroviral envelope antigen, gp70, is a major nephritogenic antigen in ddY mice, a murine model of spontaneous mesangial glomerulonephritis associated with IgA and IgG deposition. Immunofluorescence microscopy revealed that the mesangial gp70 deposition increased with age in mice over 24 weeks old, as did the IgG and IgA deposits. Immunoelectron microscopy demonstrated the reaction products of gp70 superimposed on the electron dense deposits in the mesangial matrix. Various amounts of serum gp70 were detected in mice as young as 12 weeks without any apparent increase with age. There was no correlation between the serum level of gp70 and the extent of the glomerular gp70 deposition, whereas mice with heavier IgA deposition had higher mean levels of serum IgA. The absorption test demonstrated that significant amounts of serum gp70 composed immune complexes in 40 week-old ddY mice developing glomerulonephritis; however, this bound form of gp70 was not observed in 12 week-old mice without glomerulonephritis. Systemic examinations by immunofluorescence staining showed that gp70 was mainly localized in various lymphoid tissues. These findings suggest that the gp70 antigen, mostly derived from lymphoid cells, may circulate as immune complexes and accumulate in the mesangial area, thus contributing to the development of glomerulonephritis in these mice. In addition, the pathogenic role of the increased IgA production in these mice was discussed.     

Psoriasis vulgaris associated with mesangiocapillary glomerulonephritis

A patient experienced the concomitant onset of psoriasis vulgaris and mesangiocapillary glomerulonephritis (MCGN) with massive proteinuria. Laboratory examination revealed reduced glomerular filtration rate (GFR), elevated serum IgG, IgA and circulating immune complex (CIC) levels. Both diseases responded promptly to combined therapy with prednisolone, urokinase and plasma exchange. CIC and GFR were normalized with histological improvement. To our knowledge, this is the first case of glomerulonephritis, which can be related to psoriasis vulgaris through an immune mechanism.     

Membranous glomerulonephritis associated with hepatitis B antigen in children: a comparison with idiopathic membranous glomerulonephritis

The laboratory and pathological findings are reported for 16 children with membranous glomerulonephritis (MGN) associated with hepatitis B virus (HBV) infection and compared with those of 12 children with idiopathic MGN. Serum hepatitis B surface antigen (HBsAg) was found in all children with HBV associated MGN and serum hepatitis B e antigen (HBeAg) in 11 of the 15 examined. Five patients with HBV associated MGN, but none with idiopathic MGN, showed reduced serum C3 values. Otherwise there was no difference in laboratory findings. HBeAg was detected in the glomeruli of all 7 patients with HBV-associated MGN examined but HBsAg was not detected. Of the 14 children with HBV-associated MGN examined by electron microscopy, all but one showed small mesangial deposits and 4 subendothelial deposits, whereas of 9 with idiopathic MGN only 2 showed mesangial deposits and none subendothelial deposits. Thus most of the children with HBV-associated MGN are characterized by some laboratory and pathological features of membrano proliferative glomerulonephritis in addition to those of idiopathic MGN. These observations are consistent with HBV inducing a spectrum of glomerulopathy from typical MGN to typical membranoproliferative glomerulonephritis.     

人参对家兔系膜增生性肾小球肾炎模型循环免疫复合物的影响

目的：观察人参对家兔系膜增生性肾小球肾炎模型循环免疫复合物（CIC）的影响。方法：制成家兔系膜增生性肾小球肾炎模型,将该模型分成对照组、全剂量泼尼松组、半剂量泼尼松组、人参合用半剂量泼尼松组及单用人参组,分组给药,观察用药前后家兔血清循环免疫复合物水平的变化。结果：模型兔肾功能基本正常,但24 h尿蛋白较正常组显著升高,肾脏组织学提示系膜增生明显（以基质增生为主）,足突融合明显;人参可使模型家兔血清循环免疫复合物下降至基本正常水平,而血清免疫球蛋白水平仍保持正常;虽然全剂量和半剂量泼尼松组较模型后组、对照组血清CIC的水平下降,但血清IgG水平亦同时下降,降低其免疫功能。结论：人参在使家兔系膜增生性肾小球肾炎模型血清循环免疫复合物下降的同时,不降低其正常的免疫功能。     

IgA1-containing immune complexes in IgA nephropathy differentially affect proliferation of mesangial cells

BACKGROUND: Sera of patients with IgA nephropathy (IgAN) contain circulating immune complexes (CIC) composed of galactose-deficient IgA1 complexed with antiglycan antibodies. The role of these CIC in the pathogenesis of IgAN is not known. METHODS: We studied how proliferation of cultured mesangial cells (MC) is affected by CIC prepared from sera of IgAN patients and healthy control subjects using size-exclusion chromatography. CIC-containing fractions were added to serum-starved MC in culture, and cell proliferation was measured using (3)H-thymidine incorporation. The results were confirmed by staining MC using an antibody against proliferating cell nuclear antigen. RESULTS: The incubation of starved MC with serum fractions with M(r) 800 to 900 kD, rich with galactose-deficient IgA1, stimulated proliferation, while fractions with smaller complexes were inhibitory. Furthermore, CIC-containing larger molecular mass fractions isolated from serum of an IgAN patient collected during an episode of macroscopic hematuria stimulated MC proliferation more than CIC obtained during a subsequent quiescent phase. To examine the role of IgA, we removed IgA1 from serum before fractionation. The resultant IgA1-depleted fractions were devoid of stimulatory IgA-CIC. Sera of IgAN patients were also fractionated after addition of desialylated galactose-deficient polymeric IgA1 to form additional immune complexes. Supplementation with a small quantity of this IgA1 increased cellular proliferation in assays using serum fractions of M(r)>/=800 to 900 kD; uncomplexed IgA1 did not affect MC proliferation significantly. In contrast, supplementation with a larger quantity of this IgA1 inhibited cellular proliferation in assays using serum fractions of M(r) 700 to 800 kD. CONCLUSION: Overall, these findings suggest that CIC containing aberrantly glycosylated IgA1 affect proliferation of MC in vitro and, thus, likely play a role in the pathogenesis of IgAN.     

Celiac disease associated with immune complex glomerulonephritis.

A patient with immune complex glomerulonephritis and celiac disease without dermatitis herpetiformis or other underlying disease associated with glomerulonephritis is presented. Antibodies to wheat proteins were found in serum and withdrawal of gluten from the diet resulted in disappearance of immune complexes from serum and resolution of both renal and intestinal disease, suggesting a dietary source of antigen. Despite extensive immunopathologic studies of the renal biopsy, neither dietary nor endogenous brush border antigens were demonstrated in glomeruli.     

Immune complex glomerulopathy in a child with food hypersensitivity

This report describes the occurrence of immune complex glomerulonephritis in a patient with eosinophilic gastroenteritis and food hypersensitivity. A coincident allergen injection may have been a contributing factor in the sudden development of the nephrotic syndrome. Markedly elevated levels of circulating immune complexes (greater than 6400 mg/dl) were found containing kappa-casein and bovine serum albumin (BSA), the latter predominating. Markedly elevated serum BSA hemagglutinating titers were also present (1:40,960). Cross-reacting precipitating antibodies to BSA, beef, and pork were demonstrated, but not to flounder or ovalbumin. Renal biopsy revealed immune complex glomerulonephritis with BSA, immunoglobulins M and G and complement deposited focally in the glomerular basement membrane. With strict dietary limitation of identified causative antigens and prednisone therapy, CIC levels decreased to 16,000 micrograms/dl and serum BSA antibody hemagglutinating titer fell 32-fold over a period of 15 months. There was prompt symptomatic relief and amelioration of signs of nephritis. The patient was able to consume a diet normal in protein and caloric content, and statural catch-up growth occurred. Recognition of food antigens to which the patient was hypersensitive provided a rationale for the relief of the gastrointestinal disturbance, growth stunting, and renal disease.     

Circulating immune complexes in glomerulonephritis: a longitudinal study

A longitudinal study of circulating immune complexes (CIC) was performed in 121 patients with biopsy verified glomerulonephritis (GN). 1286 blood samples were obtained during a mean observation period of 21 months. Two methods for detection of CIC were used, the Clq-binding activity and a PEG precipitation test. CIC were detected by both tests in 21% of all blood samples and detected in at least one blood sample from 57 patients. The presence of CIC was found to be either transient (34 patients), intermittent (11 patients) or permanent (12 patients). CIC were found transiently at the time of renal biopsy and disappeared within months in patients with idiopathic extracapillary GN (7 of 9 patients), endocapillary GN (2/2) and GN associated with polyarteritis nodosa (5/6), Wegener's granulomatosis (3/3) and Henoch-Schoenlein syndrome (3/6). CIC were detected either transiently, intermittently or permanently for years after renal biopsy in patients with SLE (12/14) and membranoproliferative GN type I (7/12). CIC were only occasionally detected in patients with minor change nephropathy (1/9), membranoproliferative GN type II (0/2), IgA nephropathy (6/17), focal segmental sclerosis (1/8) and membranous GN (2/11). In these patients CIC were often transiently present without apparent relationship to time since renal biopsy. Overall, a relationship was found between the presence of CIC and decreasing serum creatinine, but there was no correlation with changes in proteinuria or with increasing blood pressure. Serial measurements of CIC showed correlations with clinical events only in individual patients, but not in the population as a whole.     

Experimental glomerular lesions induced by chronic immune complex formation

Chronic immune complex formation was induced in rabbits by daily administration of 12.5 g bovine serum. In good antibody producer animals immediate immune complex production and elimination from the circulation were demonstrable. This was followed within a few minutes by the appearance of free¹²⁵I in fairly large amounts in blood, as a sign of immediate phagocytosis and disintegration of the¹²⁵I-labelled immune complexes.Phagocytic activity decreased in the host animal during chronic heteroprotein administration in every case.The earliest glomerular changes were those of exudative glomerulonephritis, the extent of which depended on the antibody productivity of the animal.Persistent immunocomplexaemia induced by administration of the antigen over 60 and 100 days, respectively, resulted in mesangioproliferative glomerulonephritis in 7, in membranoproliferative glomerulonephritis in 3, and in membraneous glomerulonephritis in 1 out of 11 laboratory animals.     

Comparative informative value of the leukogram and the level of circulating immune complexes in patients with acute appendicitis

Data of the leukocyte reaction and amount of circulating immune complexes (CIC) in blood serum of patients with acute appendicitis were studied. The determination of CIC is shown to be more informative concerning inflammatory changes in the vermiform process. The method of determination of CIC in blood serum is simple, not time-taking and may be used in urgent surgery as an additional method of diagnosis of acute appendicitis.     

Experimental studies on factors causing acute serum sickness glomerulonephritis of immune complex origin

In acute serum sickness glomerulonephritis induced in rabbits by large doses of BSA, the relationship of the host's immunological status and the severity of renal histological changes was studied. It was found that good antibody producers developed more severe renal lesions. The higher avidity of antibodies enhances the inflammatory effect of immune complexes. Kidney is favoured for deposition of immune complexes especially in the case of chronic immune complex formation in the presence of antigen excess. Diminished phagocytic function of leukocytes (probably decreased immune complex saturating capacity) may also contribute to the severity of renal histological alterations.     

Serial determinations of melanoma tumor-associated antigen and antibody in patients with stage I melanoma

The correlation of circulating immune complexes (CICs) and the clinical course of malignant melanoma has not been consistent when using nonspecific assays for CIC. To improve predictability, serial serum samples from patients with pathologic stage I melanoma were analyzed for the presence of antimelanoma tumor-associated antigen (TAA) antibody by direct radioimmunoassay and for the presence of melanoma TAA in CIC by the antigen competition method. Immunochemically characterized TAA was isolated from the spent culture medium of a melanoma cell line. Seventy-five percent of patients with melanoma TAA-specific immune complex (IC) had recurrences, while 71% of patients without melanoma TAA-specific IC remained free of disease for prolonged periods (up to 14 years of follow-up). Anti-TAA antibody titers did not correlate with disease recurrence. Our results demonstrate a correlation with melanoma TAA-specific IC and disease recurrence. The absence of melanoma TAA-specific IC is associated with a low risk of recurrence. Fluctuations in melanoma TAA-specific IC levels indicate a dynamic tumor host immunobiology and the need for serial follow-up.