[The role of interferon in the development of experimental nephritis].
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Biomedical subjects
Publications and source records attributed to P Verroust.
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The relation between the duration of bacterial infection and circulating immune complexes (CIC) level was evaluated using the C1q binding assay in a group of patients with well defined clinical sepsis. Fifty-four patients with endocarditis and 35 with post-open heart surgery mediastinitis were prospectively studied over a period of 2 years. CIC were detected in 42% of patients studied. Interindividual variations were observed but it was found that the level of CIC increased statistically with time (P less than 0.001). CIC were statistically linked with cryoglobulinemia (P less than 0.001), rheumatoid factor (P less than 0.001) and a decreased CH50 (P less than 0.05). CIC were more frequent in patients with endocarditis (53%) than in patients with mediastinitis (24%). However, when the duration of the infection was taken into account the difference was no longer significant. No relation could be evidenced between the incidence of CIC and clinical symptoms including prognosis and renal signs. In our experience, determination of CIC does not have a critical clinical value.
The sera of 87 Senegalese patients with various forms of leprosy were investigated. Two of the most reliable methods were used to detect circulating immune complexes : the radiolabelled C1q binding test and the Raji cell binding technique. Several fractions of complement, including C3, C4, factor B and the C3d product of C3 were also assayed. A material having the properties of immune complexes was detected in lepromatous and reactional leprosy. In tuberculous leprosy, only the Raji cell binding technique gave positive results. C3 and C4 were normal or slightly raised, but C3d was increased in all forms of the disease. There was no significant correlation between C3d values and the results of immune complexes detection tests.
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A total of 32 patients with Plasmodium falciparum malaria were studied. Of these, 23 had benign infections, and 9 had typical cerebral malaria. Cryoglobulins, circulating immune complexes detected by a C1q-binding assay, and hypocomplementemia were found in eight of nine patients with cerebral malaria. Raised levels of complement component 3 breakdown products (C3d) were found in the seven patients tested. Peak levels of circulating immune complexes and C3d were associated with thrombocytopenia. In contrast, in patients with benign Plasmodium falciparum malaria, cryoglobulins and circulating immune complexes were found only in 3 of 23 patients. Similarly, hypocomplementemia was detected only in 5 of 23 patients. These observations suggest that the intensity of the immune response and of the associated complement activation may be important factors in the pathogenesis of cerebral malaria.
Immunopathological studies of the kidney, determination of circulating immune complexes and interferon blood levels were obtained in adult congenitally-athymic nude mice ((nu/nu) infected with lymphocyte choriomeningitis (LCM) virus as well as in their phenotypically-normal litter mates (nu/+). As previously reported, intracerebral or intraperitoneal infection in nu/nu mice did not induce any mortality and resulted in a carrier state characterized by persistently high levels of virus in the circulation. Interferon was present in the circulation for approximately 6 days. Circulating immune complexes were not detectable and glomerulonephritis assessed by light microscopy, electron microscopy and immunofluorescence, was either absent or very mild. These observations show that although a carrier state can be induced in adult nude mice, circulating immune complexes and glomerulonephritis do not develop. This situation is markedly different from that induced in normal Swiss mice infected at birth, which is characterized by raised levels of circulating immune complexes and development of glomerulonephritis in all infected mice.
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Immune complexes and complement levels were assayed in sera from a group of 69 hemophilic children. Using the Raji cell radioimmune assay and the C1q binding assay, abnormally high levels of circulating immune complexes were rarely found in the group of hemophiliacs which did not differ statistically from the control population. These results do not exclude the presence of low and transient levels of immune complexes in the circulation, but indicate that hemophiliacs are not exposed to increased immune complex loads similar to those found in immune complex diseases. By contrast frequent abnormalities of the complement system were found. Complement levels were elevated in a large percentage of patients, reaching statistical significance for C3, C4, C5, Factor B and Properdin. Levels of the C3 breakdown product C3d were significantly raised suggesting intravascular complement activation. The significance of these abnormalities is discussed in relation to perfusion of Factor VIII preparations.
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Immune complex-like material was studied using the platelet-aggregation test (PAT) in 114 patients with idiopathic glomerulonephritis and 55 patients with SLE nephritis, and the results obtained compared with Raji cell and Clq-binding assays. The platelet-aggregating material was not thrombin, and eluted from Sepharose CL/6B columns with a molecular weight of greater than 500,000 daltons. Sera from 17 of 55 patients with SLE nephritis were positive in all three assays, 50/55 in at least one assay. No circulating material was detected by the Raji cell assay in idiopathic glomerulonephritis patients, but both the Clq-binding and PAT assays detected material in patients with acute post-infectious nephritis and mesangiocapillary glomerulonephritis. Patients with membranous nephropathy and Henoch-Schönlein purpura were positive in the PAT, although generally negative in the other assays of immune complexes. The amount of platelet-aggregating material (PAM) found in the sera of patients with both idiopathic glomerulonephritis and SLE nephritis correlated closely with the depletion of intraplatelet serotonin, suggesting that this material is a major mechanism of in vivo platelet activation in these patients.
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A marked difference was observed in the severity of disease in lymphocytic choriomeningitis (LCM) virus-infected suckling BALB/c, Swiss, and C3H mice. BALB/c mice had minimal liver lesions and none died, whereas C3H mice had extensive liver lesions and all mice died. An intermediate pattern was oberved for Swiss mice (36% mortality). Although there was no difference in the titers of LCM virus in the plasma or liver between these three strains of mice, there was a marked difference in the amount of interferon produced and the duration of interferonemia. C3H mice produced more interferon than Swiss mice which produced more interferon than BALB/c mice, indicating a direct correlation between the amount of interferon induced by LCM virus and the extent of disease. Inoculation of a potent anti-mouse interferon globulin markedly reduced the incidence of mortality in virus-infected C3H mice. BALB/c mice were as sensitive to the effects of interferon as C3H mice because daily administration of potent interferon preparations did induce disease in this strain. This ensemble of results supports our contention that endogenous interferon is in large part responsible for the manifestaions of acute LCM virus disease in suckling mice.
To determine the effect of prolonged administration of exogenous interferon on the autoimmune disease of NZB/W female mice, forty-four NZB/W mice received three injections per week of 6.4 x 10(4) interferon units from birth to 33 weeks, forty mice were injected with mock interferon and forty-eight mice were left untreated. In mice injected with interferon growth was delayed, survival was decreased, and the severity of the glomerulonephritis was enhanced. Interferon increased the titre of serum anti-ssDNA and anti-soluble nucleoprotein antibodies, but had no effect on the circulating immune complex load. These results suggest that interferon in some way affects local deposition of immune complexes within the glomerulus.
Circulating immune complexes were repeatedly searched for using the C1q-binding assay and the Raji cell test in Lewis and BN rats immunized with the Fx1A fraction from convoluted proximal tubule or with kidney homogenate, mixed with various adjuvants. An autoimmune glomerulonephritis was easily induced in Lewis rats. A potent adjuvant and a booster injection were necessary to obtain such a glomerulonephritis in the BN strain which is reputedly resistant. No circulating immune complex-like material could be found in Lewis rats using the C1q-binding assay. A high C1q-binding activity was found in Bn rats including control rats. The Raji cell test was weakly positive in Lewis and BN rats including control rats. This study demonstrates that the classical resistance of BN rats can be overcome if a potent adjuvant is used. Our failure to demonstrate circulating immune complexes suggests that in situ formation of immune deposits, as recently demonstrated in passive Heymann's nephritis, may also be operative in autoimmune complex glomerulonephritis. Other factors than the antigen used can be responsible for positive C1q-binding or Raji cell tests.
There are at present a large number of methods of searching for circulating immune complexes. No method is totally satisfactory, but the use of several methods simultaneously now permits us to draw a few conclusions. The very frequent presence of circulating immune complexes in the serum during systemic lupus erythematous, rheumatoid arthritis, and acute glomerulonephritis, is further evidence in favour of circulating immune complexes in these diseases. Furthermore, circulating IC may be observed in numerous circumstances, without causing obvious pathological consequences. It is nevertheless possible that they may play a role in the control mechanisms of immune function.
Immune complex-like material with a molecular weight of greater than 500,000 Daltons was detected in the majority of sera from patients with idiopathic glomerulonephritis, as well as in systemic lupus. In the Raji cell and Clq binding assays the glomerulonephritis sera gave, in general, negative results. Patients with membranous nephropathy, minimal change disease and Henoch-Schönlein purpura also gave positive results in the platelet test, in agreement with other tests not dependent upon complement fixation by the complexes. The amount of platelet-aggregating material detected in vitro correlated closely with in vivo depletion of intraplatelet amines, judged by serotonin concentrations; which suggests that this material may play a major role in platelet activation within the circulation.
A renal biopsy performed on a young woman with proteinuria showed a nephropathy consisting of major interstitial infiltration by lipophages and thickening of the glomerular capillary walls with a large amount of "spikes". Anti-IgG, IgM, C3 and C1q sera bound themselves to the extramembranous deposits and the anti-IgM serum to the endomembranous deposits. This striking finding was associated with a regenerative nodular hyperplasia of the liver, an entity that has been observed in only about 20 cases. An underlying immunological defect was suggested by the continuous presence of a mixed cryoglobulinemia.
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