The value of complement and immune complex determinations in monitoring disease activity in patients with systemic lupus erythematosus.

Serial serum samples from 33 patients with systemic lupus erythematosus were tested for CH50, C3, C4, and circulating immune complexes. Circulating immune complexes were determined by 5 different assays. Disease activity was determined by a scoring system we devised. On an interpatient analysis, overall disease activity correlated significantly with levels of CH50, C3, and a positive result on C1q binding assay. However, with the exception of depressed C3 levels, the sensitivity, specificity, and predictive values of all the serologic tests were low. An intrapatient analysis revealed a patient-specific activity parameter in 11 of the 33 patients. We conclude that these serologic tests are not reliable in assessing disease activity in patients with systemic lupus erythematosus, although a small subgroup of patients will exhibit a patient-specific activity parameter.

Systemic lupus erythematosus and invasive thymoma: report of two cases.

Two cases of invasive thymoma in patients with systemic lupus erythematosus (SLE) are described. In both instances the suspected diagnosis of a mediastinal tumour proved difficult to confirm. Neither surgical removal of the thymoma in one case nor irradiation in the other had any apparent clinical or serological effect on the course of the SLE. Both patients subsequently suffered from respiratory problems and the distinction between recurrent tumour and pulmonary involvement by SLE proved difficult. One patient had a good response, however, to pulse methylprednisolone, but the other later developed recurrence of tumour and died of Pneumocystis carinii infection following cytotoxic therapy three years after discovery of the tumour.

Heterogeneity, polypeptide chain composition and antigenic reactivity of autoantibodies (F-42) that are directed against the classical pathway C3 convertase of complement and isolated from sera of patients with systemic lupus erythematosus.

F-42, an autoantibody found in the sera of some patients with systemic lupus erythematosus, was isolated from sera of seven different patients. By binding of the autoantibodies to cell bound C42, the autoantibodies were purified to homogeneity and radiolabelled with 125I. Purified preparations of 125I-F-42 were bound for at least 96% by 10(9) erythrocytes bearing C4bhuC2hu. Analysis of all 125I-F-42 preparations by SDS-PAGE demonstrated apparent mol. wts of approximately 150,000. After reduction in the presence of 8 M urea each 125I-F-42 preparation yielded heavy and light chains. The heavy chains in some instances were slightly heavier than the heavy chain of normal human IgG. The reaction of 125I-F-42 from the seven patients was positive with Sepharose bound antisera to IgG, kappa, lambda, gamma 1, gamma 2, gamma 3 and in one case to gamma 4. These studies indicate that F-42 is an autoantibody directed against antigens expressed by the classical C3 convertase, C42.

Survival and cause of death in rheumatoid arthritis: a 25-year prospective followup.

In a 25-year prospective followup of 209 patients with rheumatoid arthritis, median life expectancy was shortened by 7 years in males and by 3 years in females when compared with the general population. The surplus mortality was associated in decreasing order with the disease itself, associated respiratory, urogenital and general infections, and with upper gastrointestinal tract disease, mainly bleeding.

Relative importance of C4 binding protein in the modulation of the classical pathway C3 convertase in patients with systemic lupus erythematosus.

Serum concentrations of C1q, C4, C4 binding protein (C4bp), C3 and C2 haemolytic activity have been measured in 110 samples from 20 patients with systemic lupus erythematosus (SLE). Significant reductions in comparison to normal levels were found in the mean serum concentrations of C4, C3 and C4bp as well as C2 haemolytic activities. For patients serum concentrations of C4 correlated with C2 haemolytic activities (r = 0.91) and C4bp (r = 0.79); the C2 haemolytic levels correlated with the concentration of C4b (r = 0.72). It is concluded that serum concentrations of the complement components C4 and C2, which are the constituents of the classical pathway C3 convertase, are regulated by C4bp in vivo. Further metabolic studies are required to determine the causes of decreased serum concentrations of C4bp in patients with SLE.

Regulation of immune complex-mediated complement activation by autoantibodies (F-42) isolated from sera of patients with systemic lupus erythematosus.

Sera of some patients with systematic lupus erythematosus (SLE) contain IgG autoantibodies (F-42) which have been shown to stabilize the cell bound classical pathway C3 convertase of complement, C42. C42 is susceptible to inactivation by the plasma protein C4bp while stabilized C42 is relatively resistant to C4bp. The present study demonstrates that F-42 by itself does not induce activation of the classical pathway in vitro but that it is able to modulate the immune complex-induced consumption of C2 and C3 in whole serum. Incubation of incremental concentrations of F-42 with normal human serum (NHS) for 30 min at 30 degrees C did not result in detectable consumption of C1q, C4, C2 and C3. However, when soluble immune aggregates or immune complexes were incubated in NHS together with 100 u/ml of F-42, a significant increase in consumption of C3 was seen as compared to the reaction mixture containing immune complexes or F-42 alone. In addition the presence of F-42 during the immune complex mediated consumption of complement was associated with relative protection of C2 consumption. (Fab)'2 and Fab' fragments of F-42 behaved as intact F-42, except that their activities on a molar basis were less than that of intact F-42. The results presented in this paper suggest that F-42 may play a regulatory role in the immune complex-mediated consumption at C2 and C3 in vivo.

Degradation of soluble immunoglobulin aggregates in vitro by monocytes from normal subjects and from patients with systemic lupus erythematosus.

The capacity of human peripheral monocytes to degrade soluble immunoglobulin (IgG) aggregates (AIgG) was studied in vitro. Under serum-free conditions peripheral monocytes from normal donors were able to degrade soluble AIgG in a linear and time-dependent fashion. Addition of fresh human or fresh guinea-pig serum to the incubation mixtures caused a marked increase in degradation of the amount of soluble AIgG available. The stimulatory effect of fresh serum was complement-mediated, because it was abolished by heat treatment of the serum and was not seen when C4- or C3-deficient sera were tested. Functional inactivation of C3 receptors on the phagocytes by trypsin also abolished the complement-mediated stimulation, suggesting cooperation between Fc and C3 receptor in degradation of soluble AIgG. No significant differences were found between monocytes from normal donors and those from patients with systemic lupus erythematosus, as far as degradation is concerned in the presence of complement.

Stabilization of the classical pathway C3 convertase C42, by a factor F-42, isolated from serum of patients with systemic lupus erythematosus.

Sera from sixteen patients with SLE were investigated for the presence of a factor which would conserve convertase activity on preformed EAClgp 4hu2hu for 30 min at 30 degrees in EDTA. Although such a factor could not be detected readily in the sera, chromatography on DE-52 cellulose yielded fractions appearing as three peaks in one patient and as two peaks in a second patient. These peaks were capable of conserving C42 activity and were designated as F-42. Purification of F-42 from the second peak eluting between 4 and 7 mS on DE-52 was obtained by SP-C50, S-300 and QAE-A50 chromatography. F-42 exhibited charge heterogeneity upon SP-C50 chromatography. On polyacrylamide gel electrophoresis the final material migrated as one band, which coincided with the position of F-42 activity upon eluation from a parallel gel. F-42 had an apparent molecular weight of 150,000 and reacted with anti-IgG in Ouchterlony analysis. Sepharose-bound anti-IgG was capable of neutralizing F-42 activity. The purified material was shown to prolong the half-life (T 1/2) of performed cell-bound C42 in GVB-EDTA at 30 degrees from 5 to 80 min.