Hypercatabolism of C3 and C4 in active and inactive systemic lupus erythematosus.

Abstract

SUMMARY The metabolism of the complement proteins C3 and C4 was studied in patients with active and inactive systemic lupus erythematosus (SLE) using highly purified, functionally active preparations. Nine patients with active and eight with inactive SLE were examined and 11 control subjects. There was a significant difference in the level of double stranded DNA antibodies, immune complexes, and serum C4 between the patients with active and inactive disease. Seven of 16 patients had detectable C4 null alleles and four had low serum concentrations of complement inhibitors. Each subject received approximately 370 kBq [1251]C4 and 93 kBq [1311]C3. Both patient groups showed significant C4 hypercatabolism compared with control subjects, but there was no difference between patients with active and inactive disease. The fractional catabolic rate (FCR) of C4 was comparable in subjects with and without detectable C4 null alleles. C4 production rate was significantly lower in patients with active SLE than in control subjects. There was significant C3 hypercatabolism for both patient groups, but C3 production was normal. An inverse correlation was observed between serum concentration and FCR. There was a highly significant correlation between C4 FCR and C3 FCR for control subjects + patients with inactive disease but not for those with active SLE combined with either controls or the inactive group. We conclude that complement hypercatabolism occurs in SLE irrespective of disease activity and that accelerated turnover does not account completely for the low C4 concentration observed in patients with active disease. This low concentration also results from impaired plasma production, which could reflect a high incidence of C4 null alleles or (inhibitory) factors associated with pathological complement activation, or both. Low C4 production could affect generation of the C3 converting enzyme C4b, 2a and thus influence proceeding complement activation.

The metabolism of C9 in normal subjects and in patients with autoimmune disease

“…However, the serum C9 concentration was higher in patients than controls, and this value correlated with plasma production rate rather than FCR. This contrasts with previous studies of C3 and C4 metabolism in SLE, where there was an inverse relationship between fractional catabolic rate and serum protein concentration [11]. In the absence of altered distribution therefore, plasma production became the major determinant of the serum C9 concentration, and this study demonstrates the capacity of increased production to compensate for accelerated C9 removal in autoimmune disease.…”

“…36%/h) was greater than that reported for other complement proteins such as C3 (1 . 61%/h [11]), C4 (1 . 87%/h [11]), C5 (1 .…”

“…C3 activation can be associated with gross reduction in plasma production rate as well as altered C3 distribution [11][12][13]. Similarly, acquired reduction of serum C4 concentration is determined by hypercatabolism, reduced synthesis rate and altered distribution [11]; the relative contribution of these factors varies among patients and diseases. The factors maintaining normal C9 concentration in the presence of pathological complement activation are not clear.…”

The influence of oral lipid loads on acylation stimulating protein (ASP) in healthy volunteers

“…30% of molecules reside outside the intravascular compartment under normal conditions. This percentage may increase following complement activation, 16 thus providing the potential for signi®cant interchange between intra-and extra-vascular compartments in response to speci®c stimuli. Hence, it is possible that variation in 15 min and 1 h samples re¯ects changes in compartmental distribution rather than true change in metabolic behaviour.…”

Distribution of the HindIII restriction fragment length polymorphism among patients with systemic lupus erythematosus with different concentrations of CR1.

“…As shown in the figure the I-that is, concentration of serum complements in patients 7) U/ml in with a negative CR1 was significantly lower (10) U/ml than those in patients with a positive CR1, and ie of C4 in in group II, the change in CR1 from negative to gnificantly positive was accompanied by an increase in i group I serum complement. The existence of potential (50) mg/l complement activation has been described even in patients with SLE in clinical remission.26 27 28 The erythrocyte CR1 may have a functional role in the removal of circulating immune complexes and this process would depend on complement consumption. Therefore, even if the genotypes are homozygous for the 7T4 kb allele, the CR1 activities may be negative as long as immunological disorders remain and the complement concentrations are low.…”