PubMed · 3551118
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K Yonemasu, T Sasaki. 1986. [Complement subcomponent C1q in rheumatic diseases].. https://pubmed.ncbi.nlm.nih.gov/3551118/
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The present study was undertaken to examine the effects of excess factor D build-up in the body of end-stage renal disease (ESRD) patients upon the activation of the alternative pathway and the terminal pathway in the fluid phase. First, to clarify the effect of excess factor D on the alternative pathway, purified factor D from an ESRD patient was added to normal serum and the changes in concentrations of C3a-des-Arg and C5a-des-Arg were investigated. The results showed that once the serum factor D level reached a concentration corresponding to 15 micrograms/ml in the serum of the ESRD patient, the C3a-des-Arg and C5a-des-Arg levels had climbed to about 1.7-fold the concentration in normal serum. Next, in order to clarify the effect of excess factor D on the terminal pathway, purified factor D was added to normal serum, and the changes in C5b6 generation were examined. The results indicated that as the factor D level increased in the serum, the C5b6 level rose gradually also; and when the factor D concentration reached 15 micrograms/ml, the C5b6 generation had risen to approximately 1.5-fold the level in normal serum. The present results therefore suggest that factor D build-up in ESRD patients provides a uremic toxin that can cause abnormal activation of the whole complement cascade.
We have investigated the development of substrate-based inhibitors of complement enzymes. Sequences around the scissile Arg77-Ser78 bond of C3 have been synthesized and tested as inhibitors of C3 convertase. The best inhibition was found with the tetrapeptide Ac-Arg-Ser-Asn-Leu-OH (H-576); extending this sequence in either direction reduced inhibitory activity. Preliminary experiments with peptides in which the scissile bond--CO--NH--was replaced with non-hydrolysable moieties such as--CO--CH2--(H-497) and--CH2--NH--(H-336) failed to show enhanced inhibition. One of the longer chain inhibitors H-416 containing DArg77-Ser78 was unexpectedly found to potentiate iC3 cleavage by factors I and H but did not inhibit the intact alternative pathway. The same peptide also bound to factor H. It is concluded that the binding requirements of the C3 convertase are more sophisticated than can be satisfactorily imitated simply by linear sequences around the scissile bond of C3.
Urticaria, angioedema, and arthritis are cardinal features of hypocomplementemic urticarial vasculitis syndrome (HUVS). Considered to be an immune complex-mediated disorder, HUVS has been differentiated from systemic lupus erythematosus (SLE), based on its clinical manifestations and the C1q precipitin (C1q-p) reaction, which is manifested as gel precipitation of C1q by a small percentage of HUVS IgG molecules. This phenomenon has been attributed to an Fc region abnormality, and the responsible IgG molecules are said to possess C1q-p activity. We purified IgG from 4 HUVS patients and confirmed that HUVS IgG contains C1q binding activity. F(ab')2 fragments from these patients also bound to C1q, as measured by 2 different C1q binding methods at physiologic ionic strength; HUVS IgG Fc fragments did not bind to C1q. Preincubation of HUVS F(ab')2 fragments with antibody to human F(ab')2 prevented subsequent binding to C1q. We conclude that IgG antibodies to C1q are present in HUVS serum, and it is likely that these antibodies are C1q-p. Because the clinical manifestations of HUVS and the presence of anti-C1q antibodies have been described in patients with SLE, our findings support the concept that HUVS is an autoimmune syndrome related to SLE.