Complement factor H–related hybrid protein deregulates complement in dense deposit disease
Qian Chen, Michael Wiesener, Hannes U. Eberhardt, Andrea Hartmann, Barbara Uzonyi, Michael Kirschfink, Kerstin Amann, Maike Buettner, Tim Goodship, Christian Hugo, Christine Skerka, Peter F. Zipfel
Qian Chen, Michael Wiesener, Hannes U. Eberhardt, Andrea Hartmann, Barbara Uzonyi, Michael Kirschfink, Kerstin Amann, Maike Buettner, Tim Goodship, Christian Hugo, Christine Skerka, Peter F. Zipfel
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Research Article Nephrology

Complement factor H–related hybrid protein deregulates complement in dense deposit disease

Abstract

The renal disorder C3 glomerulopathy with dense deposit disease (C3G-DDD) pattern results from complement dysfunction and primarily affects children and young adults. There is no effective treatment, and patients often progress to end-stage renal failure. A small fraction of C3G-DDD cases linked to factor H or C3 gene mutations as well as autoantibodies have been reported. Here, we examined an index family with 2 patients with C3G-DDD and identified a chromosomal deletion in the complement factor H–related (CFHR) gene cluster. This deletion resulted in expression of a hybrid CFHR2-CFHR5 plasma protein. The recombinant hybrid protein stabilized the C3 convertase and reduced factor H–mediated convertase decay. One patient was refractory to plasma replacement and exchange therapy, as evidenced by the hybrid protein quickly returning to pretreatment plasma levels. Subsequently, complement inhibitors were tested on serum from the patient for their ability to block activity of CFHR2-CFHR5. Soluble CR1 restored defective C3 convertase regulation; however, neither eculizumab nor tagged compstatin had any effect. Our findings provide insight into the importance of CFHR proteins for C3 convertase regulation and identify a genetic variation in the CFHR gene cluster that promotes C3G-DDD. Monitoring copy number and sequence variations in the CFHR gene cluster in C3G-DDD and kidney patients with C3G-DDD variations will help guide treatment strategies.

Authors

Qian Chen, Michael Wiesener, Hannes U. Eberhardt, Andrea Hartmann, Barbara Uzonyi, Michael Kirschfink, Kerstin Amann, Maike Buettner, Tim Goodship, Christian Hugo, Christine Skerka, Peter F. Zipfel

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Figure 7

Modulation and inhibition of complement activation in serum of patient no. 635.

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Modulation and inhibition of complement activation in serum of patient n...
(A) Effect of eculizumab in mixed patient serum. Eculizumab (35–350 nM) was added to serum of patient no. 635 mixed with NHS (10% each) or to NHS alone. Eculizumab did not affect C3a generation but augmented C3b deposition when used at 350 nM. Eculizumab blocked C5a generation and TCC deposition. The effect of mixed serum or NHS alone was set to 100%. (B) Effect of C3 convertase inhibitors and eculizumab in mixed patient serum. sCR1, when added to patients serum at 50 nM, inhibited C3a generation by 75% and C3b deposition by 92%. Comp-CFH15-20 used at 100 nM affected C3a generation by 16% but reduced C3b deposition by 73%. Eculizumab used at 200 nM showed no inhibition. The C3a and C3b levels detected in mixed serum in the absence of an inhibitor were set to 100%.