a Factor H-Deficient PatientH by Fibroblasts from 127 Mutant Factor H R 4-Phenylbutyric Acid Improve Secretion of Chemical Chaperones Curcumin and

Factor H (FH) is one of the most important regulatory proteins of the alternative pathway of the complement system. Patients with FH deficiency have a higher risk for development of infections and kidney diseases because of the uncontrolled activation and subsequent depletion of the central regulatory component C3 of the complement system. In this study, we investigated the consequences of the Arg 127 His mutation in FH (FH R127H ) previously described in an FH-deficient patient, on the secretion of this protein by skin fibroblasts in vitro. We observed that, although the patient cells stimulated with IFN- g were able to synthesize FH R127H , the mutant protein was largely retained within the endoplasmic reticulum (ER), whereas normal human fibroblasts stimulated with IFN- g secrete FH without retention in the ER. Moreover, the retention of FH R127H provoked enlargement of ER cisterns after treatment with IFN- g . A similar ER retention was observed in Cos-7 cells expressing the mutant FH R127H protein. Despite this deficiency in secretion, we show that the FH R127H mutant is capable of functioning as a cofactor in the Factor I-mediated cleavage of C3. We then evaluated whether a treatment could increase the secretion of FH, and observed that the patient’s fibroblasts treated with the chemical chaperones 4-phenylbutiric acid or curcumin increased the secretion rate of FH. We propose that these chemical chaperones could be used as alternative therapeutic agents to increase FH plasma levels in FH-deficient patients caused by secretion delay of this regulatory protein. The Journal of Immunology , 2012, 189: 000–000.