Hereditary complement factor I deficiency

Summary We describe four cases (from three families) of hereditary factor I deficiency, bringing the total number of cases now reported to 23. In one family there are two affected siblings: one has suffered recurrent pyogenic infections; the other is asymptomatic. In the second family, the patient had recurrent pyogenic infections and a self-limiting vasculitic illness; in the third family, the patient suffered recurrent pyogenic and neisserial infections. All four patients had markedly reduced concentrations of C3 in the serum (family 1 propositus: 28%; family 1 asymptomatic sibling: 15%; family 2: 31%; and family 3: 31 % normal human serum) which was in the form of C3b. Low lgG2 levels may occur in primary C3 deficiency, and reduction in lgG2 concentration to 1.14 g/l (normal: 1.30-5.90 g/l) was found in the patient from family 2. Using radioligand binding assays, we demonstrated increased binding of C3b to erythrocytes in a patient with factor I deficiency. This C3b could not be cleaved by autologous serum but could be cleaved by normal serum or purified factor I. We review and compare the published cases of C3, factor H and factor I deficienc

Biosynthesis and secretion of complement component C3 by activated human polymorphonuclear leukocytes

We tested the hypothesis that human polymorphonuclear leukocytes (PMN), bearing complement receptors CR1 and CR3, might also synthesize C3, particularly when activated by LPS or cytokines. Northern blot analysis of total RNA, obtained from purified PMN stimulated overnight with LPS or cytokines (IFN-gamma, TNF-alpha, and IL-1) showed the 5.3-kb RNA transcript reported for C3 in hepatocytes and monocytes. No transcripts for C4 and factor B were detected. Time course studies of C3 mRNA expression in PMN treated with LPS or TNF-alpha demonstrated a steady increase with a plateau at 24 h that correlated with secretion of C3, determined by ELISA. In contrast, IFN-gamma and IL-1 induced a transient increase in C3 transcript with a peak around 8 h after stimulation, which was not reflected in an increased rate of C3 secretion. The content of C3 protein in PMN culture media, measured by ELISA, was about 4 ng/ml/10(7) cells after overnight stimulation with LPS or TNF-alpha. A very small amount of C3 (about 0.7 ng/ml/10(7) cells) was detected in supernatants from unstimulated and IFN-gamma- or IL-1-induced PMN. Immunoprecipitation with a polyclonal anti-human C3, followed by SDS-PAGE analysis, from [35S]methionine labeled PMN, revealed the presence in culture supernatants of three major bands at 185, 115 and 70 kDa, corresponding to pro-C3, alpha and beta chains, respectively. Analysis of [14C]methylamine incorporation and of autolytic cleavage showed that the C3 produced in tissue culture by PMN contained an intact thiolester bond. The capacity of PMN to secrete functional C3 in response to LPS and TNF-alpha might be an important mechanism of host defense at sites of inflammation

Spontaneous hemolytic uremic syndrome triggered by complement factor H lacking surface recognition domains

Factor H (FH) is an abundant serum glycoprotein that regulates the alternative pathway of complement-preventing uncontrolled plasma C3 activation and nonspecific damage to host tissues. Age-related macular degeneration (AMD), atypical hemolytic uremic syndrome (aHUS), and membranoproliferative glomerulonephritis type II (MPGN2) are associated with polymorphisms or mutations in the FH gene (Cfh), suggesting the existence of a genotype-phenotype relationship. Although AMD and MPGN2 share pathological similarities with the accumulation of complement-containing debris within the eye and kidney, respectively, aHUS is characterized by renal endothelial injury. This pathological distinction was reflected in our Cfh association analysis, which demonstrated that although AMD and MPGN2 share a Cfh at-risk haplotype, the haplotype for aHUS was unique. FH-deficient mice have uncontrolled plasma C3 activation and spontaneously develop MPGN2 but not aHUS. We show that these mice, transgenically expressing a mouse FH protein functionally equivalent to aHUS-associated human FH mutants, regulate C3 activation in plasma and spontaneously develop aHUS but not MPGN2. These animals represent the first model of aHUS and provide in vivo evidence that effective plasma C3 regulation and the defective control of complement activation on renal endothelium are the critical events in the molecular pathogenesis of FH-associated aHUS