Maintenance of a normal C1 inhibitor (Clinh) serum level depends on the balance between Clinh synthesis and its catabolism. Clinh deficient patients represent one """"""""experiment of nature"""""""" where this balance is lost. Patients with hereditary angioedema (HAE) have both an abnormal Clinh gene and an acquired defect in gene expression. In patients with acquired Clinh deficiency, there is accelerated consumption of Clinh with the generation of a modified (94 kD) inactive form of Clinh. The study of Clinh synthetic and catabolic abnormalities in these patients provides a unique opportunity to elucidate the mechanisms of Clinh homeostasis. Peripheral blood monocyte and hepatoma cell models have been established to study Clinh secretion in vitro. Gamma interferon stimulates Clinh secretion from both cell types. The effect of danazol (which increases serum levels of Clinh) on Clinh secretion will be determined. Monocytes from HAE patients will be cultured with and without added gamma interferon or danazol. Their Clinh secretion will be measured and compared to normal monocytes. The rates of Clinh secretion will be correlated with levels of expressed Clinh mRNA determined by quantitative Northern blotting analysis. The nature of the synthetic defect(s) in HAE and the action of these agents will thus be localized to either a pre-translational or post-translational level. The interactions of serine proteases with Clinh in purified protein systems and in plasma will be analyzed by measuring proteolytic activity, protease-Clinh complex formation, and 94 kD Clinh generation. By studying these parameters in the relevent proteases at various molar ratios, the biochemical mechanism of 94 kD Clinh formation will be determined. The structural relationship between 94 kD Clinh and native Clinh will be assessed by amino acid end group analysis. Radiolabeled 94 kD Clinh will be utilized to calculate the fractional catabolic rate of 94 kD Clinh in AC1D and other patients. The results of these experiments should lead to improved strategies for therapeutically increasing the serum and tissue Clinh levels. This will be useful not only in the treatment of Clinh deficient patients, but also to limit contact and classical complement system activation in other inflammatory diseases.
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