C1 inhibitor: molecular and clinical aspects

Abstract

C1 inhibitor (C1-INH) is a serine protease inhibitor (serpins) that inactivates several different proteases in the complement, contact, coagulation, and fibrinolytic systems. By its C-terminal part (serpin domain), characterized by three beta-sheets and an exposed mobile reactive loop, C1-INH binds, and blocks the activity of its target proteases. The N-terminal end (nonserpin domain) confers to C1-INH the capacity to bind lipopolysaccharides and E-selectin. Owing to this moiety, C1-INH intervenes in regulation of the inflammatory reaction. The heterozygous deficiency of C1-INH results in hereditary angioedema (HAE). The clinical picture of HAE is characterized by bouts of local increase in vascular permeability. Depending on the affected site, patients suffer from disfiguring subcutaneous edema, abdominal pain, vomiting and/or diarrhoea for edema of the gastrointestinal mucosa, dysphagia, and dysphonia up to asphyxia for edema of the pharynx and larynx. Apart from its genetic deficiency, there are several pathological conditions such as ischemia-reperfusion, septic shock, capillary leak syndrome, and pancreatitis, in which C1-INH has been reported to either play a pathogenic role or be a potential therapeutic tool. These potential applications were identified long ago, but controlled studies have not been performed to confirm pilot experiences. Recombinant C1-INH, produced in transgenic animals, has recently been produced for treatment of HAE, and clinical trials are in progress. We can expect that the introduction of this new product, along with the existing plasma derivative, will renew interest in exploiting C1-INH as a therapeutic agent.

Novelties in the Diagnosis and Treatment of Angioedema

“…This phenotype causes significant personal, domestic, social, and occupational disability and exposes patients to the risk of death [38]. Mutations in 2 genes, the C1-INH gene (SERPING1) and factor XII gene (F12) have been shown to be responsible for 2 separate types of HAE, namely, C1-INH-HAE and FXII-HAE [39,40]. A third type, HAE of unknown origin (U-HAE), is not associated with SERPING1 or F12 mutations and does not involve plasma C1-INH deficiency.…”

C1-Esterase Inhibitor Protects Against Neointima Formation After Arterial Injury in Atherosclerosis-Prone Mice

“…C1-inhibitor controls both the classic and mannosebinding lectin pathways by covalent complex formation with activated C1r, C1s, and MASPs. 14 The alternative pathway differs in that it is constantly activated in the fluid phase. C1-inhibitor can also inhibit the alternative pathway by binding to C3b and interfering with factor B binding to C3b.…”

“…3 Beyond the direct effects on C1 activity, the C1-inhibitor can subsequently result in reduced generation of biologically active end products, such as the anaphylatoxins C3a and C5a, as well as C5b-9 membrane attack complex, all of which can induce tissue injury. 14 Because it is the central acute-phase component of complement activation, we focused on serum levels of C3 and its local expression in the vascular wall. Interestingly, an association with C3 levels has been implied for human coronary artery disease.…”

“…14 Here, we report the first use of C1-inhibitor for long-term treatment in mice. The dosage used in vivo was based on previous studies in mice.…”

“…Underlying mechanisms have been attributed primarily to an inhibition of the complement and contact system, which results in a reduction in the generation of its biologically active products, such as C3a, C5a, C5b-9 membrane attack complex, and bradykinin. 13,14 Effects of the C1-inhibitor resulted in the decreased release of various cytokines, including tumor necrosis factor, IL-10, IL-6, and IL-8, in sepsis. 15,16 In addition to effects on the complement system, the C1-inhibitor has also been described to inhibit factors of the intrinsic coagulation system.…”