C1-inhibitor

Overview
C1-inhibitor (C1-inh, C1 esterase inhibitor) is a serine protease inhibitor (serpin) protein, the main function of which is the inhibition of the complement system to prevent spontaneous activation. C1-inh is an acute phase protein, it circulates in blood at levels of around 0.25 g/l, which levels rise ~2-fold during inflammation. C1-inh irreversibly binds to and inactivates C1r and C1s proteinases in the C1 complex of classical pathway of complement. MASP-1 and MASP-2 proteinases in MBL complexes of the lectin pathway are also inactivated. This way, C1-inh prevents the proteolytic cleavage of later complement components C4 and C2 by C1 and MBL. Although named after its complement inhibitory activity, C1-inh also inhibits proteinases of the fibrinolytic, clotting, and kinin pathways. Most notably, C1-inh is the most important physiological inhibitor of plasma kallikrein, fXIa and fXIIa.

Proteomics
C1-inh is the largest member among the serpin class of proteins. Remarkably, C1-inh has a 2-domain structure, unlike most family members. The serpin domain is similar to other serpins, and this part of C1-inh provides the inhibitory activity of C1-inh. The other domain, named N-terminal domain or N-terminal tail is not essential for C1-inh to inhibit proteinases. This domain has no similarity to other proteins. C1-inh is highly glycosylated glycosylated, bearing both N- and O-glycans. Especially the N-terminal domain is glycosylated heavily.

Genetics
The human C1-inhibitor gene is located on the eleventh chromosome (11q11-q13.1).

Role in disease
Deficiency of this protein is associated with hereditary angioedema (or "hereditary angioneurotic edema"), which in layman's terms means swelling of the blood vessels. Deficiency of C1-inh permits plasma kallikrein activation, which leads to the production of the vasoactive peptide bradykinin. Also, C4 and C2 cleavage goes unchecked, resulting in auto-activation of the complement system. Most commonly, it presents as marked swelling of the face, mouth and/or airway that occurs spontaneously or to minimal triggers (such as mild trauma), but such swelling can occur in any part of the body. In 85% of the cases, the levels of C1-inh are low, while in 15% the protein circulates in normal amounts but it is dysfunctional. In addition to the episodes of facial swelling and/or abdominal pain, it also predisposes to autoimmune diseases, most markedly lupus erythematosus, due to its consumptive effect on complement factors 3 and 4.

Despite uncontrolled auto-activation, it is important to note that levels of key complement components are low during an acute attack, because they are being consumed - indeed, low levels of C4 are a key diagnostic test for hereditary angioedema. This situation is analagous to the low levels of clotting factors found in Disseminated intravascular coagulation (DIC).

In hereditary angioedema
Patients with frequent attacks of angioedema are most frequently treated using attenuated androgens, like Danazol. The obvious choice, replacement therapy using blood-derived C1-inh is feasible, but often too expensive for prophylactic treatment. Recently, new methods of treatment have emerged: a plasma kallikrein inhibitor and a bradykinin receptor antagonist. A cheaper C1-inh alternative, recombinant C1-inh was also developed.

For other conditions
The activation of the complement cascade can cause damage to cells, therefore the inhibition of the complement cascade can work as a medicine in certain conditions. When someone has a heart attack, for instance, the lack of oxygen in heart cells causes necrosis in heart cells: dying heart cells spill their contents in the extracellular environment, which triggers the complement cascade. Activation of the complement cascade attracts phagocytes that leak peroxide and other reagents, which may increase the damage for the surviving heart cells. Inhibition of the complement cascade can decrease this damage.

Production
C1-inhibitor is contained in the human blood; it can therefore be isolated from donated blood. Risks of viral transmission and relative expense of isolation prevented widespread use. It is also possible to produce it by recombinant technology, but Escherichia coli (the most commonly used organism for this purpose) lacks the eukaryotic ability to glycosylate proteins; as C1-inh is particularly heavily glycosylated, this recombinant form would be ineffective. C1-inh was also produced in glycosylated form using transgenic rabbits. This form of recombinant C1-inh also has been given orphan drug status for delayed graft function following organ transplantation and for capillary leakage syndrome.