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C1-inhibitor (C1inh) is a serine protease inhibitor (serpin) protein, the main function of which is inhibition of the complement system. It circulates in blood at levels of around 0.25-0.45 g/l.
Proteomics
C1inh is the largest member of the serpin class of proteins (G1). It is probably the highest glycosylated protein. Remarkably, it has O-glycosylated residues, which is uncommon for proteins that are not membrane-bound (the immunoglobulins IgA1 and IgD are other examples). Especially a certain section of the protein, the 'tail', is highly glycosylated.
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 "angioneurotic edema"), which in layman's terms means swelling of the blood vessels. 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 C1inh 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.
Therapeutic use
In hereditary angioedema
Patients with frequent attacks of angioedema may be administered prophylactic C1-inhibitor. It may also shorten the duration or decrease the severity of attacks.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 conditionsCaliezi C, Wuillemin WA, Zeerleder S, Redondo M, Eisele B, Hack CE. C1-esterase inhibitor: an anti-inflammatory agent and its potential use in the treatment of diseases other than hereditary angioedema. Pharmacol Rev 2000;52:91-112. PMID 10699156. 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. Concentrations in human blood are relativelely low, however, and C1-inhibitor from other species may cause immune reactions. It is also impossible to produce it by recombinant technology, as Escherichia coli (the most commonly used organism for this purpose) lacks the eukaryotic ability to glycosylate proteins; as C1-inh is particularly heavily glycosylated, recombinant forms would be ineffective.References
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