C1-inhibitor (C1-inh, C1 esterase inhibitor) is a protease inhibitor belonging to the serpin superfamily.[5] Its main function is the inhibition of the complement system to prevent spontaneous activation but also as the major regulator of the contact system.[6][7]
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C1-inhibitor is the largest member among the serpin superfamily of proteins. It can be noted that, unlike most family members, C1-inhibitor has a 2-domain structure. The C-terminal serpin domain is similar to other serpins, which is the part of C1-inhibitor that provides the inhibitory activity. The N-terminal domain (also some times referred to as the N-terminal tail) is not essential for C1-inhibitor to inhibit proteases. This domain has no similarity to other proteins. C1-inhibitor is highly glycosylated, bearing both N- and O-glycans. N-terminal domain is especially heavily glycosylated.[7]
Deficiency of this protein is associated with hereditary angioedema ("hereditary angioneurotic edema"), or swelling due to leakage of fluid from blood vessels into connective tissue.[8] Deficiency of C1-inhibitor 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. In its most common form, 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-inhibitor 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. Mutations in the gene that codes for C1-inhibitor, SERPING1, may also play a role in the development of age-related macular degeneration.[9] At least 97 disease-causing mutations in this gene have been discovered.[10]
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Hereditary angioedema
Blood-derived C1-inhibitor is effective but does carry the risk associated with the use of any human blood product. Cinryze, a pharmaceutical-grade C1-inhibitor, was approved for the use of HAE in 2008 in the US after having been available in Europe for decades.[17] It is a highly purified, pasteurized and nanofiltered plasma-derived C1 esterase inhibitor product; it has been approved for routine prophylaxis against angioedema attacks in adolescent and adult patients with HAE.[18]
A recombinant C1-inhibitor obtained from the milk of transgenic rabbits, conestat alfa (brand name Ruconest), is approved for the treatment of acute HAE attacks in adults.[13][16][19]
Other products also have been introduced including plasma-derived products such as Berinert and Haegarda.[20][21][22]
Synthesis
C1-inhibitor is contained in the human blood; it can, therefore, be isolated from donated blood. Risks of infectious disease transmission (viruses, prions, etc.) 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-inhibitor is particularly heavily glycosylated, this sialylated recombinant form would have a short circulatory life (the carbohydrates are not relevant to the inhibitor function). Therefore, C1-inhibitor has also been produced in glycosylated form using transgenic rabbits.[23] This form of recombinant C1-inhibitor also has been given orphan drug status for delayed graft function following organ transplantation and for capillary leakage syndrome.[24]
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.[25]
Davis AE (January 2008). "Hereditary angioedema: a current state-of-the-art review, III: mechanisms of hereditary angioedema". Annals of Allergy, Asthma & Immunology. 100 (1 Suppl 2): S7-12. doi:10.1016/S1081-1206(10)60580-7. PMID 18220146. "Cinryze EPAR". European Medicines Agency (EMA). 15 June 2011. Retrieved 27 September 2024. "Ruconest EPAR". European Medicines Agency (EMA). 28 October 2010. Retrieved 30 August 2024. Bernstein JA (January 2008). "Hereditary angioedema: a current state-of-the-art review, VIII: current status of emerging therapies". Annals of Allergy, Asthma & Immunology. 100 (1 Suppl 2): S41-6. doi:10.1016/S1081-1206(10)60585-6. PMID 18220151. Caliezi C, Wuillemin WA, Zeerleder S, Redondo M, Eisele B, Hack CE (March 2000). "C1-Esterase inhibitor: an anti-inflammatory agent and its potential use in the treatment of diseases other than hereditary angioedema". Pharmacological Reviews. 52 (1): 91–112. PMID 10699156.
- Lappin D, Whaley K (July 1989). "Regulation of C1-inhibitor synthesis by interferons and other agents". Behring Institute Mitteilungen (84): 180–92. PMID 2478116.
- Stein PE, Carrell RW (February 1995). "What do dysfunctional serpins tell us about molecular mobility and disease?". Nature Structural Biology. 2 (2): 96–113. doi:10.1038/nsb0295-96. PMID 7749926. S2CID 21223825.
- Davis AE, Bissler JJ, Cicardi M (December 1993). "Mutations in the C1 inhibitor gene that result in hereditary angioneurotic edema". Behring Institute Mitteilungen (93): 313–20. PMID 8172583.
- Davis AE (January 2005). "The pathophysiology of hereditary angioedema". Clinical Immunology. 114 (1): 3–9. doi:10.1016/j.clim.2004.05.007. PMID 15596403.
- Siddique Z, McPhaden AR, McCluskey D, Whaley K (1992). "A single base deletion from the C1-inhibitor gene causes type I hereditary angio-oedema". Human Heredity. 42 (4): 231–4. doi:10.1159/000154075. PMID 1339401.
- Davis AE, Aulak K, Parad RB, Stecklein HP, Eldering E, Hack CE, et al. (August 1992). "C1 inhibitor hinge region mutations produce dysfunction by different mechanisms". Nature Genetics. 1 (5): 354–8. doi:10.1038/ng0892-354. PMID 1363816. S2CID 29076504.
- Frangi D, Aulak KS, Cicardi M, Harrison RA, Davis AE (April 1992). "A dysfunctional C1 inhibitor protein with a new reactive center mutation (Arg-444-->Leu)". FEBS Letters. 301 (1): 34–6. doi:10.1016/0014-5793(92)80204-T. PMID 1451784. S2CID 28082291.
- Lappin DF, Guc D, Hill A, McShane T, Whaley K (January 1992). "Effect of interferon-gamma on complement gene expression in different cell types". The Biochemical Journal. 281 (Pt 2): 437–42. doi:10.1042/bj2810437. PMC 1130704. PMID 1531292.
- Siddique Z, McPhaden AR, Lappin DF, Whaley K (December 1991). "An RNA splice site mutation in the C1-inhibitor gene causes type I hereditary angio-oedema". Human Genetics. 88 (2): 231–2. doi:10.1007/bf00206079. PMID 1684567. S2CID 20492891.
- Frangi D, Cicardi M, Sica A, Colotta F, Agostoni A, Davis AE (September 1991). "Nonsense mutations affect C1 inhibitor messenger RNA levels in patients with type I hereditary angioneurotic edema". The Journal of Clinical Investigation. 88 (3): 755–9. doi:10.1172/JCI115373. PMC 295456. PMID 1885769.
- Carter PE, Duponchel C, Tosi M, Fothergill JE (April 1991). "Complete nucleotide sequence of the gene for human C1 inhibitor with an unusually high density of Alu elements". European Journal of Biochemistry. 197 (2): 301–8. doi:10.1111/j.1432-1033.1991.tb15911.x. PMID 2026152.
- Parad RB, Kramer J, Strunk RC, Rosen FS, Davis AE (September 1990). "Dysfunctional C1 inhibitor Ta: deletion of Lys-251 results in acquisition of an N-glycosylation site". Proceedings of the National Academy of Sciences of the United States of America. 87 (17): 6786–90. Bibcode:1990PNAS...87.6786P. doi:10.1073/pnas.87.17.6786. PMC 54622. PMID 2118657.
- Stoppa-Lyonnet D, Carter PE, Meo T, Tosi M (February 1990). "Clusters of intragenic Alu repeats predispose the human C1 inhibitor locus to deleterious rearrangements". Proceedings of the National Academy of Sciences of the United States of America. 87 (4): 1551–5. Bibcode:1990PNAS...87.1551S. doi:10.1073/pnas.87.4.1551. PMC 53513. PMID 2154751.
- Levy NJ, Ramesh N, Cicardi M, Harrison RA, Davis AE (January 1990). "Type II hereditary angioneurotic edema that may result from a single nucleotide change in the codon for alanine-436 in the C1 inhibitor gene". Proceedings of the National Academy of Sciences of the United States of America. 87 (1): 265–8. Bibcode:1990PNAS...87..265L. doi:10.1073/pnas.87.1.265. PMC 53243. PMID 2296585.
- Theriault A, Whaley K, McPhaden AR, Boyd E, Connor JM (April 1990). "Regional assignment of the human C1-inhibitor gene to 11q11-q13.1". Human Genetics. 84 (5): 477–9. doi:10.1007/BF00195824. PMID 2323781. S2CID 21989261.
- Aulak KS, Cicardi M, Harrison RA (June 1990). "Identification of a new P1 residue mutation (444Arg----Ser) in a dysfunctional C1 inhibitor protein contained in a type II hereditary angioedema plasma". FEBS Letters. 266 (1–2): 13–6. doi:10.1016/0014-5793(90)81494-9. PMID 2365061. S2CID 35981265.
- Skriver K, Radziejewska E, Silbermann JA, Donaldson VH, Bock SC (February 1989). "CpG mutations in the reactive site of human C1 inhibitor". The Journal of Biological Chemistry. 264 (6): 3066–71. doi:10.1016/S0021-9258(18)94031-7. PMID 2563376.
- Ariga T, Igarashi T, Ramesh N, Parad R, Cicardi M, Davis AE (June 1989). "Type I C1 inhibitor deficiency with a small messenger RNA resulting from deletion of one exon". The Journal of Clinical Investigation. 83 (6): 1888–93. doi:10.1172/JCI114095. PMC 303909. PMID 2723063.
- Tosi M, Duponchel C, Bourgarel P, Colomb M, Meo T (1986). "Molecular cloning of human C1 inhibitor: sequence homologies with alpha 1-antitrypsin and other members of the serpins superfamily". Gene. 42 (3): 265–72. doi:10.1016/0378-1119(86)90230-1. PMID 3089875.
