C1 Inhibitor/C1-INH Deficiency of Classical Pathway

C1 Inhibitor/C1-INH Deficiency of Classical Pathway (Proteins | Antibodies | Genes | ELISA Kits)

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C3 Deficiency of Classical Pathway Background

C3 is cleaved by C4b2a, releasing C3a and leaving C3b, the major opsonin of the complement system. C3b also acts on C5 to initiate the MAC (C5b-C9). C3 deficiency results in impaired opsonization and impaired initiation of the final common pathway (MAC). C3 deficiency is extremely rare with only 27 reported cases among 19 families worldwide. Individuals deficient in C3 usually have less than 1% of normal levels of C3 antigenically and functionally. C3 deficiency rarely leads to systemic lupus erythematosus / SLE-like disease, rather it typically results in recurrent pyogenic infections and membrano-proliferative glomerulonephritis / MPGN. Infections are often caused by N. meningitidis, H. influenzae, Enterobacter aerogenes, and Escherichia coli. Respiratory tract infections are prominent, including pneumonia, tonsillitis, sinusitis, and otitis. Renal disease, including MPGN and mesangiocapillary glomerulonephritis, has been seen in 26% of reported cases of C3 deficiency. An SLE-like syndrome with fever, vasculitic skin lesions, and arthritis has been seen in 28% of reported cases of C3 deficiency.

C1 Inhibitor/C1-INH Deficiency of Classical Pathway Background

C1-INH controls the initiation of the classical pathway of the complement system by covalently binding to C1r and C1s, resulting in disassembly of the C1 macromolecular complex. C1-INH also inhibits early steps of the MBL pathway, Hagemann factor, clotting factors XI and XIIa, plasma kallikrein, and plasmin. C1-INH deficiency is known to cause angioedema, and, although the exact mechanism is unknown, it is related to an excess of bradykinin. Angioedema from C1- INH deficiency can be hereditary or acquired. Hereditary deficiency of C1-INH is responsible for the clinical disease known as hereditary angioedema / HAE, a rare disease with an estimated global prevalenc ebetween 2–10 cases per 100,000 people. The disorder is inherited in an autosomal dominant manner. There are three known types of HAE. Type I HAE comprises 80% of cases and is from inadequate production of C1-INH. Type II HAE comprises 20% of cases and is from production of a dysfunctional C1-INH molecule at normal levels. Type III HAE is extremely rare, is believed to be related to hormonal responses of the C1-INH system, and only occurs in women.

The clinical manifestation of C1-INH deficiency is recurrent episodes of localized submucosal or subcutaneous edema involving almost any part of the body, including skin, gastrointestinal tract, or upper airways, that usually last 24-72 h. The most worrisome complication is laryngeal edema, which has been a major cause of death in HAE individuals. A traumatic event can trigger an episode of edema, but episodes can also occur spontaneously. Most notably, in HAE, edema is not associated with urticaria or pruritus. Edema of the bowel wall can occur and is typified by self-limited severe abdominal pain, guarding (without fever), abdominal rigidity, vomiting, diarrhea, and leukocytosis that can last 1-3 days.

C1 Inhibitor/C1-INH Deficiency of Classical Pathway References

1. Pettigrew H D, et al. (2009). Clinical significance of complement deficiencies. Annals of the New York Academy of Sciences, 1173(1), 108-123.
2. Botto M. (1999). C1q knock-out mice for the study of complement deficiency in autoimmune disease. Experimental and clinical immunogenetics, 15(4), 231-234.