Genetic Disease

The complement system plays a major role in host protection against invasive pathogens, in maintenance of organism’s homeostasis, and in immune complex processing. Involved in more than 40 zymogens, receptors and regulators, the complex system can be activated via 3 separate activation pathways which appear at different times in evolution: the classical, alternative, and lectin pathways.

Every step of the enzymatic cascade is under strict regulation to avoid excessive or insufficient activation. In immune reactions, two activation pathways appear before the evolution of the adaptive immune system, because they do not require antibody for initiation. Three pathways come together to activate C3, the principle opsonic protein of the complement cascade, and all continue together to the generation of membrane attack complex (MAC) for lysis of apoptotic/necrotic cells and microbes.

Genetic Disease

The indispensable role of complement system in immune system reveals that any deficiency in complement proteins may cause increased susceptibility to a variety of diseases, such as genetic disease. Usually, the complement defects are rare due to the rigorously genetic control, while defects in the proteins in circulation and on cell membranes that downregulate complement to limit uncontrolled inflammation are more common. These deficiencies can be inherited or acquired.

The typical complement related genetic disorder is angioedema, which is characterized by nonpitting edema of the dermis and subcutaneous layers. The acute, recurring, and self-limiting edematous episodes can occur on face, extremities, trunk, upper airways, genitals or the gastrointestinal tract, in which airway swelling is life-threatening. Hereditary angioedema and acquired angioedema are the common branches and both are closely associated with complement components.

1. Hereditary Angioedema

Hereditary angioedema (HAE) is a rare disorder, which belongs to the group of bradykinin-mediated angioedemas. HAE induced edemas can affect the face, the extremities, the trunk, and the genitals. In the gastrointestinal tract, angioedema may mimic an abdominal catastrophe, whereas in the upper airways, it may cause obstruction leading to suffocation. There are main types of HAE:

1. Hereditary angioedema with complement C1-inhibitor (C1-INH) deficiency (C1-INH-HAE)
2. Hereditary angioedema with normal C1-INH function (nC1-INH-HAE)

C1-INH can inhibit activation of C1 to regulate the complement, coagulation, and fibrinolytic plasma enzyme cascades. The deficiency of C1-INH leads to the uncontrolled, spontaneous activation of C1, and to the consumption of C4 and C2. nC1-INH-HAE is often due to a mutation of the factor XII (F12) gene, which results in the increased functional (amidolytic) activity and can escape inhibition by the C1-inhibitor.

1. Acquired Angioedema

Similar to hereditary angioedema, acquired angioedema (AAE) can also cause serious and potentially fatal attacks of subcutaneous and submucosal edemas of upper airways, facial structures, abdomen, and extremities, due to inadequate control of BK generation. The main etiology is similarly due to C1-inhibitor deficiency (C1-INH-AAE).

Fig 1. Pathways inhibited by C1-INH and pathogenesis of hereditary angioedema. (Li, 2016)

As a key correlation factor in the pathomechanism of genetic disease (HAE and AAE), complement has been studied as an important diadynamic criteria, and is beneficial to predict the severity of diseases. Therefore, the complement components have become an attractive therapeutic target for genetic disease.

Creative Biolabs provides numerous therapeutic antibodies, inhibitors, soluble complement regulators, as well as customized services. Our comprehensive complement platform offers a great number of complement-related products in a rapid and cost-effective manner. If you are interested, please feel free to contact us for more details.

Reference
1. Li, H. H. (2016). Self-administered C1 esterase inhibitor concentrates for the management of hereditary angioedema: usability and patient acceptance. Patient preference and adherence. 10,1727.

Related Product

• Autoimmune Disease
• Nephropathy
• Osteology
• Infection
• Neurology
• Inflammatory Disease
• Ophthalmology
• Cardiovascular Disease
• Hereditary Angioedema
• Acquired Angioedema