Complement Deficiencies and Related Diseases

Complement is an important part of the body's immune regulation network, not only participates in anti-infection immunity, but also has multiple functions such as regulating inflammatory response, processing autoantigens, and regulating immune-related gene expression. It also participates in immune conditioning, apoptosis regulation, and autophagy regulation, which plays a significant role in maintaining the body's immune stability.

Studies have found that defects can occur in many components of the complement system, such as the components C1 to C9, H factor, I factor, D factor, C1INH, properdin, receptor protein, etc., abnormality of which directly causes or participates in the occurrence of related diseases, and has a close relationship with the prognosis of the disease, such as systemic lupus erythematosus (SLE), atypical hemolytic uremic syndrome (aHUS), paroxysmal nocturnal hemoglobinuria (PNH), hereditary angioedema (HAE) and age-related macular degeneration (AMD), etc.

In view of the important role of complement in immune regulation and effects, the relationship between complement mutations and disease occurrence has become a research hotspot.

aHUS is a disease characterized by the triad of microvascular hemolytic anemia, reduced platelets, and acute renal failure, and the majority of patients are children. aHUS is complex in etiology, and the main pathogenesis is the excessive activation of the complement bypass pathway. A membrane attack complex (MAC) is formed on the surface of tissue cells, resulting in cells dissolve. Recent related studies have shown that the onset of aHUS is related to gene mutations in complement factor H, factor I, serum complement components (complements C3, factor B), membrane cofactor protein (CD46, MCP), and thrombomodulin. Detection of complement regulatory proteins and related genetic analysis can be used to differentially diagnose aHUS.

AMD is a disease with increasing incidence with increasing age. Clinically, AMD is divided into two types: dry and wet. Dryness is mainly manifested by macular warts, pigmentation disorders, and map-like atrophy. Wetness is mainly manifested as destruction of the vitreous membrane and the invasion of the choroidal blood vessels under the retina constitute new blood vessels, causing exudative or hemorrhagic detachment. Genetic factors, chronic macular damage, metabolic and nutritional factors are all involved in its pathogenesis. Studies in recent years have shown that abnormal activation of the complement system plays an important role in the pathogenesis of AMD. Mutations or defects of C3, C5, and factor H have the greatest correlation with the pathogenesis of the disease.

HAE is a rare autosomal dominant genetic disease with a global incidence of 1/10 000 to 1 / 50,000. Nearly 200 species of c1inh gene mutations were found in HAE patients, and this gene is located at the 11q12-q13.1 site. Clinically, HAE is generally divided into two types, type I accounts for about 85%, in which c1inh gene insertion or deletion cannot normally synthesize related proteins, and serum C1INH levels decrease; type II accounts for about 15%, and point mutations in the C1INH coding region occur, and the serum C1INH level is normal or increased, but has no physiological function. In recent years, more and more c1inh gene mutation sites have been found, suggesting that HAE is a genetic heterogeneous disease.

PNH is a disease caused by abnormal GPI synthesis, which is because of the mutations in acquired pig-A gene in hematopoietic stem cells. Many studies have shown that pig-A gene mutations can cause PNH. The pig-A gene encodes a subunit of acetylglucosamine transferase, which is involved in the synthesis of GPI. GPI is an anchoring protein that is responsible for anchoring a variety of protein regulatory factors such as CD55 complementcand CD59 complement to the cell surface. When mutation occurs in the pig-A gene, CD55 and CD59 cannot be anchored to the surface of red blood cells, resulting in the inability to regulate the formation of membrane attack complexes, and thus lead to abnormal complement-mediated intravascular hemolysis of PNH.

Complement defects are related to the type and severity of susceptible diseases. The accurate and timely identification of the types and number of complement defects in susceptible people is important for the diagnosis, treatment, identification and prevention of diseases.