Complement System and Targeted Therapy (II)

Homologous restriction of complement regulation

1. When both target cells and complement are from the same genus, the complement cytolytic effect is suppressed.

2. Regulatory proteins that cause homology restriction are called homologous restriction factors (HRF): CD46 (MCP), CD55 (DAF), CD59, CR1, etc.

Biological function of complement

(1) Bacteriolytic and cytolytic effects

After the complement system is activated through the classical pathway, the bypass pathway or the MBL pathway, it can form a membrane attack complex on the target cells, resulting in the lysis of the target cells;

This function of complement plays an important defense and immune surveillance role in the body’s immune system and can resist infection by pathogenic microorganisms;

When some patients have congenital or acquired complement defects, the most important manifestation is that they are susceptible to pathogenic microorganisms and recurrent infections.

(2) Conditioning effect

The opsonization effect is also called phagocytosis, and both complement and antibody have opsonization effects. There are a variety of complement receptors on the surface of phagocytic cells, such as CR1, CR2, CR3 and other complement fragments (C3b/C4b) that bind to target cells or antigens can specifically bind to complement receptors on the surface of phagocytic cells and promote contact between the two. Enhance phagocytosis and intracellular oxidation, and ultimately enhance the body’s ability to resist infection.

(3) Immune adhesion and removal of immune complexes

After bacteria or immune complexes activate complement and bind C3b/C4b, if they bind to RBC and platelets with corresponding complement receptors (CR1) on the surface, a larger polymer can be formed, which reaches the liver and spleen through blood circulation.

(4) Promote the effect of neutralizing and dissolving virus

Adding complement to the complex formed by the virus and the corresponding antibody can significantly enhance the neutralization effect of the antibody on the virus;

In the absence of antibodies, complement can also dissolve and inactivate viruses.

(5) Inflammation

C3a, C4a, C5a, with allergic toxins, can degranulate mast cells and basophils with corresponding receptors on the surface, release vasoactive substances such as histamine to cause vasodilation, enhanced permeability, smooth muscle contraction and Branch spasm, etc.;

C3a and C5a have a chemotactic effect on neutrophils, attracting neutrophils and monocyte phagocytic cells with corresponding receptors to migrate and aggregate to the inflammatory area activated by complement, enhancing the inflammatory response;

C2a has kinin-like effects: dilates small blood vessels, enhances permeability, and causes inflammatory hyperemia and edema.

(6) Immunomodulation

The active fragments produced during the activation of complement can interact with immune cells and regulate immune function. For example, C3d, Ba, Bb and other fragments can regulate the function of B cells; C5a can promote the production of various cytokines such as IL-1, IL-6, IL-8, and TNFa.

Complement system and diseases

1. Complement defects

Apart from the relatively common defects of C2 and C1 INH, defects of other complement components are very rare. The two major clinical manifestations of patients with congenital defects of complement are repeated infections and autoimmune diseases, which also confirms the importance of complement in anti-infection immunity and immune regulation from the negative side.

2. Complement and inflammatory diseases

The fragments produced by complement during activation have some new biological activities. Among them, C5a, C3a, and C4a have allergic toxin effects, and C5a has chemotactic activity. These fragments play an important role in promoting inflammatory reactions, and thus have some inflammation in related diseases, complement plays an important pathological role; Including autoimmune diseases, cardiovascular diseases, inflammatory tissue damage during infection, hyperacute transplant rejection, etc.;

By inhibiting complement, it is possible to suffer the effect of treating diseases.

3. Complement and virus infection

The relationship between complement receptors and complement membrane surface regulatory proteins and viral infections has received more and more attention,some viruses can infect host cells through complement receptors, etc.;

EB virus infects B cells through CR2, measles virus infects body cells through MCP, Coxsackie virus, Echovirus and enterovirus can infect cells through DAF, etc.;

In clinical practice, consider the use of complement receptor blockers to treat certain viral infections of a certain line.

  1. Complement and tumor

The body’s immunity to tumors includes cellular immunity and humoral immunity. In humoral immunity, antibody-dependent cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) are used as important anti-tumor mechanisms in humoral immunity;

Complement regulatory protein (CRP) plays a very important role in regulating complement attack on tumor cells and in evading immune attacks from tumors;

It is highly expressed complement regulatory proteins (CD46 (MCP), CD55 (DAF), CD59) on the surface of tumors such as gastric cancer, intestinal cancer, lung cancer, renal cancer, endometrial cancer, neurofibroma and breast cancer. Inhibits the cytolysis of complement on tumor cells, allowing tumors to escape immune attacks.

Research progress of complement-related drugs

l SLE (lupus) (systemic lupus erythematosus)

l Rheumatoid arthritis

l Multiple Sclerosis

l Renal disease/nephritis

l Transplant rejection (organ transplantation)

l Cardiopulmonary bypass syndrome

l Myocardial infarction

l Septic shock

l Ischemia and reperfusion injury

l Stroke