Hereditary complement deficiency

Introduction to hereditary complement deficiency disease Almost every component of the complement system may have a genetic defect. Most complement genetic defects are autosomal recessive, a few are autosomal dominant, while properdin deficiency is X-linked recessive inheritance. Compensity deficiency is often associated with immune diseases and repeated bacterial infections. In general, the first front-end response components of the complement system, such as C1, C4, and C2, are often associated with immune complex disease, especially SLE; C3, factor H, and factor I deficiency increase the patient's septic bacterial infection. Susceptibility, while patients with deficiencies, C5, C6, C7, and C8 defects are prone to severe Neisserial infections. basic knowledge The proportion of illness: 0.001% Susceptible people: no special people Mode of infection: non-infectious Complications: antibody immunodeficiency disease

Causes of hereditary complement deficiency

Most complement genetic defects are autosomal recessive, a few are autosomal dominant, while properdin deficiency is X-linked recessive inheritance.

According to genetic characteristics, complement genetic defects can be divided into four categories: homozygous genetic defects, heterozygous genetic defects, complement protein dysfunction and complement defects caused by allogeneic, homozygous genetic defects in the body of the complete complement Deletion, often manifested as no CH50 activity, while other complement levels were normal; patients with heterozygous defects lacked a level of complement that was half of normal, CH50 was half of normal, and other complement levels were normal; complement protein dysfunction The patient's blood complement level is within the normal range, sometimes even higher than normal, but the complement protein function is very low; the allogeneic genetic defect of complement is usually autosomal codominant inheritance, and the complement defect can also be divided into complete Defects and partial defects due to the regulatory characteristics of complement and the correlation between their structures.

Clinically, although in most cases the level of defective complement components is significantly reduced or undetectable, while other levels of complement are normal, there are some exceptions, such as the concentration of C1s in homozygous C1r defects, Some patients with C2-deficiency have a decreased level of factor B due to a high degree of structural homology between the primary defective complement protein and the secondary-deficient complement protein. In addition, the B factor and C2 genes are on chromosome 6. The upper positions are very similar, and thus have similar regulatory mechanisms. In the case of hereditary angioedema (HAE), the levels of C4 and C2 are decreased, and the factors of factor I and factor H are decreased. Due to the over-activation of the classical and alternative pathways, the lack of complement components impairs the function of the classical and/or bypass activation system and the defective antibody response to T cell-dependent antigens, resulting in prolonged viral infection or immune complexation in patients The object has a prolonged time in the circulation.

Hereditary C1 defects:

There are two kinds of hereditary C1q defects. One type of genetic C1q defect is due to the inability to synthesize C1q (60%), so the antigenicity of C1q is not detected in blood sputum; the other C1q defect is due to the synthesis of non-functional C1q molecules (40%), therefore, although the antigenicity of C1q can be detected, C1q is dysfunctional, causing C1q function defects, and C1q is composed of 6 copies of any of the A, B, and C3 chains. Studies have shown that C1q defects are often due to the inability to synthesize B chains, while C1r and C1s defects are rare.

Almost all patients with C1 deficiency have immune complex diseases, such as systemic lupus erythematosus or discoid lupus or glomerulonephritis. A few patients with hereditary C1 deficiency may be accompanied by serious bacterial infections such as pneumonia and meningitis. Staphylococcus aureus caused by sepsis and other diseases, but some patients have no clinical manifestations. The occurrence of immune complex disease is caused by C1 deficiency, which can not inhibit the deposition of immune complexes, resulting in deposition of immune complexes on tissues. Determination of serum C1 levels It can be diagnosed. In patients with SLE, when other indicators of clinical disease activity are improved but there is still a sustained decrease in CH50, the possibility of this disease should be considered.

Hereditary C2 defects:

Hereditary C2 deficiency is the most common hereditary complement deficiency in whites, with an incidence of about 1 in 10,000. About 40% of patients with heterozygous C2 complement deficiency have SLE at the same time. Studies on SLE have found that HLA-DR2 in SLE patients And the incidence of DR3 increased, patients with hereditary C2 deficiency with SLE often do not detect anti-nuclear antibodies and anti-dsDNA antibodies or titers are extremely low, nervous system involvement and severe renal damage are rare, but skin lesions and joints are obvious, Often it is difficult to diagnose SLE clinically. The MHC markers in patients with C2 deficiency are highly restricted. Most C2 null genes C2QO are located on haploids of HLA-A25 (A10), B18, BFS, C2QO, C4A4, C4B2 and DR2. Almost all of these genes coexist with some of these genes, suggesting that C2-deficient patients have intact haplotypes, and existing C2-deficient haplotypes are derived from these primitive mutations.

It is known that patients with C2 deficiency often have pneumonia, meningitis or bacteremia caused by pneumococci, Staphylococcus aureus, naphthobacteria and influenza bacilli, HLA-A and HLA-B genes and antigen recognition. The immune response is related, and the HLA-D gene is associated with the immune response of soluble antigen. HLA-A and HLA-B and HLA-B and HLA-DR genes cross in 1% of meiosis. Some people think that C2 Defective patients are susceptible to infectious diseases, but some patients with C2 deficiency have no clinical manifestations.

Hereditary C3 defects:

There are three types of hereditary C3 deficiency, one patient's C3 gene is a null gene or C3 gene function is low, causing C3 function loss; the other is C3 deficiency with hereditary 3b inactivation of C3B INA substance defect, can not cause C3 cleavage Inactivated by C3c and C3d, the persistent interaction of C3b and B causes the positive feedback regulation of the bypass activation system to be out of control, causing further consumption of C3, which is called excessive decomposition, ie type I, inactivation of C3b inactivation; Some patients have circulating factors that can cleave or activate C3, causing C3 deficiency (over-decomposition type II), genetic complement C3 deficiency secondary to regulatory protein factor I, factor H deficiency, and other patients may be accompanied Glomerulonephritis or vasculitis, but there are a few patients who can be asymptomatic. The C3-deficient patients are obstructed by the pathogen's opsonization, which impairs the phagocytosis of C5a and the lytic cells of the membrane attack complex, which is easy to develop suppurative infection. Frequent pneumonia, bacteremia or peritonitis, the pathogens are often Staphylococcus aureus, pneumococcal and naphthal bacteria, etc., clinically found some C3 deficient patients with membrane proliferative glomeruli Inflammation, hematuria or proteinuria, and C3 deficiency is thought to be related to a substance called C3 nephritis factor. It has been determined that C3 nephritis factor is a specific IgG antibody against a new antigen on the C3bBb complex, which stabilizes C3bBb. The role of the active form.

Hereditary complement deficiency prevention

The disease is a hereditary disease, and there is no effective preventive measure at present. Early detection and early treatment are the key to the prevention and treatment of this disease.

Hereditary complement deficiency complications Complications, immunodeficiency

Complement lacks often complicated with immune diseases and repeated bacterial infections.

Hereditary complement deficiency symptoms Common symptoms Bacterial infections Inflammation fever

When a patient repeatedly develops a bacterial infection, especially a purulent bacterial infection or a Neisserial infection, the possibility of complementing the defect should be considered. The complement hemolysis test CH50 and CH100 can determine whether there are C1, C2, C3, C4, C5, C16, C7 and C8 function defects, lack of any of the above components, CH50 will be reduced, CH50 is caused by hemolysis of antibody-sensitized sheep red blood cells in the presence of complement, thus measuring the classical pathway components, using rabbits with low sialic acid The hemolysis test of red blood cells, ie APH50, can detect defects in the bypass pathway components. APH50 normally indicates the presence of factor B, factor D, properdin, C3 and C5-8. If the above screening test results show that CH50 activity is very low, then it needs to be performed. For the detection of each complement component, if a patient has a heavy infection but no antibody defects or abnormal phagocytic cells, a CH50 test should be performed.

If the CH50 test result is normal, check APH50; if APH50 is very low or its activity is not detected, then factor B should be measured. If factor A or factor I is lacking, there will be excessive consumption of factor B, and the original factor B. The defect has not been discovered so far. If the family history suggests X-linked inheritance, it may be a defect in the preparation of the yarn, but the final diagnosis still requires quantitative analysis of each complement component.

Examination of hereditary complement deficiency disease

Complement hemolysis test: CH50 and CH100 can determine whether there are C1, C2, C3, C4, C5, C16, C7 and C8 functional defects. In the absence of any of the above components, CH50 will decrease, and CH50 will sensitize antibodies in the presence of complement. The sheep red blood cells are caused by hemolysis, and thus the components of the classical pathway are determined. The hemolysis test using rabbit erythrocytes with low sialic acid, ie, APH50, can detect defects in the bypass pathway component, and APH50 normally indicates that there are factor B and factor D. The presence of C3 and C5-8. If the above screening test results show that the CH50 activity is very low, then each complement component should be tested. If a patient has a heavy infection but no antibody defect or phagocytic abnormality, CH50 should be performed. an examination.

If the CH50 test result is normal, check APH50; if APH50 is very low or its activity is not detected, then factor B should be measured, because in the absence of factor H or factor I, there will be excessive consumption of factor B, and the original factor B The defect has not been discovered so far.

Diagnosis and identification of hereditary complement deficiency

diagnosis

Diagnosis can be based on medical history, clinical symptoms, and laboratory tests.

Differential diagnosis

Acquired complement deficiency is caused by the process of complement activation (such as in the presence of circulating immune complexes or endotoxin), which increases the patient's susceptibility to infection. Clinically, acquired primary defects are common, such as burns. Patients with low-complementemia and sepsis; patients with nephrotic syndrome are susceptible to infectious diseases, and their serum complement levels are also abnormal; patients with cancer chemotherapy may be associated with hypocomplementemia, conditioning and bactericidal dysfunction.

Patients with sickle cell anemia often have secondary complement defects. These patients are often accompanied by severe bacterial infections, especially pneumococcal and Haemophilus influenzae infection. Koethe et al believe that this is due to the patient's conditioning function due to partial defects in the D factor in the patient. Caused by damage; conditioning disorder after spleen resection; in poor nutritional status, insufficient protein calorie, it will also cause all complement components to function poorly, in addition, some autoimmune diseases and immune complex disease process The large consumption of complement is also the cause of complement deficiency, and the treatment of primary disease can correct the complement defect.

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