bubble_chart Overview

In the components of the complement system, almost every one can have genetic defects. Most complement genetic defects are autosomal recessive, a few are autosomal dominant, while properdin deficiency is X-linked recessive. Complement deficiencies are often associated with immune diseases and recurrent bacterial infections. Overall, defects in the first front-end reaction components of the complement system, such as C₁, C₄, and C₂ deficiencies, are often accompanied by immune complex diseases, especially SLE; deficiencies in C₃, factor H, and factor I increase susceptibility to pyogenic bacterial infections, whereas patients with properdin, C₅, C₆, C₇, or C₈ deficiencies are prone to severe Neisseria infections.

bubble_chart Epidemiology

The incidence of complement deficiency is similar in both sexes, but C₂ deficiency is more common in females, while properdin deficiency is seen only in males. In the general population, the incidence of hereditary complement deficiency is one in ten thousand. C₂ hereditary deficiency is the most common type of complement deficiency, and the incidence of C₂ heterozygous hereditary deficiency can be as high as 1%.

bubble_chart Clinical Manifestations

Based on genetic characteristics, complement hereditary deficiency diseases can be divided into four categories: homozygous genetic deficiency, heterozygous genetic deficiency, complement protein dysfunction, and complement deficiency caused by allotypes. In individuals with homozygous genetic deficiency, the complement component is completely absent, often manifesting as no CH₅₀ activity, while other complement levels remain normal. Heterozygous deficiency patients have half the normal level of the deficient complement, with CH₅₀

also at half the normal level, while other complement components remain normal. In cases of complement protein dysfunction, the blood complement levels are within the normal range or even elevated, but the function of the complement protein is significantly impaired. Complement allotype genetic deficiencies are typically autosomal codominant. Additionally, complement deficiencies can also be classified as complete or partial deficiencies. Due to the regulatory characteristics of complements and their structural correlations, in clinical practice, although most cases involve significantly reduced or undetectable levels of the deficient complement component while other complement levels remain normal, there are exceptions. For example, in homozygous C_1r deficiency, the concentration of C_1s is also reduced, and some C₂ deficiency patients exhibit reduced levels of factor B, due to the high structural homology between the primarily deficient complement protein and the secondarily deficient complement protein. Moreover, the genes for factor B and C₂ are located very close to each other on chromosome 6, which is also related to their similar regulatory mechanisms. In hereditary angioedema (HAE), the levels of C₄ and C₂ are reduced. Deficiencies in factor I and factor H lead to reduced levels of factor B and C₃, respectively, due to excessive activation of the classical and alternative pathways. The lack of complement components impairs the function of the classical and/or alternative activation systems and results in defective antibody responses to T-cell-dependent antigens, leading to prolonged viral infections or extended circulation of immune complexes.

(1) Hereditary C₁ Deficiency There are two types of hereditary C_1q deficiency. One type is due to the inability to synthesize C_1q (accounting for 60%), so no C_1q antigenicity is detectable in the blood. The other type of C_1q deficiency results from the synthesis of non-functional C_1q molecules (accounting for 40%). Although C_1q antigenicity can be detected, the dysfunction of C_1q leads to functional deficiency. C_1q is composed of six copies of any one of the A, B, or C chains. Some studies suggest that C_1q deficiency is often due to the inability to synthesize the B chain, while deficiencies in C_1r and C_1s are extremely rare.

Almost all patients with C₁ deficiency suffer from immune complex diseases, commonly systemic lupus erythematosus or discoid lupus or glomerulonephritis. A few hereditary C₁ deficiency patients may be accompanied by severe bacterial infections, such as pneumonia, meningitis, and sepsis caused by Staphylococcus aureus, among other diseases. However, some patients may show no clinical manifestations. The occurrence of immune complex diseases is due to the inability of C₁ deficiency to inhibit immune complex deposition, leading to the deposition of immune complexes in tissue sites. Measurement of serum C₁ levels can confirm the diagnosis. In SLE patients, when other indicators of clinical disease activity improve but there is still persistent CH₅₀ reduction, the possibility of this disease should be considered.

(II) Hereditary C₂ Deficiency

Hereditary C₂ deficiency is the most common inherited complement deficiency in white populations, with an incidence of approximately 1 in 10,000. About 40% of heterozygous C₂ complement-deficient patients also have SLE. Studies on SLE have found an increased prevalence of HLA-DR₂

and DR₃ among SLE patients. Patients with hereditary C₂ deficiency and SLE often have undetectable or very low titers of antinuclear antibodies and anti-dsDNA antibodies in their blood, with rare neurological involvement or severe kidney damage, but prominent skin lesions and joint manifestations, which often complicate the clinical diagnosis of SLE. The MHC markers of C₂ deficiency patients are highly restricted, with most C₂ null genes C₂QO located on the haplotype of HLA-A₂₅ (A₁₀), B₁₈, BFS, C₂QO, C₄A₄, C₄B₂, and DR₂. Almost all these genes coexist with some of the others, suggesting that C₂ deficiency patients have a complete haplotype. The existing haplotypes of C₂ deficiency are all derived from these original mutations. Currently, it is known that C₂ deficiency patients frequently experience recurrent pneumonia, meningitis, or bacteremia caused by pneumococci, Staphylococcus aureus, Neisseria, and Haemophilus influenzae. HLA-A and HLA-B genes are associated with antigen recognition and immune responses, while HLA-D genes are related to immune responses to soluble antigens. In 1% of meioses, genetic crossover occurs between HLA-A and HLA-B, and between HLA-B and HLA-DR. Some believe that the susceptibility of C₂ deficiency patients to infectious diseases is related to this, but some C₂ deficiency patients show no clinical manifestations.

(III) Hereditary C₃ Deficiency

Hereditary C₃ deficiency has three types. In one type, patients have non-functional C₃ genes or hypofunctional C₃ genes, resulting in loss of C₃ function. Another type is C₃ deficiency accompanied by hereditary _3b inactivation, where the C_3B INA substance is defective, preventing the cleavage of C₃ into C_3c and C_3d and thus its inactivation. The persistent C_3b interacts with factor B, causing the positive feedback regulation of the alternative pathway activation system to go out of control, leading to further consumption of C₃, known as excessive degradation (Type I), where the C₃b inactivator is defective. Some patients have serum containing circulating factors that can cleave or activate C₃, causing C₃ deficiency (excessive degradation Type II). Hereditary complement C₃ deficiency can also be secondary to deficiencies in regulatory proteins such as factor I or factor H. Additionally, some patients may present with glomerulonephritis or vasculitis, though a few may remain asymptomatic. Patients with C₃ deficiency have impaired opsonization of pathogens, leading to compromised phagocytosis via C_5a and impaired cytolytic activity of the membrane attack complex. This predisposes them to recurrent pyogenic infections, such as pneumonia, bacteremia, or peritonitis, often caused by Staphylococcus aureus, Streptococcus pneumoniae, or Neisseria species. Clinically, some C₃ deficiency patients exhibit membranoproliferative glomerulonephritis, hematuria, or proteinuria, which is thought to be related to a substance called C₃ nephritic factor. It has been established that C₃ nephritic factor is a specific IgG antibody targeting a neoepitope on the C_3bBb complex, which stabilizes the active form of C_3bBb.

(IV) Hereditary C₄ Deficiency

There are two genes for C₄, namely C₄A and C₄B. In a patient, it is rare for both gene loci of C₄A and C₄B to simultaneously carry null genes (C₄AQO-C₄BQO). Clinically, it is more common for one haplotype to carry a null gene, mostly manifesting as C₄ deficiency. Patients with C₄ deficiency exhibit infection susceptibility similar to those with C₄ deficiency, characterized by recurrent severe systemic pyogenic infections.

C₄A is more effective than C₄B in preventing immune complex deposition, so patients with C₄A null genes are more prone to immune complex diseases. Recent observations indicate that 10–15% of SLE patients have a defect in one of the C₄ genes, with 80–90% of these patients having partial C₄ deficiency. Heterozygous C₄ deficiency occurs in 20–40% of the general population, but in SLE patients and other autoimmune diseases such as type II diabetes, chronic hepatitis, and subacute sclerosing panencephalitis, it accounts for 50–80%. Fielder et al. found that 15% of SLE patients carry the C₄A null gene. Surveys in Australia, Japan, China, and the United States also show that 10–15% of SLE patients carry the C₄A null gene, compared to only 2% in the control population. In most patients, the C₄A null gene results from a 30 kb DNA deletion. Although complement deficiency and Ro antibodies are somewhat correlated, the clinical manifestations of SLE in patients with the C₄A null gene are similar to those of typical SLE.

(V) Deficiency of Terminal Complement Components

The terminal complement components, namely C_5b─9, collectively form the MAC (membrane attack complex), which functions to lyse cells and pathogens. Patients with terminal component deficiencies often experience recurrent severe systemic infections, typically presenting as Neisseria meningitidis meningitis and bacteremia, and sometimes gonococcemia leading to systemic gonococcal infections. Although an increased incidence of immune complex diseases has also been observed in patients with terminal component deficiencies, its clinical significance remains unclear. Clinically, some _5b─9 deficient patients appear as healthy individuals.

1. C₅ Deficiency

Rosenfeld et al. reported the first case of C₅ deficiency in an SLE patient with multiple infectious complications, such as axillary abscess, otitis media, herpes zoster, enterococcal sepsis, and severe oral and vaginal candidiasis. Subsequent case reports have shown that most C₅ deficient patients are susceptible to Neisseria infections. Heterozygous C₅ deficient patients have serum C₅ levels at only half the normal level, while homozygous C₅ deficient individuals show no detectable C₅ protein in their blood, and their serum exhibits abnormal chemotactic activation of bacteria.

2.C₆Defect

Case 1 C₆ deficiency presents as gonococcal sepsis and gonococcal arthritis. Subsequent case reports suggest that most C₆ deficient patients are accompanied by Neisseria meningitis. Heterozygous C₆ deficient patients have only half the normal level of C₆ in their blood. Family investigations revealed the presence of a C₆ null gene, and homozygous deficient patients lack bactericidal activity. Some patients also have immune complex diseases such as SLE.

3. C₇ deficiency

The incidence of C₇ deficiency is similar to that of C₇ deficiency. Some C₇ deficient patients are healthy individuals. The most common clinical manifestation in C₇ deficient patients is also Neisseria infection, with a few patients developing complications such as SLE, scleroderma, and spondyloarthritis. Studies have shown that the C₆ and C₇ genes are linked, so combined deficiencies of C₆ and C₇ are common clinically. However, this deficiency is incomplete, with abnormal C₆ and normally structured C₇ levels both reduced in patient serum. Some believe that deletion of the C₆ gene can also lead to reduced synthesis of C₇, possibly because the mRNAs of C₆ and C₇ are transcribed simultaneously during initial transcription, so deletion of the C₆ gene can result in reduced synthesis of both.

4. C₈ deficiency

C₈ consists of three chains: α, β, and γ, with the α and γ chains forming a subunit together, and the β chain linked non-covalently to the α and γ subunits. There are two complementation types of C₈ deficiency: one where only the α and γ subunits can be detected in patient serum, indicating β chain deficiency, and another where the α and γ subunits are deficient, with the β chain present in patient serum. When both deficiencies coexist, normal C₈ can form. The clinical manifestations caused by these two deficiencies are the same, similar to C₅, C₆, and C₇ deficiencies, with patients experiencing recurrent Neisseria infections, gonococcemia, and Neisseria meningitis. Some patients may also develop SLE. Deficiency of the α and γ subunits of C₈ is more common in Black individuals, while β chain deficiency is more common in Caucasians.

5. C₉ deficiency

C₉ is also one of the components of MAC. Hereditary C₉ deficiency is more common in the Japanese population. Although clinically there are cases of Neisseria infections and Neisseria meningitis caused by C₉ deficiency, its association with Neisseria infections is weaker compared to other terminal component deficiencies. Typically, C₉ deficiency does not cause clinical symptoms.

(VI) Properdin deficiency

There are relatively few reports on deficiencies in the complement alternative pathway components, with only reports on properdin deficiency. Properdin deficiency is inherited in an X-linked recessive manner. Currently, three types of properdin deficiency have been identified: ① No properdin protein is detected in the serum; ② The level of active properdin in the serum is only 10% of that in healthy individuals; ③ The serum level of properdin is normal but lacks functionality. Patients with properdin deficiency are prone to infectious diseases, particularly meningococcal infections. Some other reports also suggest that patients with properdin deficiency frequently suffer from Neisseria infections.

(VII) Factor I Deficiency

Factor I deficiency is often accompanied by excessive consumption of C ₃ , and therefore is also associated with C ₃ deficiency. Thus, the clinical manifestations of Factor I deficiency are essentially the same as those of C ₃ deficiency. Patients with Factor I deficiency may exhibit severe immunodeficiency, recurrent meningococcal meningitis, while some may show no clinical symptoms, and others may develop a Coombs-positive reaction. Alper reported a case of Factor I deficiency with massive histaminuria, suggesting excessive activation of C ₃ into C _3a as the cause.

(VIII) Factor H Deficiency

Factor H deficiency is relatively rare and represents an incomplete deficiency. Patients with Factor H deficiency have serum levels of Factor H that are only 5% of normal levels. The clinical manifestations it causes are similar to those of Factor I deficiency, with most patients presenting as recurrent infections. Factor H deficiency can lead to severe acquired C ₃ deficiency. Some patients with Factor H deficiency may develop hemolytic uremic syndrome, while others may be accompanied by glomerulonephritis. A small number of patients with Factor H deficiency may show no clinical symptoms.

(IX) C ₁ INH Deficiency

The regulatory protein C₁INH deficiency, although also associated with some autoimmune diseases, does not cause immunodeficiency disorders. C₁INH deficiency clinically leads to hereditary angioedema (HAE). C₁INH deficiency is inherited in an autosomal dominant manner and represents a heterozygous genetic defect. C₁INH deficiency has two types: one where C₁INH is only 17% (5–31%) of normal levels, and another where, although serum C₁INH levels are within the normal range or up to four times normal, the C₁INH exhibits functional dysfunction. C₁INH dysfunction is mostly caused by gene mutations, and the molecular structure of dysfunctional C₁INH differs from that of normal C₁INH, with variations in both peptide chains and carbohydrates. 85% of patients belong to the first type of deficiency, and the clinical manifestations of these two types are indistinguishable. Due to C₁INH deficiency, C₁ is activated without restraint, leading to the cleavage of C₄ and C₂. Therefore, patients with C₁INH deficiency often exhibit reduced levels of C₂ and C₄. During disease episodes, C₄ and C₂ may be undetectable. C₁INH deficiency increases the release of plasma kallikrein, thereby elevating both bradykinin and kinin levels, which increases vascular permeability and leads to tissue edema. Some suggest that a C₂ plasma regulatory fragment, C₂ kinin, contributes to increased vascular permeability in HAE. Studies on the metabolism of ¹²⁵I-labeled normal C₁INH found that in HAE patients, the clearance of C₁INH is accelerated, while its synthesis rate is only half of normal, indicating that complement activation induced by dysfunctional C₁INH hastens the clearance of normal C₁INH.

The incidence of HAE is 1/150,000. When patients reach the age of 50, HAE gradually stops occurring. Each HAE episode lasts 2 to 3 days. When the skin is affected, it can cause painless, non-erythematous edema without cutaneous pruritus. It can be triggered by trauma. If the intestines are involved, severe watery diarrhea and abdominal colicky pain may occur. When the upper respiratory tract is affected, it can lead to laryngeal edema and suffocation.

(10) Complement Receptor Protein Deficiencies

Complement proteins located on the cell surface can act as receptors for activated complement products, mediating phagocytosis, chemotaxis, and leukocyte digestion. In this system, the CR₁ receptor, which is associated with immune complex clearance, has attracted significant attention.

During the activation of C₃ and C₄, a thioester bond is broken. Subsequently, C_3b and C_4b covalently bind to immune complexes via ester and amine linkages. After C_3b binds to immune complexes, it prevents their deposition, keeping them in a soluble state. Additionally, C_3b or C_3b receptors bind to cell surfaces, such as red blood cells and tissue monocytes, causing immune complexes to immediately attach to cells rather than remain in the bloodstream. _{Red blood cells bound to C}3b _{transport immune complexes to mononuclear phagocytes and then return to circulation. In this process, the C}3b _{receptor plays a role in transporting immune complexes. Therefore, when the number of C}3b _{receptors on red blood cells decreases, immune complexes deposit in tissues, leading to disease.} Studies have found that the C_3b receptor on cells in SLE patients is reduced by 50%. Some reports indicate that the expression of CR₁ receptors on red blood cells exhibits many heritable polymorphisms. In SLE patients, the number of CR₁ receptors on red blood cells is reduced, and CR₁ levels correlate with disease activity. Some SLE patients have been found to have CR₁ antibodies, suggesting that CR₁ receptor defects impair immune complex clearance, thereby predisposing patients to SLE. However, recent reports suggest that the reduction in CR

1 _{receptor numbers may be a consequence of SLE rather than its disease cause.} CR₃ deficiency can cause severe immunodeficiency. Arnaout et al. reported the first case of CR₃ deficiency with severe immunodeficiency. Subsequently, a series of reports in the U.S. described children with CR₃ deficiency being prone to infectious diseases, particularly skin infections and gingivitis. After healing, these infections leave paper-thin scars, clinical manifestations similar to those of polymorphonuclear leukocyte deficiency. _{Research has shown that CR}3 _{is only present on the membranes of neutrophils and monocytes. Additionally, CR}3 _{can directly bind to fungi, making it crucial for the body's defense against infections. When CR}3{|155|} is deficient, patients are more susceptible to infections.

bubble_chart Diagnosis

When patients experience recurrent bacterial infections, especially pyogenic bacterial infections or Neisseria infections, the possibility of complement deficiency should be considered. The complement hemolysis tests CH₅₀ and CH₁₀₀ can determine whether there are functional deficiencies in C₁, C₂, C₃, C₄, C₅, C₁₆, C₇, or C₈. A deficiency in any of these components will result in a decreased CH₅₀. CH₅₀ is caused by the hemolysis of antibody-sensitized sheep red blood cells in the presence of complement and thus measures the components of the classical pathway. The hemolysis test using rabbit red blood cells with low sialic acid content, APH₅₀, can detect deficiencies in the alternative pathway components. A normal APH₅₀ indicates the presence of factor B, factor D, properdin, C₃, and C5_─8. If the screening test results show very low CH₅₀ activity, further testing for each complement component is required. If a patient has severe infections but no antibody deficiency or phagocyte abnormalities, CH₅₀ testing should be performed. If the CH₅₀ results are normal, APH₅₀ testing should be conducted. If APH₅₀ is very low or undetectable, factor B levels should be measured, as excessive consumption of factor B occurs in cases of factor H or factor I deficiency, while primary factor B deficiency has not been reported to date. If family history suggests X-linked inheritance, properdin deficiency may be suspected, but definitive diagnosis requires quantitative analysis of each complement component.

bubble_chart Treatment Measures

Overall, complement deficiencies respond well to antibiotic treatment when complicated by infections, but the fundamental treatment lies in correcting the complement deficiency. Some scholars adopt replacement therapy, which involves infusing purified deficient components into patients to rectify the deficiency. Replacement therapy can restore the levels of deficient complement components to normal and improve clinical symptoms. Some scholars use fresh plasma transfusion to treat complement deficiencies, but theoretically, repeated transfusions carry the potential risk of inducing immune reactions in patients. Research on the treatment of HAE (hereditary angioedema) is extensive, and there are three main approaches: ① Promoting the expression of the normal chromosome for C₁INH: Synthetic androgens such as danazol and stanozolol can stimulate the normal chromosome to synthesize more C₁INH, restoring C₁INH levels to normal. This treatment is highly effective and can effectively control attacks. ② Reducing the consumption of C₁INH by inhibiting the enzymes that interact with it. Derivatives of 6-aminocaproic acid, such as tranexamic acid, can inhibit the conversion of plasminogen to plasmin and, to some extent, activate C₁ through autolytic pathways. Tranexamic acid is highly effective in controlling HAE attacks. ③ Both of the above treatment methods are preventive. The most ideal treatment is intravenous infusion of C₁INH to restore its levels to normal. Infusion of purified C₁INH is more effective than plasma.

bubble_chart Differentiation

Differential Diagnosis of Acquired Complement Deficiencies:

Acquired complement deficiencies result from complement activation (such as in the presence of circulating immune complexes or internal toxins), which increases the patient's susceptibility to infections. The differences between hereditary and acquired complement deficiencies are outlined in Table 80-2. Clinically, acquired complement deficiencies are common, such as hypocomplementemia and sepsis in burn patients; patients with nephrotic syndrome are prone to infectious diseases, and their blood moistening and tonifying complement levels are also abnormal; cancer patients undergoing chemotherapy may exhibit hypocomplementemia, impaired opsonization, and bactericidal dysfunction; sickle cell anemia patients often develop secondary complement deficiencies, frequently accompanied by severe bacterial infections, particularly pneumococcal and Haemophilus influenzae infections. Koethe et al. suggest that this is due to partial deficiency of factor D, impairing opsonization; splenectomy also leads to opsonization dysfunction; poor nutritional status and protein-calorie deficiency can result in reduced function of all complement components. Additionally, excessive complement consumption during autoimmune diseases or immune complex diseases can also cause complement deficiencies, which may be corrected by treating the underlying condition.

Table 80-2 Comparison of Hereditary and Acquired Complement Deficiencies

Hereditary	Acquired
Homozygous deficiency leads to extremely low or absent levels of a specific protein component	Multiple protein levels may decrease simultaneously, but their levels are higher than those in homozygous hereditary deficiencies
It is a persistent abnormality	It is reversible
Other family members may exhibit similar conditions, and silent or null genes may be identified	No family history
May be linked to other genes	No gene linkage phenomenon
If associated with other diseases, immune complexes or (and) complement cleavage products may appear	Immune complexes and complement cleavage components often appear