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Defects in innate immunity and the complement system
Last reviewed: 07.07.2025

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Complement system defects are the rarest type of primary immunodeficiency states (1-3%). Hereditary defects of almost all complement components have been described. All genes (except the properdin gene) are located on autosomal chromosomes. The most common deficiency is the C2 component. Complement system defects vary in their clinical manifestations.
In general, defects of early complement fractions (C1-C4) are accompanied by a high frequency of autoimmune diseases, including systemic lupus erythematosus; infectious manifestations in these patients are rare. It is believed that the association of complement component defects with the development and severity of systemic lupus erythematosus depends on the position of the defective component in the activation cascade. Thus, homozygous deficiency of Clq, Clr or Cls, as well as C4 is associated with the risk of developing systemic lupus erythematosus in 93%, 57% (for Clr and Cls together), and 75%, respectively. The probability of developing systemic lupus erythematosus with a deficiency of the C2 component is, according to various data, from 10% to 50%. There is an association between hereditary angioedema and systemic lupus erythematosus: excessive proteolysis of C4 and C2 in the absence of a C1 inhibitor probably leads to an acquired deficiency of C4 and C2, which increases the risk of developing systemic lupus erythematosus in these patients.
Defects in the terminal components (C5-C9) predispose to severe infections caused by members of the genus Neisseria. This is because Neisseria can survive intracellularly, so cellular lysis by the membrane-attack complex is the primary mechanism for killing this organism. In some parts of the world where meningococcal disease is highly endemic, a high incidence of patients with deficiencies in membrane-attack complex components is found.
Deficiency of the C3 component often resembles humoral primary immunodeficiency states and is accompanied by severe recurrent infections: pneumonia, meningitis, peritonitis. On the other hand, some patients with deficiency of C2, C4, C9 may not have any clinical manifestations.
Deficiency of mannose-binding lectin (MBL) function results in increased susceptibility to infections with bacteria with a terminal mannose group. Low MBL levels in children with frequent infections suggest that the mannose-binding lectin pathway is important during the period between the decline of passive immunity acquired from the mother and the development of the body's own acquired immunity. Interestingly, some groups have a high prevalence of dominant alleles of the MBL gene leading to low levels of protein expression. It is possible that in these individuals, defects noted in early childhood have advantages later in life. For example, there is evidence that low MBL levels protect against mycobacterial infection. High levels of MBL have been found in patients with leprosy compared with their healthy compatriots.
A special case is the deficiency of complement inhibitor C1, the clinical manifestation of which is hereditary angioedema.
In most cases of complement defects, etiopathogenetic and replacement therapy are impossible, and therefore symptomatic therapy of the corresponding manifestations of deficiencies is carried out.
What tests are needed?
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