Complement system deficiencies

Many antigen-antibody complexes are eliminated by phagocytosis. Others are attacked by complement, a group of serum proteins that aids in the defense against microorganisms. Individuals with a deficiency in their complement system are subject to repeated bacterial infections, just as are individuals deficient in antibodies themselves. 

The strong association between human lupus and a deficiency of the early components of the classic complement system provides valuable guidance in the study of the pathogenesis of SLE. Complete deficiency of Clq is almost always associated with lupus (over 90%) (S19). Defects in each of the three Clq peptide chains encoded by three genes in tandem on chromosome 1 have been described in human lupus. Seventy-five percent of patients with complement deficiency of C4 have lupus. The deficiency of any of four alleles of the two C4 genes, C4A and C4B, is associated with lupus. The deficiency of C4A appears to be the closest association (F4). About 33% of European patients with C2 deficiency also have lupus (W2). These patients also tend to have a higher frequency of anti-Ro autoantibody (P6). 

Impaired function of phagocytes and deficiency of early components of the classic pathway of the complement system result in increased apoptotic waste. This waste, including nucleosomes and other autoantigens, is formed and altered by the protease of apoptotic cells. They are expressed on the surface of apoptotic blebs and activate bystander dendritic cells. Subsequently the dendritic cells activate helper T cells, which then help B cells to generate high-affinity autoantibodies (Fig. 1). 

There are also immunodeficiency states that are primary and can be caused by phagocytic cell defects, deficiencies in the complement system, B- and T-cell deficiency, and other causes. Secondary immunodeficiency disorders can result from malnutrition, cytotoxic drugs, infections with pyrogenic bacteria, and infections with an RNA retrovirus, as in the acquired immunodeficiency syndrome (AIDS). 

The clinical importance of the complement system is demonstrated by the disease associations seen in inherited or secondary deficiencies of the various components. Several of the more important of these are listed in Table 20-9. Most of the complement components also demonstrate genetic polymorphism. The genetic aspects of C3 and C4 are discussed in the individual sections following. 

Complement deficiencies are associated with several diseases. Alternative pathway deficiencies are rare, but when they exist more than one-half of factor D or properdin-deficient individuals suffer from Neisseria infections of which 75% are fatal. Individuals with deficiencies in the MAC components, e.g., C5, C6, Cl, and C8, are also susceptible to infection with Neisseria. Deficiencies in C1, C4, and C2 are associated with systemic lupus erythematosus and glomerulonephritis. Hereditary angioedema, a disease characterized by recurrent submucosal and subcutaneous edema, is caused by a deficiency in Cl inhibitor. Complexes and interactions similar to those of the complement system are also characteristic of the clotting system (Chapter 36). 

The MHC class III region maps between the MHC class I and class II gene clusters and contains genes for tumour necrosis factor, heat shock protein 70, and some components of the complement system (for review, see Arnett Moulds, 1991). Many proteins coded by MHC class III genes may be involved in the development of autoimmunity. The importance of deficiencies in complement factors has been described in subsection 2) of section 4.1.2.1. The role of tumour necrosis factor gene polymorphisms is shown in section 4.1.2.2. 

Complement system. A group of serum proteins with the capacity to interact with each other when activated. The chain reaction of the activated complement components results in formation of a lytic complex and several biologically active peptides of low molecular weight (anaphylatoxins). The system can be activated by antigen-antibody complexes (classical pathway) and by other components, e.g. bacteria (alternative pathway). As an effector mechanism of the humoral immune response, the activated complement system facilitates opsonization, phagocytosis, and lysis of cellular antigens. Some defects in components of complement are associated with autoimmune diseases (see complement deficiency). 

Complement deficiency. Congenital deficiencies in the various components of the complement system. Rheumatic disorders (mainly systemic lupus erythematosus) are associated with deficiencies of the early components of the classical pathway. More than 30% of individuals with C2 deficiency and nearly 80% with either C3 or C4 deficiency have an autoimmune manifestation. 

A genetic condition characterized by a deficiency of Cl esterase inhibitor. This is an a2-globulin which inhibits the action of Cl the first complement component, and in this way prevents possible damaging effects of the complement system. Patients affected with the condition suffer from oedematous swellings in various parts of the body, particularly the eyes and mouth. 

K8. Korb, L. C., andAhearn, J. M., Cutting Edge Clq binds directly and specifically to surface blebs of apoptotic human keratinocytes Complement deficiency and systemic lupus erythematosus revisited. J. Immunol. 158, 4525-4528 (1997). 

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