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We described above how the complement system plays an important role in defending the host against microorganisms. It is particularly important in defending against pyogenic (pus‐forming) polysaccharide‐encapsulated bacteria, which include Neisseria species (the bacteria responsible for meningitis and some sexually transmitted diseases), S. pneumoniae, H. influenzae, and S. aureus. The major pathway of defense against these organisms appears to be the production of IgG antibody that binds to the bacteria, resulting in opsonization, complement activation, phagocytosis, and intracellular killing. Thus, genetic deficiencies or acquired conditions in which any one of these activities is diminished render a person particularly susceptible to these organisms. In addition, complement is important in removing immune complexes from the circulation; therefore, deficiencies of certain complement components can also result in immune complexes depositing in tissues, leading to inflammatory conditions. More information about complement deficiencies is provided in Chapter 16.

We now also recognize that some complement components show allelic variation—frequently the result of just a single nucleotide change or polymorphism—in their genes. These differences in allelic forms result not in outright deficiencies, but in variations in level and function of the component. The impact of these variations is also discussed below.

Table 4.3 summarizes the clinical conditions that develop from deficiencies of either specific complement components or regulators of complement function. Individuals genetically deficient in specific complement components are relatively rare (approximately 1 in 10,000), and deficiencies are not always associated with the development of a clinical condition. C3 deficiency is rare but can be severe and even life‐threatening because C3 is central to all the complement pathways. C3‐deficient individuals are susceptible to recurrent pyogenic infections and may also develop symptoms resembling those of SLE, involving fever, rash, and glomerulonephritis. These symptoms presumably result from an impaired ability to process and clear immune complexes. Deficiencies in any of the early components of the classical pathway—C1, C4, or C2—also have an increased risk of infection with pyogenic bacteria and the development of SLE‐like symptoms. Individuals deficient in alternative pathway components or the later components common to all pathways, however, have an even higher risk of infection with pyogenic bacteria. This suggests that activation of the classical complement pathway may not be as important as the alternative pathway in defense against these bacteria.

TABLE 4.3 Complement Deficiencies

Deficient complement component	Effect on complement function	Clinical condition
C3	C3b and other opsonic fragments not produced; terminal components not activated	Severe pyogenic infections (encapsulated bacteria) and SLE‐like symptoms
C1, C4, or C2	No activation of classical pathway	Pyogenic infections and SLE‐like symptoms
Properdin, factor B, or factor D	No activation of alternative pathway	Severe pyogenic infections
Mannose binding lectin	No activation of lectin pathway	Recurrent bacterial infections
C5, C6, C7, C8, or C9	Inability to form MAC	Recurrent neisserial (Gram‐negative) infections
C1 inhibitor (C1INH)	Unregulated activation of all activation pathways	Angioedema

Deficiency of the alternative pathway component properdin, or of factors B or D, is associated with pyogenic, particularly neisserial, infections. Deficiency of MBL can be a major problem in early life, manifesting as severe recurrent infections. Individuals who lack components of the MAC, C5b‐C9, tend to get recurrent neisserial infections.

Deficiencies or disorders of complement receptors or complement regulatory proteins may also have serious consequences. Patients with a defect in CR3 (CD11a/CD18) may have a disorder known as leukocyte adhesion deficiency I (see Chapter 16) in which adhesion and migration of all leukocytes are impaired. These patients suffer from recurrent pyogenic bacterial infections, but pus is not formed.

Deficiency of factor H or factor I results in uncontrolled activation of the alternative pathway. One outcome is membranoproliferative glomerulonephritis, inflammation of the capillary loops in the glomeruli of the kidney, characterized by increased cell number and thickening of capillary walls. Factor H deficiency is also associated with atypical hemolytic‐uremic syndrome (10% of all hemolytic‐uremic syndrome cases). Usually resulting from bacterial infection, it is characterized by destruction of red blood cells, damage to endothelial cells, and in severe cases kidney failure. A monoclonal antibody that blocks C5 cleavage is being evaluated to treat this syndrome.

The regulatory protein C1INH is the only control protein for classical pathway components C1r and C1s, and deficiency results in uncontrolled cleavage of C2 and C4. (As we described above, C1INH also inhibits steps in both the lectin and alternative pathways.) Genetic deficiency of C1INH results in hereditary angioedema. The condition is characterized by localized edemas in the skin and mucosa resulting from dilation and increased permeability of the capillaries. The symptoms are recurrent attacks of swelling, such as of the face and limbs, pain in the abdomen, and swelling of the larynx, which can compromise breathing. This condition is thought to be due to the lack of inhibition by C1INH of enzymatic activity in serum cascades other than the complement cascade; one of these pathways forms kinins, including bradykinin, which are potent vasodilators and inducers of vascular permeability and smooth muscle contraction. Deficiency of C1INH is thought to lead to increased production of these vascular mediators. In the USA, injectable C1INH prepared from human plasma has been approved as a treatment for this condition.

	Read the related case: Hereditary Angioedema
In Immunology: Clinical Case Studies and Disease Pathophysiology

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare disorder that also involves complement regulatory proteins. The condition occurs primarily in young adults and is characterized by chronic destruction of red blood cells and thrombus formation (an aggregate of platelets and blood factors that causes vascular blockage), hemolytic anemia, and the presence of hemoglobin in urine, predominantly at night. The acquired condition (there is also an inherited condition) results from a mutation in the gene that controls the production of the glycosylphosphatidylinositol (GPI) anchor that attaches many membrane proteins to the cell surface (see Chapter 6). In PNH, the anchor is not made properly, and the proteins do not attach to the cell surface; they are secreted from the cell into the fluid phase. Several proteins are affected, including the complement regulatory proteins DAF and CD59. The absence of these molecules makes the red cell membrane particularly sensitive to complement‐mediated lysis. The monoclonal antibody described above to block C5 cleavage and used to treat atypical hemolytic‐uremic syndrome is also being used to treat PNH.

In other acquired conditions, C3 may become depleted to such an extent that immune complexes are not cleared or an individual becomes susceptible to infection. This can occur in some people who produce an autoantibody known as C3 nephritic factor; the antibody stabilizes the alternative pathway C3 convertase (C3bBb), generating a highly efficient and long‐lived fluid‐phase enzyme that cleaves C3. C3 nephritic factor has been described in some individuals with SLE and a rare disease known as partial lipodystrophy, involving the loss of fat from the upper part of the body. These conditions are also characterized by glomerulonephritis. Fat cells, particularly those in the upper part of the body, produce factor D, which cleaves C3bBb. The loss of fat cells in partial lipodystrophy may result from localized complement‐mediated cell lysis.

Finally, we now recognize that differences in expression of complement components, and in particular the complement regulator factor H, are associated with either increased or, alternatively, decreased risk of developing age‐related macular degeneration; in this condition, abnormal growth of new blood vessels behind the retina results in vision loss. Variations in factor B, C3, and factor I have also been implicated in this condition, suggesting that the development of age‐related macular degeneration is associated with dysregulation of the alternative complement pathway.