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The complement system provides an important effector arm for many of the innate immune system functions, including host defense, regulation of acquired immunity, and clearance of immune complexes and other potentially dangerous material.

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Complement consists of an interacting network of many different individual proteins that are present in the circulation, in most body fluids, and on many cell surfaces. Like the coagulation system, the complement system is a tightly controlled enzyme cascade in which proenzyme components are activated and a cleavage sequence is initiated by which biologically active protein fragments are produced. Figure 189-1 shows the basic schematic of the complement activation pathways. Although each pathway is activated differently, they merge at the C3 step and have a common end point of promoting inflammation, eliminating pathogens, and enhancing the immune response. When any one of the complement proteins is missing, including the control proteins and cell-associated receptors, the resulting dysfunctional system generally leads to disease.1,2 Patients with complement component deficiencies often present with pyogenic infections, particularly of encapsulated bacteria including Streptococcus pneumoniae and Haemophilus influenza type B or with autoimmune disorders as discussed for each pathway below. Outright genetic deficiencies are relatively rare, with an estimated prevalence of 0.03% in the general population, except for deficiency of the mannan-binding lectin (MBL), which may be present in the homozygous form in as many as 3–10% of the population. Subtle changes in the gene sequence that lead to enhanced or decreased function have been described for several complement proteins.

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Figure 189-1.
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Schematic of the three activation pathways and the terminal pathway of complement. MASP, MBL-associated serine protease; MBL, mannin-binding lectin.

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Complement abnormalities may underlie disorders, including angioedema, vasculitis, recurrent bacterial infections, impaired or improper immune responses, certain renal conditions, and increased incidence of autoimmune disease. A family history of these symptoms should increase suspicion of a potential complement deficiency. Specific complement deficiency associations with particular disease processes are discussed below.

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Identifying a patient with low complement and distinguishing between an inherited or acquired deficiency can be challenging. However, understanding the reason(s) for low or absent complement guides treatment decisions, including when to use antibiotics, immunizations, or protein replacement, as well as whether genetic counseling for inherited deficiencies is needed.

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Evaluation of the complement system is best accomplished using functional screening tests that are designed to evaluate the integrity of each pathway.2,3 The classical pathway is evaluated using the CH50 laboratory test. This test was initially developed as a hemolytic assay based on complement dependent reactions with a surface antigen on sheep red blood cells that led to cell lysis. Because cell lysis required the sequential action of all 9 components of the classical (C1, C4, and C2) and the terminal pathway (C3, C4, C6, C7, C9). The CH50 represents the reciprocal of the serum ...

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