Complement Deficiencies
Complement plays a role in the recognition, opsonization, and killing or clearance of invading microorganisms, immune complexes and altered host cells. There are three main pathways of complement activation: the classical pathway (C1 dependent), the lecti
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Complement Deficiencies
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Maryam Mahmoudi, Tom Eirik Mollnes, Taco W. Kuijpers, and Dirk Roos
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Complement plays a role in the recognition, opsonization, and killing or clearance of invading microorganisms, immune complexes and altered host cells. There are three main pathways of complement activation: the classical pathway (C1 dependent), the lectin route (mannan-binding lectin/ficolin and MASP dependent), in which both C4 and C2 play a role, and the alternative pathway (Factor B, D, and properdin dependent). MBL deficiency occurs frequently and acts as a disease-modifying factor. All other complement deficiencies are rare and result in recurrent pyogenic infections or autoimmune disease reminiscent of systemic lupus erythematosus. Novel assays have made the diagnosis of complement deficiencies easier. C1INH (C1 inhibitor) replacement therapy is available for hereditary (or acquired) angioedema (HAE), and replacement therapy is being developed for MBL (mannan-binding lectin). Complement-targeted therapy (e.g., C1INH, soluble CR1, antibodies against C5, C5aR antagonists) will become important in the near future for adjuvant treatment in ischemia-reperfusion injury, transplantation medicine, and inflammatory disease.
8.1 Introduction The complement system is an important part of innate and adaptive immunity [102, 103]. This system was discovered shortly before 1900 [39], but the first complement-deficient patient was described in 1960 [107]. The human complement system consists of more than
30 proteins, which are primarily produced in the liver and circulate in general in their inactive forms. When activated, they have several important biological functions, such as the recognition, processing, presentation and retention of foreign antigens, regulation of acquired immunity, and clearance of immune complexes and cellular debris such as apoptotic cells [8, 63, 106]. The complement system is activated via the classical (CP), lectin (LP) or alternative (AP) pathways [56, 81, 102, 103] (Fig. 8.1), which are initiated by different mechanisms [17, 73, 107]. This system forms an enzymatic reaction cascade of one component activating the next, resulting in an amplification process. Most complement proteins are produced in the liver by hepatocytes and secreted in plasma constitutively or induced by inflammatory cytokines during the acutephase response. Some proteins, like C1q, C7 and factor D, are mainly produced extra-hepatically, e.g., C1q by macrophages and factor D by adipose and renal cells. Local synthesis of complement proteins by resident or infiltrating cells is pivotal to drive inflammatory processes. During complement activation, fragments of C4 and C3 are deposited on pathologic or senescent targets for the purpose of opsonization, i.e., covering the surface with proteins to enhance uptake and breakdown by phagocytic leukocytes. The final step of complement activation implies release of C5a, a highly potent vasoactive peptide that promotes the inflammatory reaction, and formation
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