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Key Points

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  • Disease summary:

    • Complement deficiencies are rare, and typically result in one or more of the following phenotypes: increased susceptibility to encapsulated bacteria (Streptococcus pneumoniae, Haemophilus influenzae, Neisseria meningitidis), and autoimmunity (systemic lupus erythematosus [SLE], atypical hemolytic uremic syndrome [HUS], and membranoproliferative glomerulonephritis [GN]).

    • This chapter does not address a single disease and its implicated genes, but rather a subdivision of the immune system. Deficiencies of the complement system (Table 80-1) will be discussed in clusters of similar phenotypic presentation. Given that the genetic basis for individual deficiencies of the complement components is sundry (and seldom clinically relevant), individual genes will be commented on only when germane to clinical management.

  • Overview of the complement system:

    • Complement is a system composed of serum glycoproteins that coordinate cascades of events leading to clearance of foreign antigens and host-derived debris such as apoptotic cells. Complement is involved in recognition of micro-organisms, direct killing of micro-organisms, processing and clearance of immune complexes, as well as regulation of lymphocytes.

    • Three pathways of antigen recognition and activation converge in a common final pathway designed to permeabilize micro-organism invaders by way of a protein C5 to C9 protein complex that forms a pore in microbial lipid membranes. The pathways of activation are the classical, alternative, and mannose-binding lectin pathways (MBL). C1, C4, and C2 are early classical complement components. Factors D, B, are components of the alternative pathway. C3 and C5 to C9 are shared components. Complement regulatory proteins include factor I, factor H, C4-binding protein, and properdin. The proteins CD59 and DAF are also regulatory proteins whose deficiency is associated with paroxysmal nocturnal hematuria and are not described here. The C1 inhibitor protein (C1-INH) deficiency is associated with hereditary angioedema and is described in Chap. 79. There are multiple causes for secondary deficiencies of C3, for example, deficiency of factors H and I. Deficiency of some complement receptors are also implicated in leukocyte adhesion deficiency (LAD) and will not be discussed in this chapter.

  • Inheritance:

    • Almost all complement components are inherited in an autosomal recessive fashion, except for properdin deficiency, which is X-linked recessive, and C1 esterase inhibitor deficiency, which is autosomal dominant. Heterozygously deficient individuals of components inherited in autosomal recessive fashion are typically asymptomatic.

  • Differential diagnosis:

    • The differential diagnosis for adult-onset immune deficiency includes anatomic derangement (ie, fistula, cerebrospinal fluid [CSF] leak etc), common variable immune deficiency, specific antibody deficiency, antibody subclass deficiencies, congenital phagocyte dysfunctions, medication or toxin effects, hematologic cancers such as multiple myeloma or chronic lymphocytic leukemia, and HIV or AIDS.

  • Incidence:

    • Complement deficiencies account for less than 1% of primary immunodeficiency states. Among C1 to C9 components, C2 deficiency is the most common in Western countries. Studies estimate 5/100,000 is completely deficient in C2.4 C9 deficiency is the most common in Japan. There are dozens of case reports of deficiencies in C1q, and C3. C4 protein is encoded in two genes, C4A and C4B, ...

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