Complement Deficiencies

Klaus O Rother and Ursula A Rother, Institute of Immunology, University of Heidelberg, Germany

Inherited deficiencies of all known complement (C) components, of most regulator proteins and of the respective receptors have been found in humans. Table 1 is a compilation of the defects. Although acquired deficiencies - be they by consumption or otherwise - may also cause clinical conditions comparable to those listed in Table 1, they will not be specifically addressed in this entry.

Inherited deficiencies are rare. Since complement is not routinely measured in healthy persons, the incidence is difficult to determine and so is the disease incidence in a given component deficiency. In a Japanese study of healthy blood donors, C5, C6, C7 and C8 have each been found missing in about 3 per 100 000. C9 was absent in 3 per 1000. The prevalence of deficiencies of the late-acting components together was calculated at approximately 12 per 100 000. Some combined deficiencies - total or subtotal - of two or more components were reported when the terminal complex was afflicted. Deficiency in C7 in some cases was combined with the additional absence of C4 (C4a and/or C4b).

Considering the many biological activities associated with complement activation (Figure 1), it initially came as a surprise that clinical symptoms were absent in many cases of missing components. However, experimentation with defective animals clarified the situation by showing that redundant pathways are operative to assure complement-dependent life-preserving functions. Thus, a missing link in one pathway may cause defect symptoms only if other pathways are also affected, or if control of a given condition requires mobilization of all reserves.

By and large, the syndromes expected in complement-deficient states may be subdivided into three groups.

1. Recurrent and/or persistent infections

Bacteria may cause life-threatening conditions in the absence of C3 or factor I or any part of the alternative pathway. Since absence of factor I results in total consumption of C3, the outcome in functional terms is identical with a primary lack of C3. Opsonization and phagocytosis are drastically diminished in these conditions. A contributory factor in combined deficiencies may be a defective immune response, as shown in C4-, C2- and C3-deficient states.

Deficiencies of the later reacting components C5, C6, C7 or C8 are often associated with infections, almost exclusively with meningococci or gonococci, suggesting that the normal defense against these strains rests mainly with the bactericidal (membrane attack) function of complement. In this light, the apparent health of the C9-deficient individuals may be explained with the intact membrane attack function of C5b678 in the absence of C9, although proceeding somewhat more slowly.

2. Connective tissue or immune complex diseases

Most striking is the association of unclear nature of systemic lupus or other autoimmune conditions with Clqrs, C4 or C2 defects alone or in combination with other factor defects. It is surmised that the pathophysiology in these disease states is a defect in

Biological function

Activation pathway

Classical

Alternative

Biological function

Classical pathway activation:

Virus neutralization Inhibition of IC-precipitation Enhancement of a. p. activation

C1 INH:

Inactivation of plasmin, Kallikrein

C3a: Anaphylatoxin Cell stimulation C3b and its split products: Activation of TCC Ligandfor CR1,CR2, CR3, CR4 Aggregation Phagocytosis t Enzyme release Release of arachidonic acid products Respiratory burst IL-2 dependent proliferation of lymphocytes T-cell receptor I Mobilization of PMN

C5a: Anaphylatoxin

Chemotaxis Cell stimulation via specific receptor Enzyme release Release of arachidonic acid products IL-1

Mitogen forT-lymphocytes CR1 expression ^

Antigen + antibody Virus? Bacteria - surfaces?

'Activator' (blocks inhibition)

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