Introduction: Genetic Deficiencies of Complement Proteins—Consequences and Molecular Basis

Abstract

The complement system represents one of the major host defense mechanisms and contributes to the regulation of the physiological and pathological immune response. Insight into the organization of this system of soluble and membrane-associated proteins was obtained from numerous immunochemical studies. After the identification of a given protein and purification, its functional characterization in various, often sophisticated in vitro systems was required for the understanding of complement-dependent reactions. These studies revealed the importance of complement proteins or their fragments as both regulatory and effector elements within the immune system: complement has obviously a critical role in defense mechanisms like opsonization or cell lysis; it represents a major mediator of the inflammatory reaction; complement fragments or complexes regulate the functional status of lymphoid and non-lymphoid cell populations and affect thereby directly the course of the immune response; finally, the proper handling of immune complexes is complement-dependent . The corroboration of the in vitro findings by suitable in vivo systems attracted much attention. One experimental approach used depletion in vivo by induction of systemic complement activation, e.g. with cobra venom factor. Complement depletion-albeit transiently-is rapidly achieved, paralleled however by massive generation of biologically highly active complement fragments. These mediators potentially affect the homeostasis of the immune system. A direct correlation between the absence of a complement protein and the impairment of a given biological response or a pathological phenomenon is therefore difficult. For this reason, selective genetic deficiencies of individual complement proteins as experiments of nature provided a valuable model. The impairments observed in affected patients or animals provided crucial evidence for the biological role of a given component and represent a kind of substantiation for the laboratory findings. The relative importance of the protein within the physiological immune response becomes obvious in a deficient individual without the need for prior pretreatment or experimental manipulation. In addition, the contribution of the principal elements of the complement cascade is clearly revealed, e.g. classical vs. alternative pathway or terminal components.