THE MEMBRANE ATTACK MECHANISM OF COMPLEMENT
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Abstract:
The membrane attack mechanism of complement, C5 to C9, has previously been postulated to associate on the target cell surface to a stable decamolecular complex with a calculated mol wt of 995,000. A soluble and stable complex consisting of C5, C6, C7, C8, and C9 has now been demonstrated to arise as a consequence of complement activation by the classical or alternate pathway. It has a sedimentation coefficient of 22.5S and a mol wt of 1 million daltons, and it migrates on electrophoresis at pH 8.6 as an alpha-globulin. The stable and soluble C5b-9 complex cannot bind to erythrocytes and has no demonstrable cytolytic activity. However, due to partially unsaturated binding sites for C9, it can bind additional C9 and thus function as an inhibitor of lysis of EAC1-8 by C9. These results support the concept according to which the membrane-bound attack system of complement represents a stable, decamolecular assembly of C5b-9. Unlike its analogue in free solution, the membrane-bound complex is cytolytically active.Keywords:
Complement
iC3b
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Immunofluorescence
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The complement system plays an important role in defence of the host against infection and in the clearance of immune complexes. Defects in complement proteins are often associated with infections or auto/immune complex diseases. Investigation of complement is useful for diagnosis and following of auto-immune diseases. The aim of this Article is to provide an overview of important applications of complement in medicine, emphasizing the role of complement in pathogenesis and the usefulness of measurements of complement proteins in diagnosis and assessment of the evolution of disease states. Emphasis has been placed on practical applications and understanding basic mechanisms of disease. The best screen for complement deficiencies or significant activation is the CH50, which measures total classical pathway activity and the measurement of C3 and C4. The absence or decrease of multiple components is usually due to consumption of complement. Complete lack of CH50 associated with normal C3 antigen is a strong indication for complement deficiency and should be followed up with further tests to determine which component is missing.
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Complement control protein
Complement component 2
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Decay-accelerating factor
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Measurement of complement in clinical medicine is traditionally based on the determination of CH50 and immunochemical and/or functional measurement of complement proteins C1q, factor B, C3 and C4. The interpretation of these measurements, as far as complement activation is concerned, can however be difficult as these tests do not allow to discriminate between consumption due to activation, hereditary deficiency, increased rate of synthesis or even hyposynthesis. This explains why their use as markers of evolutivity in diseases where complement activation is occurring has given variable results. New tests for complement activation have been more recently introduced. These are mainly the measurements of the anaphytotoxins, the degradation products of C3 and the membrane attack complex. As these tests reflect more directly complement activation, they may be more reliable markers. The immunochemical and functional measurements of C1-inhibitor are of special interest as they are the tests which allow definitive diagnosis of the hereditary angio-oedema. General principles for the interpretation of the different tests used to evaluate the complement system are presented and discussed.
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The biological role of the complement system and the clinical importance of complement measurements.
Properties of serum proteins belonging to the complement system, two pathways of the complement activation (classical and alternative pathway) as well as the physiological role of the complement system are discussed. Complement has essential importance in some physiological processes: In the induction of the humoral immune response, in the elimination of immune complexes and in the protection against bacterial and viral infections. After a short discussion of the genetics of the complement system, the principle and possibilities of clinical applications of the complement measurements are described. Finally, different approaches to the therapeutic manipulation of the complement system are discussed.
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This chapter will describe various approaches and laboratory tests which have been employed to analyze the reaction mechanisms of the complement system and to demonstrate its involvement in model systems and in human diseases. Emphasis will be placed on new assay systems which detect specific features of the activated complement system. In addition to the unequivocal demonstration of complement activation, such assays are highly sensitive and have the ability to detect and quantitate low levels of complement activation in the circulation, in tissues, or in vitro.
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