K. Rother

The complement system

1 Components and Reactivity.- 1.1 Components.- 1.1.1 Factors of the Classical Pathway.- 1.1.2 Components of the Alternative Pathway.- 1.1.3 Late Components.- 1.2 Reactivity.- 1.2.1 Classical Pathway of Activation.- 1.2.2 Lectin Pathway of Non-self Recognition.- 1.2.3 Alternative Pathway: Activation and Regulation.- 1.2.4 Complement Attack Phase.- 1.2.5 Control Mechanisms.- 1.2.5.1 Membrane Cofactor Protein (CD46) and Decay-Accelerating Factor (CD55).- 1.2.5.2.1 Control of C5b-9 by Fluid Phase Factors.- 1.2.5.2.2 Membrane-Bound Inhibitors of C5b-9.- 1.2.5.3 Interspecies Incompatibilities of Complement Factors and of Regulators.- 1.3 Surface Receptors and Signaling Pathways.- 1.3.1 Receptor for C1q.- 1.3.2 Receptors for Human C3 Fragments.- 1.3.3 Receptors for C5a, C3a, and Factor H.- 2 Biologic Functions.- 2.1 Complement in the Induction of Antibody Response.- 2.2 Maintenance of Immune Complex Solubility and Immune Adherence.- 2.3 Interaction with Effector Cells.- 2.3.1 Leukocyte Mobilisation/Recruitment.- 2.3.2 Chemotactic Peptides.- 2.3.3 Cellular Responses to Activation Products.- 2.4 Host Defense Against Infection.- 2.4.1 Defense Against Bacteria.- 2.4.2 Complement-Dependent Virus Neutralization.- 2.4.3 Evasion of Complement-Mediated Damage by Microorganisms.- 2.5 Possible Role of Complement Regulators in Reproduction.- 2.6 Network Interactions of the Complement System with Other Serum Mediator Systems.- 3 Pathology.- 3.1 Complement Deficiencies in Animals: Impact on Biological Functions.- 3.2 Complement Deficiencies in Humans.- 3.2.1 Inherited and Acquired Deficiencies of C1 Esterase Inhibitor in Humans.- 3.2.2 Deficiencies in the Classiral Pathway.- 3.2.3 Deficiencies in the Alternative Pathway: Factors I and H.- 3.2.4 Deficiency in Terminal Reactivity.- 3.2.5 Deficiency in Lysis Control Proteins.- 3.2.6 C3 Receptor Deficiencies.- 3.3 C3 Nephritic Factor.- 3.4 Complement in Inflammation.- 3.5 Role of Complement in Graft Rejection.- 3.6 Complement Activation on Artificial Surfaces in Biomedical Therapies.- 3.7 Adverse Reactions to Drugs.- 4 Complement Manipulation In Vivo.- 5 The Clinical Laboratory: Testing the Complement System.

The complement membrane attack complex stimulates the prostanoid production of cultured glomerular epithelial cells

Incubation of cultured rat glomerular epithelial cells (GEC) with sublytic amounts of the purified complement components C5b6, C7, C8 and C9 greatly stimulated the release of the prostanoids prostaglandin E (PGE) and thromboxane B2. Incubation of GEC with C5b-8 was also stimulatory, whereas omission of C7 abolished the enhanced prostanoid production. These effects were dose-dependent. The increased release of PGE was biphasic with peaks at 5 min and 24 h of incubation. The second peak could be prevented by treatment with cycloheximide, suggesting its dependence on protein synthesis. The observations on cultured GEC provide evidence that terminal complement components alter the metabolism of glomerular cells, resulting in increased production of prostanoids. The results are consistent with the concept that deposition of nonlytic amounts of complement in the glomerular capillary wall may affect the GEC in vivo and may indirectly contribute to abnormalities of the glomerular filter as it is seen in glomerular disease.

Complement in Inflammation: Induction of Nephritides and Progress to Chronicity

The C5b-9 complex has a dual role as a factor involved in the initiation of nephritides and in the progress to chronicity and sclerosis. The unique pathophysiology of the membrane attack complex, distinct from other mediators, is its independence from specific receptors. It inserted in any membrane lipid bilayer tested so far.

Interleukin-4 augments production of the third complement component by the alveolar epithelial cell line A549.

The elements of allergic inflammation and the involvement of helper T lymphocytes are increasingly being recognized in the immunopathogenesis of asthma. Allergen exposure leading to the activation of allergen-specific T cells present in the lung can result in the release of cytokines which in turn can locally stimulate the cellular constituents of the lung. The airway epithelial cells may be the key participants in such an interaction. Therefore, we examined the ability of T-cell-derived IL-4 to modulate the production of C3 and C5 by the human type-II pneumocyte cell line A549, which is known to produce all the components and the regulatory proteins of the complement system. For estimation of C3 an ELISA detecting native C3 was used. Following stimulation of A549 with hrIL-4 a dose-dependent (1-50 U/ml) enhancement of C3 production was observed, which reached its maximum (5-fold of unstimulated cells) at 48 h and gradually declined thereafter. Concentrations of hrIL-4 higher than 50 U/ml did not further increase C3 production. In parallel experiments hrIFN-gamma at concentrations between 10 and 50 U/ml stimulated the C3 production to more than twice the quiescent state level within 24 h. In the pneumocyte cell line A549 we demonstrated the expression of a gene for the IL-4 receptor which appears to mediate the biological effect of this lymphokine. A diminution in the functionally active C5, estimated by ELISA at the same time, was observed in supernatants of A549 cultures following stimulation with hrIL-4 as well as with hrIFN-gamma.(ABSTRACT TRUNCATED AT 250 WORDS)

The Role of Complement in Inflammation

The inflammatory process may be initiated by a great variety of stimuli. Amongst the diverse pathogenic pathways that lead from the primary stimulus to the tissue response, the serum complement system (C) seems the most important and, certainly, it is the best analyzed of the mediator systems.

Deviated Lysis: Lysis of Unsensitized Cells by Complement. V. Generation of the Activity by Low pH or Low Ionic Strength

In serum exposed to acid pH (6.4), a serum activity was generated which lyzed unsensitized erythrocytes in the presence of EDTA. It was similar to the d.l. activity found following serum activation by inulin (2). In contrast to the d.l. generation by the classical or by the alternative pathway of C activation, the generation of d.l. by acid pH did not require C4 plus C2 or C3 plus factor B resp. It was, thus, not dependent on any hitherto known pathway of C activation. A similar activity appeared when NHS was centrifuged in a sucrose gradient at low ionic strength. Physicochemical alterations of the component proteins which influence their affinity for each other are seen as the basis for the activation of the attack phase of C.

Chronic Glomerulonephritis: Inflammatory Mediators Stimulate the Collagen Synthesis in Glomerular Epithelial Cells

C5b-9 membrane attack complexes of complement (MAC) stimulate the production of type IV collagen in cultures of human glomerular epithelial cells. Together with other known effects of MAC interaction with glomerular cells, the complex is ascribed a role in the progress of acute glomerulitis into the chronic nephritic state.

Deviated Lysis: Transfer of Complement Lytic Activity to Unsensitized Cells II. Generation of the Activity by Inulin and by Antigen Antibody Complexes

Deviated lysis (d.l.) activity, i.e. lysis of unsensitized cells by lytic C activity, was generated via the classical pathway of Cactivation (ag ab complexes) and via the alternative pathway (inulin). The activity was observed on the surface of the activating particles and in the fluid phase. The activity was relatively stable at 32 degrees C. Its generation involved the C components C6 through C9 and possibly also C5.

Deviated lysis: transfer of complement lytic activity to unsensitized cells. IV. Parital isolation of the activity.

Deviated lysis (d.l.) was previously characterized as the lysis of non-sensitized erythrocytes by activated complement (C) in the presence of EDTA (1, 2, 3). The lytic activity was present in serum fractions of a m.w. in the proximity of 220,000. All the C factors C5 through C9 were found in these fractions and they were all needed for lysis. It is proposed that in d.l. small aggregates of the C components C5 through C9 coexist in the reaction mixture without further interaction. Only when appropriate receptors such as present on target cells surfaces are available, the factors react in a sequential order eventually to result in lysis of the target cell.

Leukocyte Mobilization from Bone Marrow: Effect of the RGD-Containing Peptides of C3 and Fibronectin

A peptide derived from complement component C3 caused leukocyte release in a perfused rat femur model. The function was related to the complement receptor 3 (CR3)-binding region in the α-chain of human C3. The peptide spanning this region contained RGD, a known ligand mediating cell-cell and cell-matrix interactions. We present data that also RGD and RGDS released leukocytes. Moreover the 120 kD RGD-containing fragment of fibronectin and monoclonal antibodies to its receptor α5β1 induced a massive leukocyte release. Leukocyte detachment from the marrow is mediated by interference with RGD-peptides of C3 and fibronectin.