Complement component

Most of the serum complement proteins are produced primarily in the liver, but monocytes and macrophages constitute an important source of extrahe-patic production of many complement components. Local production of complement at tissue sites of inflammation may be of considerable importance in host defences and immunopathological reactions. 

Posttranslational modification of precursor proteins appears to be an important regulatory step in the synthesis and secretion of complement proteins, as it is with other proteins (Ooi et al. 1980). Hall and CoLTEN (1978) showed in the guinea pig, that deficiency of C3 resulted from a translational defect in the synthesis of C4 protein. Under cell-free conditions, hepatic polysomes from C4-deficient guinea pigs synthesised only nascent C4 polypeptides that remain polysome-bound. Thus, the mRNA appears to be present but not completely translated. 

The complement peptides C5a and C5a-desArg have been found to elicit the respiratory burst human C5a has a threshold of 10 M for O2 generation maximum is still not reached at 10 (Da-hinden et al. 1983, McPhail and Snyderman 1983, Gerard et al. 1986). C5a-desArg from the same species is approximately 50 times less potent (Webster et al. 1980). The activity of human C5a is greatly enhanced in the presence of a yet unidentified serum factor (protein ) (Maly et al. 1983). 

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Humoral immunity depends on soluble, noncellular effector mechanisms of the immune system. These include defensins and complement components (proteins of the innate immune system) and antibodies (products of the adaptive immune system). They are capable of reacting with foreign substances (e.g., bacteria and viruses) to produce detoxification and elimination. 

Microbial toxins such as diphtheria toxin and activated serum complement components can produce large pores in cellular membranes and thereby provide macromolecules with direct access to the internal miheu. 

Class 3 MHC molecules consist of several complement components. 

Nozaki, M, Raisler, BJ, Sakurai, E, Sarma, JV, Bamum, SR, Lambris, JD, Chen, Y, Zhang, K, Ambati, BK, Baffi, JZ, and Ambati, J, 2006. Drusen complement components C3a and C5a promote choroidal neovascularization. Proc Natl Acad Sci USA 103, 2328-2333. 

Ahrenstedt, O., Knutson, L., Nilsson, B., Nilsson-Ekdahl, K., Odlind, B. et al., Enhanced local production of complement components in the small intestines of patients with Crohn s disease, N. Engl. J. Med. 1990, 322, 1345-1349. 

Reiter, Y., and Fishelson, Z. (1989) Targeting of complement to tumor cells by heteroconjugates composed of antibodies and of the complement component C3b. J. Immunol. 142, 2771. 

Ligand recognition/binding The carbohydrate content of antibodies, for example, plays a role in antibody binding to monocyte Fc receptors and interaction with complement component Clq... 

HIV infection1 12 13 CD4+T lymphocyte count Diabetes, heart disease, chronic pulmonary disease, chronic alcoholism Asplenia12 (Including elective splenectomy and terminal complement component deficiencies) Chronic liver disease Kidney failure, end-stage renal disease, receipt of hemodialysis... 

Medical indications Adults with anatomic or functional asplenia, or terminal complement component deficiencies. 

During complement activation via the classical pathway, nine major complement components (designated C1-C9) become activated in a sequential process, the product of each activation step being an enzyme that catalyses a subsequent step in the cascade. The purpose of the cascade is twofold firstly, a sequential activation process decreases the possibility of nonspecific activation secondly, the initial response is amplified so that large numbers of complement molecules become activated in response to small amounts of initial signal. The order of events is as follows. 

Figure 1.15. Complement activation via the alternative pathway. Always present in serum are trace amounts of C3b, which may attach to recognition sites on, for example, yeast cell walls. C3b may combine with serum factor B to form C3bB, and this complex is acted upon by factor D to form C3bBb. This latter complex is a C3 convertase and may act upon C3 to form more C3b to amplify the process. The C3bBb-coated particles may activate other complement components (C4-C9) or be recognised by complement receptors on neutrophils.

The acute-phase response is characterised by the enhanced (two- to threefold) synthesis of a number of proteins, such as antiproteinases, complement components, fibrinogen and ceruloplasmin, which are normally synthesised at fairly low rates. The rate of synthesis of some proteins is enhanced 100-1000-fold - for example, C-reactive protein, a-macroglobulin and acid-1-glycoprotein. Thus, serum levels of these proteins serve as indicators of disease. 

During complement activation, several components are generated that serve as ligands for leukocytes (see 1.3.2.1-2) and that bind to specific receptors on the plasma membrane. Those complement components recognised by neutrophils may be soluble (e.g. C3a, C5a) and initiate chemotaxis and... 

B cell bh4 bp BPI BSA C domain C1-C9 cAMP CAP CD cDNA CFU CFU-GEMM bone-marrow-derived lymphocyte tetrahydrobiopterin base pairs bactericidal/permeability-inducing protein bovine serum albumin constant domain complement components cyclic adenosine monophosphate cationic antimicrobial protein cluster of differentiation complementary deoxynucleic acid colony-forming unit granulocyte-erythroid-monocyte-megakaryocyte CFU... 

Rothman BL, Merrow M, Bamba M, Kennedy T, Kreutzer DL (1989) Biosynthesis of the third and fifth complement components by isolated human lung cells. Am Rev Respir Dis 139(1) 212-220. 

Opsonization by complement components also represents a potential barrier for intravenous gene delivery. Cationic charges of the particles activate the complement, which then takes part in particle elimination. This hurdle is possibly limited by using short hydrophobic chains, reducing the particle size, and eventually PEG insertion into lipoplexes (18). The interaction effect between the lipoplex and the complement might not be such a limitation. Indeed, it was reported that depletion of complement by injection of cobra venom factor and anti-C3 antibodies in mice indicated no differences upon intravenous injection of lipoplexes, neither in terms of tissue distribution nor in lipofection efficiency (19). 

Human plasma kallikrein has also been described as being directly chemotactic for human neutrophils (57). Kallikrein incubated with the complement component C5 generates chemotactic activity, providing a further mechanism for C5 activation. C5a is the most active and probably the most biologically important of the complement derived chemotactic and anaphylatoxic peptides. 

In general, serum should be heat-inactivated by heating at 56°C for 15 min to inactivate complement components prior to ammonium sulfate fractionation. Ascitic fluid should first be filtered through a cushion of glass wool. 

Particles are most efficiently phagocytized when they are opsonized with complement components or immunoglobulins. This is accomplished by incubating the particles with autologous or normal human pooled serum, or with specific antibodies that recognize antigens on the particle surface. 

Macrophages and neutrophils are the major phagocytes they possess receptors that recognise the presence of specific molecules or groups of molecules on the surface of pathogens (for example, lipo-polysaccharide) or when they are in the form of a complex with an antibody or in a complex with a complement component. Once bound to the receptors, actin filaments of the phagocyte polymerise and part of the plasma membrane surrounds the pathogen or complex which then draws... 

This calcium-activated enzyme [EC 3.4.21.75] catalyzes the hydrolysis of peptide bonds in protein precursors that results in the release of mature proteins from their proproteins by hydrolysis of ArgXaaYaaArg—Zaa bonds, where Xaa can be any amino acid and Yaa is an arginyl or a lysyl residue. Albumin, complement component C3, and von Willebrand factor are thus released from their respective precursors. Furin is a member of the peptidase family S8. 

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