Of the classical pathway

Kaplan A Mechanisms of activation of the classical pathway of complement by Hageman factor frag- 91 ment. J Chn Invest 1983 71 1450-1456. 

Complement A term originally used to refer to the heat-labile factor in serum that causes immune cytolysis, the lysis of antibody-coated cells, and now referring to the entire functionally related system comprising at least 20 distinct serum proteins that is the effector not only of immune cytolysis but also of other biologic functions. Complement activation occurs by two different sequences, the classic and alternative pathways. The proteins of the classic pathway are termed components of complement and are designated by the symbols... 

Figure 1.1 illustrates a condensed version of the classical pathway of bile-acid synthesis, a series of 12 enzymatic reactions that convert cholesterol, which is insoluble, into BAs, which are water soluble. The cholesterol is first converted to 7 alpha-hydroxy cholesterol, followed by the series of enzymatic transformations, eventually producing cholic and chenodeoxycholic acids (not all steps shown). The rate-limiting enzyme in this pathway is cholesterol 7 alpha-hydroxylase (CYP 7A1), which originates from microsomal cytochrome P-450 enzymes, expressed only in the liver hepatocytes. 

The classic pathway is triggered by the formation of factor Cl at IgG or IgM on the surface of microorganisms (left). Cl is an 18-part molecular complex with three different components (Clq, Clr, and Cls). Clq is shaped like a bunch of tulips, the flowers of which bind to the Fc region of antibodies (left). This activates Clr, a serine proteinase that initiates the cascade of the classic pathway. First, C4 is proteolytically activated into C4b, which in turn cleaves C2 into C2a and C2b. C4B and C2a together form C3 convertase [1], which finally catalyzes the cleavage of C3 into C3a and C3b. Small amounts of C3b also arise from non-enzymatic hydrolysis of C3. 

Figure 3. Hypothetical alternative enzyme path between 3-dehydroquinate and shikimate. A reversed order of the dehydratase and dehydrogenase steps of the classical pathway (top) would produce the quinate route (bottom).

A comprehensive review of the methods used for the preparation of indolizidines is far beyond the scope of this article. Following a short description of the classical pathways, those methods are presented which have either been used extensively or met interest in the field of stereospecific synthesis. Several methods have already been described in Section 3.08.3. 

Impaired function of phagocytes and deficiency of early components of the classic pathway of the complement system result in increased apoptotic waste. This waste, including nucleosomes and other autoantigens, is formed and altered by the protease of apoptotic cells. They are expressed on the surface of apoptotic blebs and activate bystander dendritic cells. Subsequently the dendritic cells activate helper T cells, which then help B cells to generate high-affinity autoantibodies (Fig. 1). 

This pathway of complement activation, which starts when antibody has bound to antigen on the microbe surface, is called the classical pathway. An alternative pathway of activation also exists which is activated directly by polysaccharides in the cell wall of microorganisms even in the absence of antibody. The alternative pathway therefore defends the body against attack in the early stages before an immune response can occur and also augments the effects of the classical pathway of complement activation when the immune response has occurred. 

In most of 19 renal specimens from autopsies of intravenous diamorphine users there was severe lymphomono-cytic glomerulonephritis as a result of activation of the classical pathway of the complement binding system (40). This could have been a result of diamorphine itself, adulterants, or active hepatitis B and/or C infection. 

L-Tryptophan provides the anthranilate part of the molecule, most probably via a diversion of the classic pathway which forms 3-hydroxyanthranilate from L-tryptophan. Hydroxylation at C-8 of the antibiotic occurs prior to hydroxylation at C-7 and is accompanied by an NIH shift (27). The 8-methyl group of an-thramycin as well as the 7-methoxy carbon of 1 l-demethyltomaymycin are derived from methionine. 

Any of several mechanisms can activate complement, including continuous and spontaneous tickover, activation of the classical pathway (e.g., by the antigen antibody complexes or CRP), activation of the alternative pathway, and action of proteases released by leukocytes and other inflammatory cells. The common step involved in aU of these is the conversion of C3 to C3b, as shown in Figure 20-7. This figure also demonstrates the sites of action of the inhibitors and inactivators of complement (shown in gray shading), which prevent excessive or continuous depletion of the complement components in addition to controlling complement activity in sites of inflammation. 

Clr 34-48 (6Ax 26,500) (6B X 26,500) (6C X 24,000) 83,000 collagen-like domains and petals , globular domains. Globular domains bind Fc regions of IgG and IgM antigen-antibody complexes, leading to activation of Clr and initiation of the classical pathway. Proenzyme to serine protease auto-activates and... 

Activation of C2 and C4 produces the C3 convertase and, via the same reactions sequences of the classical pathway, leads to formation of the MAC. 

Ouaissi MA, Auriault C, Santoro F, Capron A (1981) Interaction between Schistosoma mansoni and the complement system role of IgG Fc peptides in the activation of the classical pathway by schistosomula. J Immunol 127 1556-1559... 

Ruffet et al. [12] demonstrated that preincubation of protein Fv with human monoclonal IgGl and IgM activates the complement cascade by forming nonimmune complexes. Activation of the classical pathway is due to the binding of immunoglobulins with protein Fv. These results confirm that protein Fv binding mimics antigen-antibody reaction and suggest its involvement in some inflammatory gut diseases [13]. 

Rufifet E, Pires R, Pillot J, Bouvet JP Activation of the classical pathway of complement by non-immune complexes of immunoglobulins with human protein Fv (Fv fragment-binding protein). Scand J Immunol 1994 40 359-362. 

Complement deficiency. Congenital deficiencies in the various components of the complement system. Rheumatic disorders (mainly systemic lupus erythematosus) are associated with deficiencies of the early components of the classical pathway. More than 30% of individuals with C2 deficiency and nearly 80% with either C3 or C4 deficiency have an autoimmune manifestation. 

Fig. 4. The bile acid biosynthetic pathways. The classical pathway operates entirely in the liver and cholesterol 7a-hydroxylase (CYP7A1) initiates the pathway. In other tissues, the entry of cholesterol into the alternate pathways is facilitated by sterol 27-hydroxylase (CYP27A1), cholesterol 24-hydroxylase (CYP46A1), and cholesterol 25-hydroxylase (CH25H). The oxysterols generated by these enzynies are 7a-hydroxylated by oxysterol 7a-hydroxylases CYP7B1 and CYP39A1, and the products enter the latter steps of the classical pathway.

Feeding rats with a cholesterol-enriched diet induces bile acid synthesis. This increase is attributable to the rise in CYP7A1 activity, which catalyzes the rate-limiting step of the classical pathway (Fig. 6). Interruption of the return of bile acids to the liver, by... 

Seven hydroxycoumarins were further tested at a single concentration (5.0x1 O 4 M) for their ability to influence Cl and C3 functional activities after preincubation with undiluted NHS. 7-Methylesculin (11) had a good effect on reducing total, Cl, and C3 hemolysis via both pathways. Scoparone (6) strongly inhibited C3 alternative activity but in the case of the classical pathway only the total hemolysis was diminished without influence on Cl and C3. Esculin (1) slightly increased C3 classical activity but caused exhaustion of alternative C3 activity. 

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