Classical pathway

Arabinofuranosides were removed from PVa, which resulted in an increase in the activity this was in contrast to the findings of Kiyohara et al. [35] who foimd no change in activity after removal of similar units from A. acutiloba pectin. For this polymer it was suggested that the minimum requirement for complement activation via the classical pathway was j6-l,6-linked galactan attached to the rhamnogalacturonan backbone, which also appears to be an important part of the backbone for PVa. 

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

Few prospective studies of induced anaphylaxis have been performed in human subjects to imderstand the molecular basis of systemic anaphylaxis, because of the potentially rapid, Ufe-threatening outcome. Accordingly, various models of anaphylaxis have been estabUshed in laboratory animals, particularly mice, and extensively studied to clarify the underlying mechanisms. Such studies revealed that the classical pathway utilizing mast cells, IgE and histamine cannot explain all cases of anaphylaxis. 

Complement can be activated by two pathways, the classical pathway and the alternative pathway (Fig. 14.4). 

The first component of complement is Cl. This is a complex of three molecules designated Clq, Clr and Cls. The classical pathway is only initiated by an immune complex (antibody bound to antigen) when Clq binds to the Fc portion of the complexed antibody (IgM or IgG). The binding of Clq activates the Clr and Cls molecules associated with it to yield activated Cl which now cleaves C4 and then C2 (subunits of... 

Proteins B, D and P also amplify the effects ofthe classical pathway in that some of the 3b generated by this pathway interacts with these proteins to form additional C3 convertase that supplements that provided by C4b.2a. Likewise, enhanced cleavage of C5 occurs due to the dual activity of C4.2a.3b and C3b.Bb.C3b complexes. 

The complement cascade may become activated via two pathways the classical pathway or the alternative pathway. 

The classical pathway can become activated by immune complexes, bacteria, viruses, and F-XIIa. Binding occurs to the complement C1 q, a part of complement factor 1 (Cl). This initiates a cascade of activations, first of Clr, Cls, then of C4. This C4 activates C2, after which C3 becomes activated. Activated C3 initiates a cascade of activations, which are in common with the alternative pathway and which end up in activated C5-9, a membrane attack complex that lyses the target. 

However, an alternative pathway that bypasses clathrin-mediated endocytosis and EEs appears to be available as well. This model of endocytosis known as kiss and run or its variant kiss and stay have attracted increasing interest in recent years [74] (Fig. 9-9B). Kiss and run has been directly demonstrated with dense-core granules in neuroendocrine cells [84, 85], and this model would explain some observations that are not readily accommodated by the classical pathway. The kiss and run model proposes that neurotransmitters are released by a transient fusion pore, rather than by a complete fusion with integration of the synaptic vesicle components into the plasma membrane. Synaptic membrane proteins never lose their association and the vesicle reforms when the pore closes. As a result, the empty vesicle can be refilled and reused without going through clathrin-mediated endocytosis and sorting in the EEs. 

Some crucial steps in the biology of CVD have demonstrated sensitivity to estrogen agonists. Some of these actions have shown to be mediated by the classical pathway of estrogen receptors (ERs), though in other cases the involved mechanisms seem more complex and require the consideration of alternative options (Mendelsohn 2002). The available evidence concentrates on actions on lipids or on direct actions on the vascular wall. 

IgA has a short half-life in serum (6 days) and comprises about 12-20% of the total serum immunoglobulins. However, because of its presence in bodily fluids, it is the most abundant immunoglobulin present in the body. It comprises three constant domains, and neutrophils, monocytes and some other immune cells possess receptors for IgA (FcaR). Neither of the two IgA subclasses, IgAi and IgA2, can fix complement via the classical pathway. Instead, these antibodies neutralise antigens at mucosal surfaces, in the absence of complement fixation (which would be pro-inflammatory), and the neutralised antigens are cleared. 

The complement system comprises twenty plasma proteins present in the blood and in most bodily fluids. They are normally present in an inactive form but become activated via two separate pathways the classical pathway, which requires antibody, and the alternative pathway, which does not. Once the initial components of complement are activated, a cascade reac-... 

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 1.14. Complement activation via the classical pathway. The sequential activation of complement following antibody deposition onto a surface is shown. C9 forms a pore in the membrane, eventually leading to cell death by osmotic lysis. See text for details.

IgG The major immunoglobulin in human serum. There are four subclasses of IgG IgGl, IgG2, IgG3 and IgG4, but this number varies in different species. All are able to cross the placenta, and the first three subclasses fix complement by the classical pathway. The molecular mass of human IgG is 150 kDa and the normal serum concentration in man is 16 mg ml-1. 

These treatments have been also applied to S/yAr. For example, for a neutral nucleophile, all the classical pathways identified at present are represented by the general reaction mechanism shown by Scheme 2. A concerted mechanism, indicated by the diagonal path in Scheme 2, had not been discussed until lately, but was observed, among other systems, in the hydrolysis of l-chloro-2,4,6-trinitrobenzene and 1-picrylimidazole. The study was then extended to other related substrates and structure-reactivity relationships could be obtained78. 

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 5.25 Complement cascade. The classical pathway requires antigen antibody (Ag Ab) interaction to activate Cl, the alternative pathway is antigen independent...

Activation of the Complement System by Antibody-Antigen Complexes The Classical Pathway R. R. Porter and K. B. M. Reid... 

The classical pathway may be activated immunologically by antigen-antibody complexes and aggregated immunoglobulins, and non-immunologically by a number of chemically diverse substances, including DNA, C-reactive protein. Staphylococcal protein A, trypsin-like enzymes and certain cellular membranes (Table III). 

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