The alternative pathway

Activation of complement via the alternative pathway requires no antibody-antigen complexes. It may be activated by endotoxin (LPS) on the surface of many Gram-negative organisms, by zymosan of the cell walls of many yeasts or by aggregated IgA. 

Neutrophils and host defence The fight against infection 

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Although most cells have the same basic set of central metabolic pathways, different cells (and, by extension, different organisms) are characterized by the alternative pathways they might express. These pathways offer a wide diversity... 

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

FACS Flow activated cell sorter factor B Serine protease in the C3 converting enzyme of the alternative pathway... 

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. 

The alternative pathway may become activated by lipopolysaccharides, endotoxin (sepsis), virus, fungi, immunoglobulin A-antigen (IgA-Ag) immunocom-plexes, and foreign material. These activate C3, after which the common pathway of complement activation takes place (Fig. 4). There are also a number of inhibitors that regulate and control complement activation. The most important are the Cl-esterase inhibitor (Cl-Inh) and the membrane attack complex inhibitor factor (MACIF CD59). In sepsis a relative deficiency of Cl-Inh has been reported. Administration of Cl-Inh to patients with septic shock attenuates complement acti-... 

Scheme 7 The alternative pathway of formation of the dioxetane moiety in an oxidised polypropylene chain.

The alternative pathway shown in Scheme 15 has the advantage that it is equally suitable for the preparation of gram quantities of both the fi-2 isomer (116) and the jS-3 isomer (117).150... 

A similar conclusion, that the alternative pathways sometimes differ only slightly in the energy barrier, was reached in several more recent theoretical papers which investigated methane activation in ( N2 )PtCl2 systems relevant to the Catalytica process. It has been demonstrated experimentally that compared with (bipyrimidine)PtCl2,... 

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-... 

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 alternative pathway is the biochemical route. It processes starches/sugars into ethanol, a standard technology with installations world-wide, but in a biorefinery the start is the whole-plant material or biomass residues containing hemicel-lulose, which is broken into sugars that then can be fermented to ethanol and/or other alcohols such as butanol. As mentioned before, there is the need to develop novel and/or improved biocatalysts for alternative organic fuels, such as biobutanol, by fermentation processes. 

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

Example Ethyl loss clearly predominates methyl loss in the El mass spectrum of 2-(l-methylpropyl)-phenol. It proceeds via benzylic bond cleavage, the products of which are detected as the base peak at m/z 121 and m/z 135 (3 %), respectively (Eig. 6.34a). The McLafferty rearrangement does not play a role, as the peak at m/z 122 (8.8 %) is completely due to the isotopic contribution to the peak at m/z 121. From the HR-El spectrum (Fig. 6.34b) the alternative pathway for the formation of a [M-29] peak, i.e., [M-CO-H]", can be excluded, because the measured accurate mass of this singlet peak indicates CgHgO". HR-MS data also reveal that the peak at m/z 107 corresponds to [M-CHs-CO]" and that the one at m/z 103 corresponds to [M-C2H5-H20]. Although perhaps unexpected, the loss of H2O from phenolic fragment ions is not unusual. 

A operable, one would anticipate hydrogen atom incorporation into the aromatic ring to afford 198, while the alternative pathway places deuterium there and would lead to compound 200. The data indicates a clear and distinct preference for the latter ( > 95% 200). 

Once the "synthesis tree" has been elaborated, we must proceed to the evaluation of the alternative pathways and compare them with possible synthetic schemes in order to optimise the chosen route and make it as self-consistent as possible. However, all synthetic plans must be flexible enough to allow new alternative solutions when things do not happen as anticipated. In this sense. Woodward referred very often to opportunism and of taking advantage of the "surprises" which may occur during the execution of a synthesis. Through the different stages of a synthesis new aspects may evolve and even important discoveries may be made. Such was the case, for instance, in the vitamin B12 synthesis in which the considerations of the stereochemistry of an intermediate, opposite to the one anticipated, led Woodward to the discovery of the principle of conservation of orbital symmetry [29]. 

Cotton dust activates complement vitro by both the classical (antibody dependent) and alternative (antibody independent) pathways (12,47,48). It is proposed that endotoxins may be the agents responsible for complement activation (49). Cotton dust extractions maximizing endotoxin content are 10 times more potent than other extracts in activating complement (12). Activation of complement via the alternative pathway has also been... 

If disease is mediated by non-specific activation of the alternative pathway, it does not explain why some mill workers, who are presumably exposed to equal dust levels, do not develop symptoms. One possible explanation is that there is host factor variability, such as end-organ sensitivity. It has also been proposed that pre-existing, non-specific bronchial hyperreactivity may be Important in development of byssinosis (51), but, to date, there is little evidence for this hypothesis (52- ). 

Prevalence of byssinosis correlates better with airborne endotoxin concentration than with total dust (65). Also, gramnegative bacteria levels in the mill correlate well with disease (66). It has been hypothesized that endotoxins elicit symptoms of byssinosis by activation of both the classical and the alternative pathway of complement with subsequent release of anaphylatoxins, which lead to airway narrowing, and chemotaxins, which cause the influx of PMNs followed by release of lysosomal enzymes and, ultimately, tissue damage. In experiments with guinea pigs using bract, cotton, and gin mill trash extracts, there is a strong correlation between number of PMNs recruited to airways and level of endotoxin (67). 

In vitro studies indicate that cotton mill dust extracts do activate complement by the alternative pathway. Kutz et al. (36) proposed that endotoxin is not the only agent responsible for complement activation, as microgram rather than nanogram quantities of purified endotoxin are required to induce the degree of complement activation observed with crude cotton dust extract. Several investigators (36, 37) have thus proposed endotoxin... 

Recently, other reports have appeared (31). as well as our own studies (32). showing that cotton dust activates the alternate pathway of complement. Previous studies in this laboratory (33.34). showed that antibodies to water extracts of cotton dust, cotton bract, and a highly purified fraction of dust elicited positive immunological responses in rabbits. 

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