Activators of the classical pathway

The classical pathway is activated, via Clq or MBL, by a wide range of materials. Both Clq and MBL mediate antibody-dependent and nonantibody-dependent activation. These are summarized in Table 1. For Clq, activators include immune complexes containing IgG or IgM, or in vitro, aggregated IgG. Human subclasses IgG3 and IgGl are more efficient activators than IgG2 and IgG4. Interaction with IgG is via the C.;2 domain, and protein engineering studies by Winter and Duncan indicate that charged residues Glu318, Lys320 and Lys322 in IgG are of major importance in Clq binding. In IgM, the C,^ domain is implicated in Clq binding. MBL binds to glycosylation variants of IgG (IgG

lacking terminal galactose residues on the Fc oligosaccharides), and activates complement. MBL also interacts with high-mannose oligosaccharides on IgM, although it is not known whether this interaction does lead to complement activation.

A wide range of gram-negative bacteria have been reported to bind Clq directly, and activate CI, without need for antibody. Mycoplasma species may also activate CI, as do some viruses, including Epstein-Barr virus and Rauscher leukemia virus, and some parasites, such as Entamoeba. Many bacteria, viruses and single-cell or multicellular parasites activate complement without need for antibody: alternative pathway activation is the commoner mechanism, but in many cases the contribution of the classical pathway has not been fully studied. Yeasts activate the classical pathway via MBL, as weil as activating the alternative pathway. MBL also binds to saccharides on a wide range of bacteria, viruses and fungi, but complement activation via MBL has not generally been examined in these sytems.

Tissue-damage products, such as mitochondrial and other subcellular membranes, cytoplasmic filaments, polynucleotides and components of myelin have also been reported to activate CI. The acute phase protein CRP (C-reactive protein), when bound to phosphorylcholine-containing phospholipids, binds and activates CI. Since C1q recognizes a very wide range of targets, mostly via its globular heads,

Table 1 Classical pathway activators

The classical pathway is mainly involved in recognizing charge groupings. This is the case for C1q and CRP, but not for MBL

which recognizes neutral sugars. Charges may be on proteins, like IgG, or on complex charged carbohydrates found on surfaces of microorganisms, or on nucleic acid-protein complexes, or on lipids and glycolipids. Sialic acid on cell surfaces tends to promote activation of the classical pathway, but to inhibit activation of the alternative pathway.

Classical pathway activation occurs via:

C1q: C1q binds to:

Fc portions of antigen-fixed IgG and IgM

Nucleic acid and chromatin

Cytoplasmic intermediate filaments (vimentin-type)

Mitochondrial membranes possibly via cardiolipin or via mitochondrial proteins Some viruses, e.g. MuLV

Gram-positive bacteria, e.g. some pneumococci, streptococci, via capsular polysaccharide (neuraminidase treatment reduces activating capacity) Gram-negative bacteria via the lipid A component of the lipopolysaccharide of the cell wall

CRP + C1q: CRP (C-reactive protein) recognizes phosphate groups in choline phosphate of pneumococcal C-type polysaccharide, and also binds to phosphocholine (PC)-containing and non-PC-containing microbial polysaccharides and lipids, polyanion/polycation complexes, and chromatin. It is also reported to bind to galactans. Bound CRP interacts with C1q, and activates the classical pathway

Mannose-binding lectin (MBL): MBL binds to high mannose and other polysaccharides and oligosaccharides on yeasts.

bacteria and viruses, and activates the classical pathway. It also binds to carbohydrate on glycosylation variants of IgG (IgG-Go), MBL probably acts, in vivo, via the proteases known as MASPs, but in vitro it can act via C1r and C1s. RaRF, formerly reported as being a specific factor mediating classical pathway activation by Salmonella Ra polysaccharide, is the same as MBL.

it is likely that the three homologous 'lobes' of each head have different binding specificities, but this has not yet been proved.

The quantitative significance of complement activation via MBL is not yet clear. MBL and the MASPs are at very low concentration in plasma relative to Clq, Clr and Cls (see Table 2).

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