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AG Lochnit - Phosphorylcholin as an immunmodulatory component

PC has been recognized as a structural component in both prokaryotic and eukaryotic pathogens. First detected in the Gram-positive bacterium Streptococcus pneumoniae in 1967 (1); it was later found in both Gram-negative bacteria and many important disease-causing parasites, such as, protozoa (2,3), and gastrointestinal (4,5) and filarial nematodes (for reviews see (6,7)). It was further found in the cestode Bothriocephalus scorpii (8) and trematode Schistosoma mansoni (5). PC can be attached to teichoic acid (9), lipoteichoic acid (10), lipopolysaccharide (11), glycolipids and glycoproteins (12). Work on PC-epitope bearing bacteria, however, has shown, that this modification can act as a double-edged sword, facilitating colonization and invasiveness but also being a target for innate and adaptive immune responses (7,11,13-15).

An immunosuppressive activity of PC-antigens was first reported from Trichinella spiralis in infected mice during the muscle phase of the life cycle (16-21). Immunolocalization studies revealed the presence of these epitopes in different internal structures (22-25). The PC-moieties are attached via complex-type N-glycans to antennae predominantly comprised of lacdiNAc (GalNAcß1-4GlcNAc) (26,27) (see Fig. 1). Somatic antigen-bound PC-epitopes were also found in Brugia (28) in addition to those on the circulating filarial antigen. These antigens were found to suppress the T cell proliferative response towards phytohemagglutinin in a dose-dependent manner (29). There is evidence for N- and O-glycan linked PC-epitopes in these parasites (30,31). Similar results have also been reported for O. gibsoni excretory-secretory (ES) products (32). The N-glycan structures of O. volvulus and O. gibsoni containing PC resemble those from A. viteae (33) (see Fig. 1). The first mass-spectrometrical localization of a PC-epitope linked via an N-glyan was performed by Haslam et al. (34) for C. elegans. It could be demonstrated, that PC is linked - similarly as for the glycosphingolipid-based epitope - to C6 of GlcNAc, substituting a trimannosyl fucosylated core structure (Fig. 1). A second, but different PC-epitope from C. elegans was published by Cipollo et al., postulating a PC-substituted Man5-structure (Fig. 5) (35). A PC-substituted ES product has also been described for Wuchereria bancrofti (36). Likewise, PC-epitopes were reported for Dictyocaulus viviparus (37), N. brasiliensis (38,39) and A. suum (40).

Most of our current knowledge on the biological implications of PC-substituted proteins results from investigations on ES-62, a secretory product from the filariid A. viteae (41-43). This glycoprotein of tetrameric structure (44) revealed homology to aminopeptidases (45,46). Sensitivity towards N-glycosidase F treatment indicated the presence of PC-substituted N-glycans (47,48) on ES-62. Mass spectrometric analysis revealed partially fucosylated trimannosyl core structures, carrying between one and four additional N-acetylglucosamine residues substituted with PC (49) (see Fig. 1). Further PC-epitopes have been found in the egg, and on uterine and intestinal membranes of A. viteae (50,51). ES-62 was found to be stage-specifically expressed and secreted in the post-L3 stages, whilst mRNA was also found in L1 and L3 stages (52).

Filariasis is characterized by a suppressed, anti-inflammatory T-helper (Th2) type of immune response with reduced IFN-g, increased IL-10 and greatly elevated IgG4 antibody levels (53). There was early evidence, that PC might be this immunomodulatory component (54). Later it was found, that ES-62 at concentrations found in filariasis patients indeed prevented proliferation of B lymphocytes, beeing associated with ligation to the B-cell receptor (BCR) (55), in a PC-dependent manner by anergizing B cells (56), whereas at high concentrations an activation was observed. Similar suppressive effects were also found for T cells (56,57).

The interference with proliferation of B cells, however, resulted in the activation of several tyrosine kinases like Lyn, Syk and Blk, and Erk2, an isoform of MAPkinase, and modulation of PKC isoform expression (55,58,59). Desensitization further resulted in a failure to activate the phosphoinositide 3-kinase (PI-3-kinase) and Ras-MAPK pathways via the BCR (58). Anergy of T cells was found to be associated with disruption of TCR coupling to the phospholipase D, PKC, PI-3-kinase and RasMAPK signalling cascades (56,57). Later, it was found that ES-62 induces the activation of two negative regulatory molecules, the tyrosine phosphatase SHP-1 and the MAPkinase phosphatase PAC-1, which dephosphorylate the immunoreceptor tyrosine-based activation motifs (ITAMS) on Ig-ß, thus preventing the recruitment of other signalling molecules, and MAPkinase (see Fig. 2) (60). Until now, it remains unclear, however, whether PC acts on the cell surface or after internalization.

In addition to the biological activities outlined above, ES-62 has further effects on antibody and cytokine responses. It induces a Th2 antibody response as indicated by the production of IgG1 antibodies (56) in an IL-4-dependent manner (61). This shift towards a Th2 response might be due to the induction of IL-10 by ES-62 (56). IL-10 downregulates IFN-g, a cytokine necessary for antibody-class switching to IgG2a, an antibody characteristic for Th1 responses. In macrophages, it suppresses the production of IL-12, a key cytokine in the development of Th1 responses, and that of the proinflammatory cytokines TNF-a and IL-6 (62). Investigations on the effects of ES-62 on dendritic cells revealed an induction of maturation of dendritic cells with the capacity to induce a Th2 response (63).


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