Abstract
ES-62 is a protein that is actively secreted by filarial nematodes during parasitism of the vertebrate host. The molecule is able to direcdy interact with a number of cells of the immune system including B-lymphocytes, dendritic cells, macrophages and mast cells. Interaction appears to be dependent on complexing with TLR4 and results in modulation of the activity of a number of signal transduction molecules including MAP kinases, PI-3 kinase and NF-κB. Immunomodulatory activity of ES-62 appears to be largely due to the presence of phosphorylcholine (PC) moieties covalendy attached to N-type glycans. The net effect of ES-62’s interaction with the immune system is the generation of an antiinflammatory immunological phenotype. As a consequence of this, ES-62 demonstrates striking drug-like activity in models of disease associated with aberrant inflammation, in particular those associated with autoimmunity and allergy.
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References
Strachan DP. Hay fever, hygiene and household size. BMJ 1989; 299(6710):1259–1260.
Sewell DL, Reinke EK, Hogan LH et al. Immunoregulation of CNS autoimmunity by helminth and mycobacterial infections. Immunol Lett 2002; 82(1–2):101–110.
Beighton P, Solomon L, Valkenburg HA. Rheumatoid arthritis in a rural south african negro population. Ann Rheum Dis 1975; 34(2):136–141.
Dunne DW, Cooke A. A worms eye view of the immune system: consequences for evolution of human autoimmune disease. Nat Rev Immunol 2005; 5(5):420–426.
Maizels R M. Infections and allergy—helminths, hygiene and host immune regulation. Curr Opin Immunol 2005; 17(6); 656–661.
WHO. Filariasis. Geneva: World Health Organisation, 2000.
Subramanian S, Stolk WA, Ramaiah KD et al. The dynamics of wuchereria bancrofti infection: a model-based analysis of longitudinal data from Pondicherry, India. Parasitology 2004; 128(Pt 5):467–482.
King CL. Transmission intensity and human immune responses to lymphatic filariasis. Parasite Immunol 2001; 23(7):363–371.
Brattig NW Pathogenesis and host responses in human onchocerciasis: impact of onchocerca filariae and wolbachia endobacteria. Microbes Infect 2004; 6(1):113–128.
Harnett W, Grainger M, Kapil A et al. Origin, kinetics of circulation and fate in vivo of the major excretory-secretory product of Acanthocheilonema viteae. Parasitol Today 1989; 99:229–239.
Stepek G, Auchie M, Tate R et al. Expression of the filarial nematode phosphorylcholine-containing glycoprotein, ES62, is stage specific. Parasitology 2002; 125(Pt 2):155–164.
Stepek G, Houston KM, Goodridge HS et al. Stage-specific and species-specific differences in the production of the mRNA and protein for the filarial nematode secreted product, ES-62. Parasitol Today 2004; 128(Pt 1):91–98.
Harnett W, Harnett MM, Byron O. Structural/functional aspects of ES-62—a secreted immunomodulatory phosphorylcholine-containing filarial nematode glycoprotein. Curr Protein Pept Sci 2003; 4(1):59–71.
Harnett W, Houston KM, Tate R et al. Molecular cloning and demonstration of an aminopeptidase activity in a filarial nematode glycoprotein. Mol Biochem Parasitol 1999; 104(1):11–23.
Taylor A. Aminopeptidases: towards a mechanism of action. Trends in Biochemical Sciences 1993; 18(5):167–171.
Acosta D, Goni F, Carmona C. Characterization and partial purification of a leucine aminopeptidase from fasciola hepatica. Journal of Parasitology 1998; 84(1):1–7.
Harnett W, Houston KM, Amess R et al. Acanthocheilonema viteae: phosphorylcholine is attached to the major excretory-secretory product via an N-linked glycan. Exp Parasitol 1993; 77:498–502.
Ackerman CJ, Harnett MM, Harnett W et al. A solution structure of the filarial nematode immunomodulatory protein, ES-62. Biophys J 2003; 84(1):489–500.
Harnett W, Harnett MM. Phosphorylcholine: Friend or foe of the immune system? Immunology Today 1999; 20(3):125–129.
Deehan M, Harnett M, Harnett W. A filarial nematode secreted product differentially modu-lates expression and activation of protein kinase C isoforms in B-lymphocytes. J Immunol 1997; 159(12):6105–6111.
Deehan MR, Frame MJ, Parkhouse RM et al. A phosphorylcholine-containing filarial nematode-secreted product disrupts B-lymphocyte activation by targeting key proliferative signaling pathways. J Immunol 1998; 160(6):2692–2699.
Deehan MR, Harnett W, Harnett MM. A filarial nematode-secreted phosphorylcholine-containing glycoprotein uncouples the B-cell antigen receptor from extracellular signal-regulated kinase-mitogen-activated protein kinase by promoting the surface Ig-mediated recruitment of Src homology 2 domain-containing tyrosine phosphatase-1 and Pac-1 mitogen-activated kinase-phosphatase. Journal of Immunology 2001; 166(12):7462–7468.
Harnett W, Harnett MM. Inhibition of murine B-cell proliferation and down-regulation of protein kinase C levels by a phosphorylcholine-containing filarial excretory-secretory product. J Immunol 1993; 151:4829–4837.
Harnett MM, Deehan MR, Williams DM et al. Induction of signalling anergy via the T-cell receptor in cultured Jurkat T-cells by pre-exposure to a filarial nematode secreted product. Parasite Immunology 1998; 20(11):551–563.
Wilson EH, Katz E, Goodridge HS et al. In vivo activation of murine peritoneal Bl cells by the filarial nematode phosphorylcholine-containing glycoprotein ES-62. Parasite Immunol 2003; 25(8–9):463–466.
Whelan M, Harnett MM, Houston KM et al. A filarial nematode-secreted product signals dendritic cells to acquire a phenotype that drives development of Th2 cells. J Immunol 2000; 164(12):6453–6460.
Goodridge HS, Wilson EH, Harnett W et al. Modulation of macrophage cytokine production by ES-62, a secreted product of the filarial nematode Acanthocheilonema viteae. J Immunol 2001; 167:940–945.
Melendez AJ, Harnett MM, Pushparaj PN et al. Inhibition of FcepsilonRI-mediated mast cell responses by ES-62, a product of parasitic filarial nematodes. Nat Med 2007; 13(11):1375–1381.
Houston KM, Wilson EH, Eyres L et al. Presence of phosphorylcholine on a filarial nematode protein influences immunoglobulin G subclass response to the molecule by an interleukin-10-dependent mechanism. Infect Immun 2000; 68(9):5466–5468.
Marshall FA, Garside P, Harnett W et al. ES-62, an immunomodulator secreted by filarial nematodes suppresses clonal expansion and skews effector function of heterologous antigen-specific T-cells in vivo. J Immunol 2005; 175:5817–5826.
Afzali B, Lombardi G, Lechler RI et al. The role of T helper 17 (Thl7) and regulatory T-cells (Treg) in human organ transplantation and autoimmune disease. Clin Exp Immunol 2007; 148(1):32–46.
Lubberts E. IL-17/Thl7 targeting: on the road to prevent chronic destructive arthritis? Cytokine 2008; 41(2):84–91.
Linden A. Rationale for targeting interleukin 17 in the lungs. Curr Opin Investig Drugs 2003; 4(11):1304–1312.
Goodridge HS, Marshall FA, Else KJ et al. Immunomodulation via novel use of TLR4 by the filarial nematode phosphorylcholine-containing secreted product, ES-62. J Immunol 2005; 174(1):284–293.
Houston K, Wilson EH, Eyres L et al. The presence of phosphorylcholine on a filarial nematode protein influences the IgG subclass response to a molecule and by a mechanism dependent on IL-10. Infect Immunity 2000; 68(9):5466–5468.
Harnett MM, Kean DE, Boitelle A et al. The phosphorycholine moiety of the filarial nematode immunomodulator ES-62 is responsible for its anti-inflammatory action in arthritis. Ann Rheum Dis 2008; 67(4); 518–523.
Goodridge HS, McGuiness S, Houston KM et al. Phosphorylcholine mimics the effects of ES-62 on macrophages and dendritic cells. Parasite Immunol 2007; 29(3):127–137.
Goodridge HS, Deehan MR, Harnett W et al. Subversion of immunological signalling by a filarial nematode phosphorylcholine-containing secreted product. Cell Signal 2005; 17(1):11–16.
Goodridge HS, Stepek G, Harnett W et al. Signalling mechanisms underlying subversion of the immune response by the filarial nematode secreted product ES-62. Immunology 2005; 115(3):296–304.
Ronnelid J, Berg L, Rogberg S et al. Production of T-cell cytokines at the single-cell level in patients with inflammatory arthritides: enhanced activity in synovial fluid compared to blood. Br J Rheumatol 1998; 37(1):7–14.
Chabaud M, Durand JM, Buchs N et al. Human interleukin-17: A T-cell-derived proinflammatory cytokine produced by the rheumatoid synovium. Arthritis Rheum 1999; 42:963–970.
Gracie JA, Forsey RJ, Chan WL et al. A proinflammatory role for IL-18 in rheumatoid arthritis. J Clin Invest 1999; 104(10):1393–1401.
Taylor PC, Williams RO, Maini RN. Immunotherapy for rheumatoid arthritis. Curr Opin Immunol 2001; 13(5):611–616.
Feldmann M, Brennan FM, Maini RN. Role of cytokines in rheumatoid arthritis. Annu Rev Immunol 1996; 14:397–440.
Mclnnes IB, Leung BP, Harnett M et al. A novel therapeutic approach targeting articular inflammation using the filarial nematode-derived phosphorylcholine-containing glycoprotein ES-62. J Immunol 2003; 171(4):2127–2133.
Mclnnes IB, Gracie JA, Harnett M et al. New strategies to control inflammatory synovitis: interleukin 15 and beyond. Ann Rheum Dis 2003; 62(Suppl 2):ii51–54.
Williams RO, Feldmann M, Maini RN. Anti-tumor necrosis factor ameliorates joint disease in murine collagen-induced arthritis. Proc Natl Acad Sci USA 1992; 89(20):9784–9788.
Al-Riyami L, Egan C, Bradley JE et al. Failure of ES-62 to inhibit T-helper Type 1 responses to other filarial nematode antigens. Parasite Immunol 2008; 30(5):304–308.
Houston KM, Harnett W. Structure and synthesis of nematode phosphorylcholine-containing glyco-conjugates. Parasitology 2004; 129(Pt 6):655–661.
Kean DE, Ohtsuka I, Sato K et al. Dissecting ascaris glycosphingolipids for immunomodulatory moieties—the use of synthetic structural glycosphingolipid analogues. Parasite Immunol 2006; 28(3):69–76.
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Harnett, W., Harnett, M.M. (2009). Immunomodulatory Activity and Therapeutic Potential of the Filarial Nematode Secreted Product, ES-62. In: Fallon, P.G. (eds) Pathogen-Derived Immunomodulatory Molecules. Advances in Experimental Medicine and Biology, vol 666. Springer, New York, NY. https://doi.org/10.1007/978-1-4419-1601-3_7
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DOI: https://doi.org/10.1007/978-1-4419-1601-3_7
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