The phosphorycholine moiety of the filarial nematode immunomodulator ES-62 is responsible for its anti-inflammatory action in arthritis

Abstract

Objective: In countries where parasitic infections are endemic, autoimmune disease is relatively rare, leading to the hypothesis that parasite-derived immunomodulators may protect against its development. Consistent with this, we have previously demonstrated that ES-62, a 62 kDa phosphorylcholine (PC)-containing glycoprotein that is secreted by filarial nematodes, can exert antiinflammatory action in the murine collagen-induced arthritis (CIA) model and human rheumatoid arthritisderived synovial tissue cultures. As a first step to developing ES-62-based drugs, the aim of this study was to determine whether the PC-moiety of ES-62 was responsible for its anti-inflammatory actions. Methods: We compared the anti-inflammatory activity of a PC-free form of recombinant ES-62 (rES-62) and a synthetic PC-ovalbumin conjugate (OVA-PC) with that of native ES-62 in the CIA model and synovial tissues from patients with rheumatoid arthritis.

The parasitic helminth product ES‐62 suppresses pathogenesis in collagen‐induced arthritis by targeting the interleukin‐17–producing cellular network at multiple sites

“…However, in areas of the world where helminth infections are endemic, rates of autoimmune diseases such as RA remain low, leading to the hypothesis that certain helminth infections may protect against the development of autoimmunity (1). In support of this theory, we have previously shown that ES-62, a phosphorylcholine-containing glycoprotein secreted by the filarial nematode Acanthocheilonema viteae, has broad immunomodulatory activities and can exert powerful antiinflammatory action in the mouse collagen-induced arthritis (CIA) model of RA (2,3).…”

“…CIA was induced in 8-10-week-old male DBA/1 mice (Harlan Olac) on day 0 by intradermal immunization with bovine type II collagen (MD Biosciences) in Freund's complete adjuvant (CFA). Mice were treated with purified endotoxin-free ES-62 (2 g/dose) or phosphate buffered saline (PBS) subcutaneously on days Ϫ2, 0, and 21 (2,3), and cells were recovered from the joints as previously described (14).…”

“…Originally, it was proposed that the ability of ES-62 to inhibit disease severity in the CIA model reflected the suppression of tumor necrosis factor ␣ (TNF␣) production and associated Th1-mediated inflammation (2,3). However, it has become increasingly clear that Th17, rather than Th1, cells appear to be the pathogenic drivers of inflammation in many autoimmune conditions, including CIA and RA (4).…”

Worms to the rescue: Can worm glycans protect from autoimmune diseases?

“…The effects were associated with decreased TNF-a, IFN-c, and IL-6, and increased IL-10 release. Interestingly, the ES-62-mediated suppression of CIA, as well as the reduction in IFN-c levels, was dependent on a phosphorylcholine (PC) moiety (14), which is linked to N-glycans of this glycoprotein (15).…”

“…Whereas mature DC incubated with LPS induce more IFN-c and less IL-4 than control cells, incubation with ES-62 had the opposite effect. This effect was dependent on the PC moiety since PC coupled to OVA could mimic the effect, whereas recombinant ES-62 had no antiinflammatory effect (14). Furthermore, deglycosylation of extracts from the free-living nematode Caenorhabditis elegans as well as the parasitic nematode Brugia malay (52) reduced the Th2-polarizing capacity of these nematodes compared with the control extracts.…”