Hyporesponsiveness of murine B lymphocytes exposed to the filarial nematode secreted product ES‐62 in vivo

Abstract

SUMMARYES-62 is a phosphorylcholine (PC)-containing glycoprotein secreted by ®larial nematodes, parasites of vertebrates including humans. We have previously demonstrated that pre-exposure to this molecule in vitro interferes with subsequent B-cell receptor (BCR)-dependent activation of murine splenic B lymphocytes. To investigate the signi®cance of this during ®larial nematode infection, we now employ mice exposed to ES-62, at concentrations equivalent to those found for PC-containing molecules in the bloodstream of parasitized humans, via release from implanted osmotic pumps. Using this approach, we reveal that splenic and lymph node mononuclear cells, and also puri®ed splenic B cells recovered from these mice have reduced ability ex vivo to proliferate in response to BCR ligation. The effect on BCR-induced proliferation was further investigated with respect to elucidating the mechanism of action of the parasite product and was shown to be associated with impaired signal transduction affecting the ErkMAPkinase pathway. Also, it was found that ES-62 did not act by promoting apoptosis or by priming for apoptosis following subsequent stimulation, but rather, appeared to render cells hyporesponsive to stimulation. ES-62 is thus shown for the ®rst time to be a potent modulator of B lymphocyte function in vivo at a concentration relevant to natural ®larial nematode infection. This ®nding considerably strengthens the idea that ES-62 plays a role in evasion of the immune response during parasitism.

ES-62, a filarial nematode-derived immunomodulator with anti-inflammatory potential

“…within the range at which PC-containing molecules can be found in the human bloodstream [28], ES-62 does not cause polyclonal stimulation. Rather, it acts to prevent proliferation of B lymphocytes associated with ligation of the antigen receptor [27,29]. The same effect on B lymphocytes was also noted ex vivo following employment of the implanted osmotic pump system referred to in Section 3.2 to release ES-62 to give serum concentrations within the range noted in natural infections [29].…”

Immunomodulation via Novel Use of TLR4 by the Filarial Nematode Phosphorylcholine-Containing Secreted Product, ES-62

“…Using ES-62 from the rodent filarial nematode Acanthocheilonema viteae, we have previously characterized, both in vitro and in vivo, the immunomodulatory properties of this major secreted (ES) product (5)(6)(7)(8)(9)(10)(11)(12). ES products are postulated to be responsible for the immunomodulatory activities of filarial parasites, thereby promoting their survival within mammalian hosts (reviewed in Ref.…”

Expansion of Foxp3+ Regulatory T Cells in Mice Infected with the Filarial Parasite Brugia malayi

“…Hyporesponsiveness can be broken by depletion of the Tregs using anti-CD25 and costimulation of the suppressed Th2 cells using anti-glucocorticoid-induced TNFR or anti-CTLA-4 (25,26). In Acanthocheilonema viteae, another rodent filarial parasite, an excretory/secretory product known as ES-62 has been shown to have down-regulatory effects, including producing a hypoproliferative defect in B and T cells (28,29). Finally, in a parasite closely related to B. malayi (B. pahangi), restimulation of splenocytes from infected mice expanded a population of CD25 worms transplanted into the peritoneal cavity live for 2-3 mo (34), in both cases inducing a highly polarized Th2 response (30,32,35).…”