Rodgers, D. T., McGrath, M. A., Pineda, M. A. , Al-Riyami, L., Rzepecka, J., Lumb, F., Harnett, W. and Harnett, M. M. (2015) The parasitic worm product, ES-62 targets MyD88-dependent effector mechanisms to suppress ANA production and proteinuria in MRL/Lpr mice. Arthritis and Rheumatology, 67(4), pp. 1023-1035. (doi: 10.1002/art.39004) (PMID:25546822) (PMCID:PMC4409857)
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Abstract
Objective. The Hygiene Hypothesis suggests that parasitic helminths (worms) protect against development of autoimmune disease as a serendipitous side-effect of worm-derived immunomodulators that concomitantly promote parasite survival and limit host pathology. We therefore investigated whether ES-62, a phosphorylcholine-containing glycoprotein secreted by the filarial nematode Acanthocheilonema viteae, protects against kidney damage, in the MRL/Lpr mouse model of systemic lupus erythematosus (SLE).<p></p> Methods. MRL/Lpr mice progressively produce high levels of autoantibodies and the resultant deposition of immune-complexes drives kidney pathology. The effects of ES-62 on disease progression were assessed by measurement of proteinuria and kidney histology, as well as by determination of anti-nuclear antibody (ANA) and cytokine levels and flow cytometric analysis of relevant cellular populations.<p></p> Results. ES-62 restores the disrupted effector:regulatory B cell balance in MRL/Lpr mice, acting to inhibit plasmablast differentiation with consequent reduction in ANA production and immune complex and C3a deposition in the kidneys. Moreover, by reducing IL-22 production, ES-62 may desensitise downstream effector mechanisms of kidney pathogenesis. Highlighting the therapeutic importance of resetting B cell responses, adoptive transfer of purified splenic B cells from ES-62-treated MRL/Lpr mice mimics the protection afforded by the helminth product. Mechanistically, this reflects downregulation of MyD88 expression by B cells and also kidney cells, resulting in inhibition of pathogenic crosstalk amongst TLR-, C3a- and immune complex-mediated effector mechanisms.<p></p> Conclusion. This study provides the first demonstration of protection against pathology by a parasitic worm-derived immunomodulator in a model of SLE and suggests therapeutic potential for drugs based on ES-62 mechanism of action. This article is protected by copyright. All rights reserved.<p></p>
| Item Type: | Articles |
|---|---|
| Status: | Published |
| Refereed: | Yes |
| Glasgow Author(s) Enlighten ID: | Harnett, Professor Margaret and Al-Riyami, Dr Lamyaa and Rzepecka, Dr Justyna and McGrath, Miss Mairi and Pineda, Dr Miguel |
| Authors: | Rodgers, D. T., McGrath, M. A., Pineda, M. A., Al-Riyami, L., Rzepecka, J., Lumb, F., Harnett, W., and Harnett, M. M. |
| College/School: | College of Medical Veterinary and Life Sciences > School of Infection & Immunity |
| Journal Name: | Arthritis and Rheumatology |
| Publisher: | Wiley |
| ISSN: | 0004-3591 |
| ISSN (Online): | 2326-5205 |
| Copyright Holders: | Copyright © 2015 The Authors |
| First Published: | First published in Arthritis and Rheumatology 67(4):1023-1035 |
| Publisher Policy: | Reproduced under a Creative Commons License |
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