Abstract
ObjectiveThe hygiene hypothesis suggests that parasitic helminths (worms) protect against the development of autoimmune disease via a serendipitous side effect of worm-derived immunomodulators that concomitantly promote parasite survival and limit host pathology. The aim of this study was to investigate whether ES-62, a phosphorylcholine-containing glycoprotein secreted by the filarial nematode Acanthocheilonema viteae, protects against kidney damage in an MRL/lpr mouse model of systemic lupus erythematosus (SLE).MethodsMRL/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, assessment of kidney histology, determination of antinuclear antibody (ANA) production and cytokine levels, and flow cytometric analysis of relevant cellular populations.ResultsES-62 restored the disrupted balance between effector and regulatory B cells in MRL/lpr mice by inhibiting plasmablast differentiation, with a consequent reduction in ANA production and deposition of immune complexes and C3a in the kidneys. Moreover, by reducing interleukin-22 production, ES-62 may desensitize downstream effector mechanisms in the pathogenesis of kidney disease. Highlighting the therapeutic importance of resetting B cell responses, adoptive transfer of purified splenic B cells from ES-62–treated MRL/lpr mice mimicked the protection afforded by the helminth product. Mechanistically, this reflects down-regulation of myeloid differentiation factor 88 expression by B cells and also kidney cells, resulting in inhibition of pathogenic cross-talk among Toll-like receptor–, C3a-, and immune complex–mediated effector mechanisms.ConclusionThis study provides the first demonstration of protection against kidney pathology by a parasitic worm–derived immunomodulator in a model of SLE and suggests therapeutic potential for drugs based on the mechanism of action of ES-62.
Highlights
The Parasitic Worm Product ES-62 Targets Myeloid Differentiation Factor 88–Dependent Effector Mechanisms to Suppress Antinuclear Antibody Production and Proteinuria in MRL/lpr Mice
This study provides the first demonstration of protection against kidney pathology by a parasitic worm–derived immunomodulator in a model of systemic lupus erythematosus (SLE) and suggests therapeutic potential for drugs based on the mechanism of action of ES-62
Studies in interleukin-23 (IL-23)– deficient mice suggest that the IL-23/IL-17 axis promotes such kidney inflammation [4], and, perhaps reflecting this, expanded populations of Th17- and IL-17– producing CD3ϩCD4ϪCD8Ϫ T cells are observed in the kidneys of both lupus-prone mice and patients with SLE [5]
Summary
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, assessment of kidney histology, determination of antinuclear antibody (ANA). Dr Rodgers’ work was supported by a Wellcome Trust studentship. Lupus-like pathology develops in MRL/Mp mice within 12–18 months, the Fas deficiency in the MRL/Mplpr/lpr (MRL/lpr) strain accelerates disease, with these mice developing (within 4 months) high-titer antinuclear antibodies (ANAs), glomerulonephritis, and arthritis-like footpad inflammation as well as the splenomegaly/lymphadenopathy typical of autoimmune lymphoproliferative syndrome [6,12]. Administered PBS (100 l) was used as a control
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