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

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.

The helminth product, ES-62 modulates dendritic cell responses by inducing the selective autophagolysosomal degradation of TLR-transducers, as exemplified by PKCδ

“…ES-62 exhibits the ability to modulate Th1-, Th17- and Th22-mediated responses, particularly when these phenotypes are dysregulated during development of pathogenesis in mouse models of rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and asthma2456. For example, in the Collagen-Induced Arthritis (CIA) model of RA where Th1/Th17 responses are pathogenic, ES-62 targets DCs to suppress their priming of such aberrant Th and γδ T cells4.…”

“…ES-62 is a PC-containing immunomodulatory glycoprotein that exhibits protective effects in models of allergic and autoimmune disease911 by homeostatically resetting the effector: regulatory B cell balance and consequently modulating the IL-23/IL-17/IL-22 inflammatory axis2345630, dysregulation of which has been implicated in the pathogenesis of chronic inflammatory disorders31. Although the precise cellular networks modulated by the worm product appear to differ depending on the inflammatory context, ES-62 likely affords protection by acting to subvert TLR signalling via partial downregulation of MyD88 expression in effector cells of both innate and adaptive immunity346917.…”

“…Although the precise cellular networks modulated by the worm product appear to differ depending on the inflammatory context, ES-62 likely affords protection by acting to subvert TLR signalling via partial downregulation of MyD88 expression in effector cells of both innate and adaptive immunity346917. The effect of targeting this key integrator of inflammatory signalling is exemplified by the ability of ES-62 to suppress both the priming and maintenance of pathogenic Th17 and IL-17-producing γδ T cells in CIA by targeting MyD88 in both DCs and Th17 cells49.…”

“…We have previously shown that ES-62, a phosphorylcholine (PC)-containing immunomodulatory glycoprotein secreted by the filarial nematode Acanthocheilonema viteae , is protective in mouse models of allergic123 and autoimmune456 disease. Such protection is associated with homeostatic resetting of the IL-23/IL-17/IL-22 inflammatory axis, which appears to become dysregulated in these inflammatory disorders: a key effector driving development of this type of inflammation is the dendritic cell (DC), which ES-62 targets by subverting TLR4 signalling789 to suppress aberrant DC-priming of Th17 cells and IL-17-producing γδ T cells24.…”

The parasitic worm product ES-62 normalises the gut microbiota/bone marrow axis in inflammatory arthritis

“…Amongst the best characterised ES products is ES-62, a phosphorylcholine (PC)-containing glycoprotein secreted by the rodent filarial nematode Acanthocheilonema viteae that we have shown to prevent initiation and progression of pathology in mouse models of certain allergic (asthma, contact dermatitis) and autoimmune (RA, SLE) inflammatory diseases 1,2,[38][39][40][41][42][43] . Collectively, our studies have identified a unifying mechanism of action that allows effective protection irrespective of the inflammatory phenotype: thus, by subverting TLR4 signalling to downregulate aberrant MyD88-responses, ES-62 acts to homeostatically reset the regulatory:effector immune cell balance, primarily to restore levels of IL-10 + regulatory B cells (Bregs) and suppress pathological IL-17-driven inflammation 1,2,[38][39][40][41][42][43][44] . In experimental models of RA and human disease, perturbation of the microbiota has been shown to disrupt the balance of pathogenic Th17 cells and the counter-regulatory Bregs and Tregs that act to homeostatically resolve inflammation 20,[24][25][26] .…”