Protection against collagen‐induced arthritis in mice afforded by the parasitic worm product, ES‐62, is associated with restoration of the levels of interleukin‐10‐producing B cells and reduced plasma cell infiltration of the joints

Abstract

We have previously reported that ES-62, a molecule secreted by the parasitic filarial nematode Acanthocheilonema viteae, protects mice from developing collagen-induced arthritis (CIA). Together with increasing evidence that worm infection may protect against autoimmune conditions, this raises the possibility that ES-62 may have therapeutic potential in rheumatoid arthritis and hence, it is important to fully understand its mechanism of action. To this end, we have established to date that ES-62 protection in CIA is associated with suppressed T helper type 1 (Th1)/Th17 responses, reduced collagen-specific IgG2a antibodies and increased interleukin-10 (IL-10) production by splenocytes. IL-10-producing regulatory B cells have been proposed to suppress pathogenic Th1/Th17 responses in CIA: interestingly therefore, although the levels of IL-10-producing B cells were decreased in the spleens of mice with CIA, ES-62 was found to restore these to the levels found in naive mice. In addition, exposure to ES-62 decreased effector B-cell, particularly plasma cell, infiltration of the joints, and such infiltrating B cells showed dramatically reduced levels of Toll-like receptor 4 and the activation markers, CD80 and CD86. Collectively, this induction of hyporesponsiveness of effector B-cell responses, in the context of the resetting of the levels of IL-10-producing B cells, is suggestive of a modulation of the balance between effector and regulatory B-cell responses that may contribute to ES-62-mediated suppression of CIA-associated inflammation and inhibition of production of pathogenic collagen-specific IgG2a antibodies.

Ellagic acid alleviates adjuvant induced arthritis by modulation of pro- and anti-inflammatory cytokines

“…In addition, EA acid exhibited a potent anti-inflammatory effect against carrageenan-induced inflammation in rats with an increased IL-10, and a decrease in TNF-α and IL-1β [91]. Recently, different approaches have been used to prevent and/or treat the CIA model in mice by enhancing IL-10 production and suppressing inflammatory cytokines through either oral administration of type II collagen [92], IL-10 gene therapy [93], treatment with ES-62, a molecule secreted by the parasitic filarial nematodes [94], or Salmonella -colonisation factor antigen I (CFA/I) to stimulate Treg cells [95]. Therefore, we suggest that EA alleviates AIA-associated pathology in mice by inhibiting inflammatory cytokines (TNF-α, IL-1β, IL-17) and by stimulating anti-inflammatory cytokine (IL-10) production.…”

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

“…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.…”

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

“…For the identification of plasmablasts and plasma cells, a dump channel (PerCP) identifying CD11c, CD11b, CD4, CD8, F4/80, and Gr‐1 (and CD3, when indicated) markers was used to facilitate exclusion of non‐B CD138+ cells . Intracellular analysis involved staining with APC‐conjugated anti–IL‐6, APC‐conjugated anti–IL‐10 (BioLegend) , or anti‐myeloid differentiation factor 88 (anti‐MyD88) (Abcam) and fluorescein isothiocyanate (FITC)–conjugated goat anti‐rabbit IgG (Vector) . Data were acquired using BD FACSCalibur and BD LSR II flow cytometers (BD Biosciences) and analyzed using FlowJo software (Tree Star) .…”

“…Intracellular analysis involved staining with APC‐conjugated anti–IL‐6, APC‐conjugated anti–IL‐10 (BioLegend) , or anti‐myeloid differentiation factor 88 (anti‐MyD88) (Abcam) and fluorescein isothiocyanate (FITC)–conjugated goat anti‐rabbit IgG (Vector) . Data were acquired using BD FACSCalibur and BD LSR II flow cytometers (BD Biosciences) and analyzed using FlowJo software (Tree Star) . MyD88 expression in the kidney (30 μg/sample) was additionally assessed by Western blotting using anti‐MyD88 (ab2068; Abcam) and densitometric analysis using ImageJ software (National Institutes of Health) .…”