A Filarial Nematode-Secreted Phosphorylcholine-Containing Glycoprotein Uncouples the B Cell Antigen Receptor from Extracellular Signal-Regulated Kinase-Mitogen-Activated Protein Kinase by Promoting the Surface Ig-Mediated Recruitment of Src Homology 2 Domain-Containing Tyrosine Phosphatase-1 and Pac-1 Mitogen-Activated Kinase-Phosphatase

Deehan, Maureen R.; Harnett, William; Harnett, Margaret M.

doi:10.4049/jimmunol.166.12.7462

Cited by 41 publications

(35 citation statements)

References 39 publications

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“…11 and results not shown). Use of this mechanism to regulate B cell proliferation is consistent with our previous findings that immunomodulatory products secreted by filarial nematodes can elicit B cell unresponsiveness by priming uncoupling of BCR-Erk-MAP kinase signaling by the MAP kinase phosphatase, Pac-1 (25).…”

Section: Mechanism Of Bcr-mediated Down-regulation Of Cycling Erk-mapsupporting

confidence: 89%

Differential Roles for Extracellularly Regulated Kinase-Mitogen-Activated Protein Kinase in B Cell Antigen Receptor-Induced Apoptosis and CD40-Mediated Rescue of WEHI-231 Immature B Cells

Gauld

Blair

Moss

et al. 2002

The Journal of Immunology

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One of the major unresolved questions in B cell biology is how the B cell Ag receptor (BCR) differentially signals to transduce anergy, apoptosis, proliferation, or differentiation during B cell maturation. We now report that extracellularly regulated kinase-mitogen-activated protein kinase (Erk-MAP kinase) can play dual roles in the regulation of the cell fate of the immature B cell lymphoma, WEHI-231, depending on the kinetics and context of Erk-MAP kinase activation. First, we show that the BCR couples to an early (≤2 h) Erk-MAP kinase signal which activates a phospholipase A2 pathway that we have previously shown to mediate collapse of mitochondrial membrane potential, resulting in depletion of cellular ATP and cathepsin B execution of apoptosis. Rescue of BCR-driven apoptosis by CD40 signaling desensitizes such early extracellularly regulated kinase (Erk) signaling and hence uncouples the BCR from the apoptotic mitochondrial phospholipase A2 pathway. A second role for Erk-MAP kinase in promoting the growth and proliferation of WEHI-231 immature B cells is evidenced by data showing that proliferating and CD40-stimulated WEHI-231 B cells exhibit a sustained cycling pattern (8–48 h) of Erk activation that correlates with cell growth and proliferation. This growth-promoting role for Erk signaling is supported by three key pieces of evidence: 1) signaling via the BCR, under conditions that induce growth arrest, completely abrogates sustained Erk activation; 2) CD40-mediated rescue from growth arrest correlates with restoration of cycling Erk activation; and 3) sustained inhibition of Erk prevents CD40-mediated rescue of BCR-driven growth arrest of WEHI-231 immature B cells. Erk-MAP kinase can therefore induce diverse biological responses in WEHI-231 cells depending on the context and kinetics of activation.

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Section: Mechanism Of Bcr-mediated Down-regulation Of Cycling Erk-mapsupporting

confidence: 89%

Differential Roles for Extracellularly Regulated Kinase-Mitogen-Activated Protein Kinase in B Cell Antigen Receptor-Induced Apoptosis and CD40-Mediated Rescue of WEHI-231 Immature B Cells

Gauld

Blair

Moss

et al. 2002

The Journal of Immunology

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“…5). In our studies, as for other filarial models, no lymphoproliferation could be measured by stimulation with Ad or larval worm extracts (13,20,21,40).…”

Section: Vol 71 2003 Resistance To Murine Filaria Litomosoides Sigmmentioning

confidence: 66%

Resistance and Susceptibility to Filarial InfectionwithLitomosoides sigmodontisAre Associated with EarlyDifferences in Parasite Development and in Localized ImmuneReactions

et al. 2003

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In order to understand natural resistance to filariasis, we compared Litomosoides sigmodontis primary infection of C57BL/6 mice, which eliminate the worms before patency, and BALB/c mice, in which worms complete their development and produce microfilariae. Our analysis over the first month of infection monitored migration of the infective larvae from the lymph nodes to the pleural cavity, where the worms settle. Although immune responses from the mouse strains differed from the outset, the duration of lymphatic migration (4 days) and filarial recovery rates were similar, thus confirming that the proportion of larvae that develop in the host species upon infection is not influenced by host genetic variability. The majority of worms reached the adult stage in both mouse strains; however, worm growth and molting were retarded in resistant C57BL/6 mice. Surprisingly, the only immune responses detected at 60 h postinfection occurred in the susceptible mice and only upon stimulation of cells from lymph nodes draining the inoculation site with infective larva extract: massive production of interleukin-6 (IL-6) and IL-5 (the latter cytokine was previously suspected to have an effect on L. sigmodontis growth). However, between days 10 and 30 postinfection, extraordinarily high levels of type 1 and type 2 cytokines and expansion of pleural leukocyte infiltration were seen in the resistant C57BL/6 mice, explaining the destruction of worms later. Our results suggest that events early in the infection determine susceptibility or resistance to subsequent microfilarial production and a parasite strategy to use specific immune responses to its own benefit.In areas where filariasis is endemic, a small proportion of the population (Ͻ5%) consistently shows neither microfilariae nor pathology. Characterization of the protective mechanisms operating in this putatively immune population is highly desirable and has consequently received great attention (18,23,41,46,47,50). However, experimental investigations or field observations aiming to correlate parasitological, immunological, and genetic factors with resistance in humans are limited for evident ethical reasons. The filaria Litomosoides sigmodontis has proven to be a good murine model (1,8,42), since in various strains of mice it mimics the spectrum of parasitological outcome of human filariasis (42). Recently, genetically modified mice have been employed to rapidly identify key immune components; the absence of Th2 (28, 48, 49) or Th1 (gamma interferon [IFN-␥]) (44) cytokines as well as of B cells and antibodies (2, 35) has been shown to modify L. sigmodontis development or survival, as observed in the nonpermissive Brugia models (6,14,27,43). However, the inherent physiological and immunological artifacts that can occur in deficient mice sometimes limit the interpretation of the results.Two previous studies compared the splenic and antibody responses to L. sigmodontis in genetically intact susceptible BALB/c mice to those in resistant B10D2 (33) or C57BL/6 (28) mice. No clear d...

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“…44). We have previously shown that exposure to ES-62 suppresses subsequent Ag-mediated proliferation of B cells by uncoupling the Ag receptors (B cell receptor) from extracellular signal-regulated kinase/mitogen-activated protein kinase-dependent proliferative signaling (45)(46)(47). Such desensitization of B cell clonal expansion can be mimicked by the PC component of ES-62 (48).…”

Section: Figure 6 Es-62 Inhibits Tnf-␣ Production From Human T Cellsmentioning

confidence: 99%

A Novel Therapeutic Approach Targeting Articular Inflammation Using the Filarial Nematode-Derived Phosphorylcholine-Containing Glycoprotein ES-62

McInnes

Leung

Harnett

et al. 2003

The Journal of Immunology

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193

216

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Understanding modulation of the host immune system by pathogens offers rich therapeutic potential. Parasitic filarial nematodes are often tolerated in human hosts for decades with little evidence of pathology and this appears to reflect parasite-induced suppression of host proinflammatory immune responses. Consistent with this, we have previously described a filarial nematode-derived, secreted phosphorylcholine-containing glycoprotein, ES-62, with immunomodulatory activities that are broadly anti-inflammatory in nature. We sought to evaluate the therapeutic potential of ES-62 in vitro and in vivo in an autoimmune disease model, namely, collagen-induced arthritis in DBA/1 mice. ES-62 given during collagen priming significantly reduced initiation of inflammatory arthritis. Crucially, ES-62 was also found to suppress collagen-induced arthritis severity and progression when administration was delayed until after clinically evident disease onset. Ex vivo analyses revealed that in both cases, the effects were associated with inhibition of collagen-specific pro-inflammatory/Th1 cytokine (TNF-α, IL-6, and IFN-γ) release. In parallel in vitro human tissue studies, ES-62 was found to significantly suppress macrophage activation via cognate interaction with activated T cells. Finally, ES-62 suppressed LPS-induced rheumatoid arthritis synovial TNF-α and IL-6 production. Evolutionary pressure has promoted the generation by pathogens of diverse mechanisms enabling host immune system evasion and induction of “tolerance.” ES-62 represents one such mechanism. We now provide proof of concept that parasite-derived immunomodulatory strategies offer a novel therapeutic opportunity in inflammatory arthritis.

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Cited by 41 publications

References 39 publications

Differential Roles for Extracellularly Regulated Kinase-Mitogen-Activated Protein Kinase in B Cell Antigen Receptor-Induced Apoptosis and CD40-Mediated Rescue of WEHI-231 Immature B Cells

Differential Roles for Extracellularly Regulated Kinase-Mitogen-Activated Protein Kinase in B Cell Antigen Receptor-Induced Apoptosis and CD40-Mediated Rescue of WEHI-231 Immature B Cells

Resistance and Susceptibility to Filarial InfectionwithLitomosoides sigmodontisAre Associated with EarlyDifferences in Parasite Development and in Localized ImmuneReactions

A Novel Therapeutic Approach Targeting Articular Inflammation Using the Filarial Nematode-Derived Phosphorylcholine-Containing Glycoprotein ES-62

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