Diminished Expression and Function of TLR in Lymphatic Filariasis: A Novel Mechanism of Immune Dysregulation

Babu, Subash; Blauvelt, Carla P.; Kumaraswami, V.; Nutman, Thomas B.

doi:10.4049/jimmunol.175.2.1170

Cited by 105 publications

(94 citation statements)

References 35 publications

(33 reference statements)

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“…Some authors have found results similar to our observations, indicating higher expression of TLR2 on PBMCs and enhanced response to the Pam3Cys ligand in Plasmodium falciparum-infected children compared with their uninfected counterparts (28). Still other reports, however, show down-regulation of TLR expression to be an important immune evasion strategy induced by some protozoan parasites (29) and observed in filaria-infected individuals (30). Interestingly, cells from uninfected subjects did not exhibit any alteration of TLR expression, suggesting that the diminished expression of TLR is a consequence of chronic Ag stimulation.…”

Section: Discussionsupporting

confidence: 78%

Helminth Antigens Modulate Immune Responses in Cells from Multiple Sclerosis Patients through TLR2-Dependent Mechanisms

Correale

Farez

2009

The Journal of Immunology

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To better understand the link between parasite infections and the course of multiple sclerosis (MS), we studied the role of TLRs in helminth product recognition by dendritic cells (DCs) and B cells. Baseline expression of TLR2 was significantly higher in infected-MS patients compared with uninfected MS subjects or healthy controls. Moreover, cells exposed to TLR2 agonists or to soluble egg Ag (SEA) from Schistosoma mansoni resulted in significant TLR2 up-regulation. SEA suppressed the LPS-induced DCs production of IL-1β, IL-6, IL-12, and TNF-α and enhanced TGF-β as well as IL-10 production. Similarly, after exposure to SEA, anti-CD40-activated B cells increased IL-10 production. Both processes were MyD88 dependent. In addition, SEA down-regulated the expression of LPS-induced costimulatory molecules on DCs in a MyD88-independent manner. DCs stimulation by SEA and TLR2 agonists induced increasing phosphorylation of the MAPK ERK1/2. Neither stimulus showed an effect on p38 and JNK1/2 phosphorylation, however. Addition of the ERK1/2 inhibitor U0126 was associated with dose-dependent inhibition of IL-10 and reciprocal enhancement of IL-12. Finally, cytokine effects and changes observed in DCs costimulatory molecule expression after SEA exposure were lost when TLR2 expression was silenced. Overall, these findings indicate that helminth molecules exert potent regulatory effects on both DCs and B cells through TLR2 regulation conducted via different signaling pathways. This knowledge could prove critical in developing novel therapeutic approaches for the treatment of autoimmune diseases such as MS.

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Section: Discussionsupporting

confidence: 78%

Helminth Antigens Modulate Immune Responses in Cells from Multiple Sclerosis Patients through TLR2-Dependent Mechanisms

Correale

Farez

2009

The Journal of Immunology

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“…In fact, monocyte dysfunction in filarial infection is one of several mechanisms proposed to explain parasite antigen-specific T cell hyporesponsiveness seen with patent lymphatic filariasis (19). It has previously been demonstrated that monocytes from filaria-infected individuals are studded with internalized filarial antigens, have diminished expression of genes involved in antigen presentation and processing, and produce fewer proinflammatory cytokines in response to surface receptor cross-linking (19,20).…”

mentioning

confidence: 99%

Human Monocyte Subsets at Homeostasis and Their Perturbation in Numbers and Function in Filarial Infection

et al. 2014

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To characterize the function and plasticity of the major human circulating monocyte populations and to explore their role in systemic helminth infection, highly purified (by flow-based sorting) human monocyte subsets [nonclassical]) were examined at homeostasis and after activation. Among these three subsets the classical and intermediate subsets were found to be the major sources of inflammatory and regulatory cytokines, as well as cytokines/chemokines associated with alternative activation, whereas the nonclassical and classical populations demonstrated an ability to transmigrate through endothelial monolayers. Moreover, it was primarily the classical subset that was the most efficient in promoting autologous T cell proliferation. The distribution of these subsets changed in the context of a systemic helminth (Wuchereria bancrofti) infection such that patent infection altered the frequency and distribution of these monocyte subsets with the nonclassical monocytes being expanded (almost 2-fold) in filarial infection. To understand further the filarial/monocyte interface, in vitro modeling demonstrated that the classical subset internalized filarial antigens more efficiently than the other two subsets but that the parasite-driven regulatory cytokine interleukin-10 was exclusively coming from the intermediate subset. Our data suggest that monocyte subsets have a differential function at homeostasis and in response to helminth parasites.

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“…Most recently, defective monocyte responses toward TLR ligands have been described in filariasis patients (8), highlighting a novel form of filarial-driven immune dysregulation with important implications for the readiness of the innate immune system to respond appropriately toward pathogens, vaccines, or allergens. Effective regulation of innate inflammation is important to prevent collateral damage to host tissues and chronic inflammatory disease.…”

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confidence: 99%

Wolbachia Endosymbiotic Bacteria of Brugia malayi Mediate Macrophage Tolerance to TLR- and CD40-Specific Stimuli in a MyD88/TLR2-Dependent Manner

Turner

Langley

Johnston

et al. 2006

The Journal of Immunology

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Lymphatic filarial nematodes are able to down-regulate parasite-specific and nonspecific responses of lymphocytes and APC. Lymphatic filariae are reliant on Wolbachia endosymbiotic bacteria for development and survival. We tested the hypothesis that repeated exposure to Wolbachia endosymbionts would drive macrophage tolerance in vitro and in vivo. We pre-exposed murine peritoneal-elicited macrophages to soluble extracts of Brugia malayi female worms (BMFE) before restimulating with BMFE or TLR agonists. BMFE tolerized macrophages (in terms of IFN-β, IL-1β, IL-6, IL-12p40, and TNF-α inflammatory cytokine production) in a dose-dependent manner toward self, LPS, MyD88-dependent TLR2 or TLR9 ligands (peptidoglycan, triacyl lipopeptide, CpG DNA) and the MyD88-independent/TRIF-dependent TLR3 ligand, polyinosinic-polycytidylic acid. This was accompanied with down-regulation in surface expression of TLR4 and up-regulation of CD14, CD40, and TLR2. BMFE tolerance extended to CD40 activation in vitro and systemic inflammation following lethal challenge in an in vivo model of endotoxin shock. The mechanism of BMFE-mediated macrophage tolerance was dependent on MyD88 and TLR2 but not TLR4. Evidence that desensitization was driven by Wolbachia-specific ligands was determined by use of extracts from Wolbachia-depleted B. malayi, aposymbiotic filarial species, and a cell line stably infected with Wolbachia pipientis. Our data promote a role for Wolbachia in contributing toward the dysregulated and tolerized immunological phenotype that accompanies the majority of human filarial infections.

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Diminished Expression and Function of TLR in Lymphatic Filariasis: A Novel Mechanism of Immune Dysregulation

Cited by 105 publications

References 35 publications

Helminth Antigens Modulate Immune Responses in Cells from Multiple Sclerosis Patients through TLR2-Dependent Mechanisms

Helminth Antigens Modulate Immune Responses in Cells from Multiple Sclerosis Patients through TLR2-Dependent Mechanisms

Human Monocyte Subsets at Homeostasis and Their Perturbation in Numbers and Function in Filarial Infection

Wolbachia Endosymbiotic Bacteria of Brugia malayi Mediate Macrophage Tolerance to TLR- and CD40-Specific Stimuli in a MyD88/TLR2-Dependent Manner

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