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Millington, Owain R.; Lorenzo, Caterina Di; Phillips, R. S.; Garside, Paul; Brewer, James M.

doi:10.1186/jbiol34

Cited by 137 publications

(61 citation statements)

References 93 publications

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“…iRBCs inhibited LPS-induced DC maturation even when separated from DCs by a 0.4-m membrane, indicating that the phenomenon is not contact mediated and excluding a role for erythrocyte We observed no inhibition of DCs by iRBC lysate, supporting previous observations in this system (50). Preparations containing the P. falciparum pigment hemozoin have been shown to inhibit LPS-induced DC maturation by others (24,43). However, in the present study, P. falciparum pigment was observed to accumulate in the cytoplasm of DCs cultured with lysate without affecting their response to LPS stimulation.…”

Section: Discussioncontrasting

confidence: 53%

Inhibition of Dendritic Cell Maturation by Malaria Is Dose Dependent and Does Not RequirePlasmodium falciparumErythrocyte Membrane Protein 1

et al. 2007

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Red blood cells infected with Plasmodium falciparum (iRBCs) have been shown to modulate maturation of human monocyte-derived dendritic cells (DCs), interfering with their ability to activate T cells. Interaction between Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) and CD36 expressed by DCs is the proposed mechanism, but we show here that DC modulation does not require CD36 binding, PfEMP1, or contact between DCs and infected RBCs and depends on the iRBC dose. iRBCs expressing a PfEMP1 variant that binds chondroitin sulfate A (CSA) but not CD36 were phagocytosed, inhibited lipopolysaccharide (LPS)-induced phenotypic maturation and cytokine secretion, and abrogated the ability of DCs to stimulate allogeneic T-cell proliferation. CD36-and CSA-binding iRBCs showed comparable inhibition. P. falciparum lines rendered deficient in PfEMP1 expression by targeted gene knockout or knockdown also inhibited LPS-induced phenotypic maturation, and separation of DCs and iRBCs in transwells showed that inhibition was not contact dependent. Inhibition was observed at an iRBC:DC ratio of 100:1 but not at a ratio of 10:1. High doses of iRBCs were associated with apoptosis of DCs, which was not activation induced. Lower doses of iRBCs stimulated DC maturation sufficient to activate autologous T-cell proliferation. In conclusion, modulation of DC maturation by P. falciparum is dose dependent and does not require interaction between PfEMP1 and CD36. Inhibition and apoptosis of DCs by high-dose iRBCs may or may not be physiological. However, our observation that low-dose iRBCs initiate functional DC maturation warrants reevaluation and further investigation of DC interactions with blood-stage P. falciparum.Dendritic cells (DCs) are specialized antigen-presenting cells that regulate both innate and adaptive immune responses and play a critical role in the initiation of primary T-cell responses. To function effectively as antigen-presenting cells, they undergo a process of maturation, characterized by increased expression of costimulator, major histocompatibility complex and adhesion molecules, and secretion of proinflammatory cytokines (reviewed in reference 35). DC maturation is usually activated by pathogens through ligation of pattern recognition receptors, such as Toll-like receptors, but may also be initiated by inflammatory cytokines and endogenous signals of cellular damage (reviewed in references 29 and 34).It has been suggested that modulation of DC function by the malaria parasite Plasmodium falciparum contributes to both the delayed acquisition of antimalarial immunity as well as immunosuppression associated with acute malaria infection. Urban et al. (50,52) showed that red blood cells infected with P. falciparum (iRBCs) at 100 iRBCs per DC inhibit maturation of human monocyte-derived DCs and interfere with their ability to activate T-cell responses. Interaction between the parasite protein P. falciparum erythrocyte membrane protein 1 (PfEMP1), expressed on the surfaces of iRBCs, and the DC scavenger receptor...

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Section: Discussioncontrasting

confidence: 53%

Inhibition of Dendritic Cell Maturation by Malaria Is Dose Dependent and Does Not RequirePlasmodium falciparumErythrocyte Membrane Protein 1

et al. 2007

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“…This mechanism is evident from a report where P. falciparum antigens induced proliferative defects in T cells 108. It was observed that PBMCs from infected people failed to proliferate when stimulated in vitro with malaria antigens, as opposed to marked proliferation that was observed in PBMCs from uninfected people, and in mitogen stimulated PBMCs from infected individuals 109.…”

Section: Mechanisms Of Reduced Inflammation At High Exposure Levelsmentioning

confidence: 94%

“…This immunomodulation of DCs by iRBCs was initially thought to depend on P. falciparum erythrocyte membrane protein (PfEMP)‐1; 110,111 however, ‘stunning’ of DCs was later shown to be PfEMP‐1‐independent 112. Subsequent reports showed a role of hemozoin in the functional impairment of DCs and monocyte/macrophages 108. It was observed that hemozoin‐laden DCs expressed lower levels of the costimulatory molecule CD40, displayed impaired T‐cell stimulation and ultimately formed unstable clusters with T cells, as opposed to normal responses observed in LPS‐stimulated DCs 113.…”

Section: Mechanisms Of Reduced Inflammation At High Exposure Levelsmentioning

confidence: 99%

Evaluating antidisease immunity to malaria and implications for vaccine design

Ademolue

Awandare

2017

Immunology

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SummaryImmunity to malaria could be categorized broadly as antiparasite or antidisease immunity. While most vaccine research efforts have focused on antiparasite immunity, the evidence from endemic populations suggest that antidisease immunity is an important component of natural immunity to malaria. The processes that mediate antidisease immunity have, however, attracted little to no attention, and most interests have been directed towards the antibody responses. This review evaluates the evidence for antidisease immunity in endemic areas and discusses the possible mechanisms responsible for it. Given the key role that inflammation plays in the pathogenesis of malaria, regulation of the inflammatory response appears to be a major mechanism for antidisease immunity in naturally exposed individuals.

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“…Intracellular bacterial infection by Ehrlichia muris inhibited splenic, but not lymph node, NP-specific IgG responses to coadministered NP-CGG secondary to impaired generation of GC responses (12). Finally, infections with Plasmodium chabaudi (13) and foot-and-mouth disease virus (14) have each been shown to suppress OVA-specific IgG responses to soluble OVA. These suppressive effects were associated with an inhibition of DC maturation and a resultant decrease in T-cell stimulatory capacity.…”

Section: Discussionmentioning

confidence: 99%

“…In addition, the expression of innate stimulating moieties (9,10), scavenger receptor ligands (11), and virulence factors by intact pathogens may further influence the immune response to coimmunizing soluble antigens. A number of studies in mice have demonstrated inhibitory effects of infectious agents on antibody responses, including germinal center (GC) reactions to soluble protein antigens (12)(13)(14)(15)(16). Although the underlying mechanisms of these inhibitory effects were not fully clarified, pathogen-mediated inhibition of dendritic cell (DC) maturation and induction of regulatory T cells (Tregs) were implicated, depending upon the specific pathogen.…”

mentioning

confidence: 99%

Immunosuppressive Property within the Streptococcus pneumoniae Cell Wall That Inhibits Generation of T Follicular Helper, Germinal Center, and Plasma Cell Response to a Coimmunized Heterologous Protein

et al. 2013

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We previously demonstrated that intact, inactivated Streptococcus pneumoniae (unencapsulated strain R36A) inhibits IgG responses to a number of coimmunized soluble antigens (Ags). In this study, we investigated the mechanism of this inhibition and whether other extracellular bacteria exhibited similar effects. No inhibition was observed if R36A was given 24 h before or after immunization with soluble chicken ovalbumin (cOVA), indicating that R36A acts transiently during the initiation of the immune response. Using transgenic cOVA-specific CD4؉ T cells, we observed that R36A had no significant effect on T-cell activation (24 h) or generation of regulatory T cells (day 7) and only a modest effect on T-cell proliferation (48 to 96 h) in response to cOVA. However, R36A mediated a significant reduction in the formation of Ag-specific splenic germinal center T follicular helper (GC Tfh) and GC B cells and antibody-secreting cells in the spleen and bone marrow in response to cOVA or cOVA conjugated to 4-hydroxy-3-nitrophenylacetyl hapten (NP-cOVA). Of note, the inhibitory effect of intact R36A on the IgG anti-cOVA response could be reproduced using R36A-derived cell walls. In contrast to R36A, neither inactivated, unencapsulated, intact Neisseria meningitidis nor Streptococcus agalactiae inhibited the OVA-specific IgG response. These results suggest a novel immunosuppressive property within the cell wall of Streptococcus pneumoniae. During the natural course of bacterial infections, the immune system is exposed to both cell-associated and soluble microbial components (1-3). Distinct differences exist in the immunologic properties between particulate and soluble antigens (Ags) (4-8), suggesting the possibility of cross-regulatory processes occurring upon their simultaneous encounter by the immune system. In addition, the expression of innate stimulating moieties (9, 10), scavenger receptor ligands (11), and virulence factors by intact pathogens may further influence the immune response to coimmunizing soluble antigens. A number of studies in mice have demonstrated inhibitory effects of infectious agents on antibody responses, including germinal center (GC) reactions to soluble protein antigens (12-16). Although the underlying mechanisms of these inhibitory effects were not fully clarified, pathogen-mediated inhibition of dendritic cell (DC) maturation and induction of regulatory T cells (Tregs) were implicated, depending upon the specific pathogen. An understanding of the interplay between intact microbes and immune responsiveness to soluble antigens may have implications on processes involving natural immunity, autoimmunity, and vaccination.We previously demonstrated that intact, heat-killed Streptococcus pneumoniae inhibited the protein-and polysaccharide-specific IgG responses to a number of soluble conjugate vaccines, as well as soluble chicken ovalbumin (cOVA), upon coimmunization of mice intraperitoneally (i.p.) in the presence of alum plus CpG-containing oligodeoxynucleotides (CpG-ODN) as an adjuvant (17). In con...

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Untitled

Cited by 137 publications

References 93 publications

Inhibition of Dendritic Cell Maturation by Malaria Is Dose Dependent and Does Not RequirePlasmodium falciparumErythrocyte Membrane Protein 1

Inhibition of Dendritic Cell Maturation by Malaria Is Dose Dependent and Does Not RequirePlasmodium falciparumErythrocyte Membrane Protein 1

Evaluating antidisease immunity to malaria and implications for vaccine design

Immunosuppressive Property within the Streptococcus pneumoniae Cell Wall That Inhibits Generation of T Follicular Helper, Germinal Center, and Plasma Cell Response to a Coimmunized Heterologous Protein

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