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See detailNew concepts in type 2 immunity: Damage-associated signals and Protective IgE
Marichal, Thomas ULg

Scientific conference (2013, November)

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See detailMast cells: potential positive and negative roles in tumor biology.
Marichal, Thomas ULg; Tsai, Mindy; Galli, Stephen J.

in Cancer Immunology Research (2013), 1

Mast cells are immune cells that reside in virtually all vascularized tissues. Upon activation by diverse mechanisms, mast cells can secrete a broad array of biologically active products that either are ... [more ▼]

Mast cells are immune cells that reside in virtually all vascularized tissues. Upon activation by diverse mechanisms, mast cells can secrete a broad array of biologically active products that either are stored in the cytoplasmic granules of the cells (e.g., histamine, heparin, various proteases) or are produced de novo upon cell stimulation (e.g., prostaglandins, leukotrienes, cytokines, chemokines, and growth factors). Mast cells are best known for their effector functions during anaphylaxis and acute IgE-associated allergic reactions, but they also have been implicated in a wide variety of processes that maintain health or contribute to disease. There has been particular interest in the possible roles of mast cells in tumor biology. In vitro studies have shown that mast cells have the potential to influence many aspects of tumor biology, including tumor development, tumor-induced angiogenesis, and tissue remodeling, and the shaping of adaptive immune responses to tumors. Yet, the actual contributions of mast cells to tumor biology in vivo remain controversial. Here, we review some basic features of mast cell biology with a special emphasis on those relevant to their potential roles in tumors. We discuss how using in vivo tumor models in combination with models in which mast cell function can be modulated has implicated mast cells in the regulation of host responses to tumors. Finally, we summarize data from studies of human tumors that suggest either beneficial or detrimental roles for mast cells in tumors. [less ▲]

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See detailResident lung CD11b+Ly6C- dendritic cells are responsible for allergic airway sensitization to house dust mite in mice
Mesnil, Claire ULg; Sabatel, Catherine ULg; Marichal, Thomas ULg et al

in Proceeding of International Congress of Immunology 2013 (2013)

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See detailPLA2G3 promotes mast cell maturation and function.
Starkl, Philipp; Marichal, Thomas ULg; Galli, Stephen J.

in Nature immunology (2013), 14(6), 527-9

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See detailSelective ablation of mast cells or basophils reduces peanut-induced anaphylaxis in mice.
Reber, Laurent L.; Marichal, Thomas ULg; Mukai, Kaori et al

in The Journal of allergy and clinical immunology (2013), 132(4), 881-81-11

BACKGROUND: Studies with c-kit mutant mast cell (MC)-deficient mice and antibody-mediated depletion of basophils suggest that both MCs and basophils can contribute to peanut-induced anaphylaxis (PIA ... [more ▼]

BACKGROUND: Studies with c-kit mutant mast cell (MC)-deficient mice and antibody-mediated depletion of basophils suggest that both MCs and basophils can contribute to peanut-induced anaphylaxis (PIA). However, interpretation of data obtained by using such approaches is complicated because c-kit mutant mice have several phenotypic abnormalities in addition to MC deficiency and because basophil-depleting antibodies can also react with MCs. OBJECTIVE: We analyzed (1) the changes in the features of PIA in mice after the selective and inducible ablation of MCs or basophils and (2) the possible importance of effector cells other than MCs and basophils in the PIA response. METHODS: Wild-type and various mutant mice were orally sensitized with peanut extract and cholera toxin weekly for 4 weeks and challenged intraperitoneally with peanut extract 2 weeks later. RESULTS: Peanut-challenged, MC-deficient Kit(W-sh/W-sh) mice had reduced immediate hypothermia, as well as a late-phase decrease in body temperature that was abrogated by antibody-mediated depletion of neutrophils. Diphtheria toxin-mediated selective depletion of MCs or basophils in Mcpt5-Cre;iDTR and Mcpt8(DTR) mice, respectively, and treatment of wild-type mice with the basophil-depleting antibody Ba103 significantly reduced peanut-induced hypothermia. Non-c-kit mutant MC- and basophil-deficient Cpa3-Cre;Mcl-1(fl/fl) mice had reduced but still significant responses to peanut. CONCLUSION: Inducible and selective ablation of MCs or basophils in non-c-kit mutant mice can significantly reduce PIA, but partial responses to peanut can still be observed in the virtual absence of both cell types. The neutrophilia in Kit(W-sh/W-sh) mice might influence the responses of these mice in this PIA model. [less ▲]

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See detailA Beneficial Role for Immunoglobulin E in Host Defense against Honeybee Venom.
Marichal, Thomas ULg; Starkl, Philipp; Reber, Laurent L. et al

in Immunity (2013), 39(5), 963-75

Allergies are widely considered to be misdirected type 2 immune responses, in which immunoglobulin E (IgE) antibodies are produced against any of a broad range of seemingly harmless antigens. However ... [more ▼]

Allergies are widely considered to be misdirected type 2 immune responses, in which immunoglobulin E (IgE) antibodies are produced against any of a broad range of seemingly harmless antigens. However, components of insect venoms also can sensitize individuals to develop severe IgE-associated allergic reactions, including fatal anaphylaxis, upon subsequent venom exposure. We found that mice injected with amounts of honeybee venom similar to that which could be delivered in one or two stings developed a specific type 2 immune response that increased their resistance to subsequent challenge with potentially lethal amounts of the venom. Our data indicate that IgE antibodies and the high affinity IgE receptor, FcepsilonRI, were essential for such acquired resistance to honeybee venom. The evidence that IgE-dependent immune responses against venom can enhance survival in mice supports the hypothesis that IgE, which also contributes to allergic disorders, has an important function in protection of the host against noxious substances. [less ▲]

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See detailIgE antibodies critically contribute to acquired enhanced resistance to honeybee venom in mice
Marichal, Thomas ULg; Starkl, Philipp; Reber, Laurent L. et al

Conference (2012, September)

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See detailKeratinocyte-restricted RabGEF-1 expression is a key regulator of skin homeostasis in vivo
Marichal, Thomas ULg; Reber, Laurent; Tam, See Ying et al

in Proceedings of Stanford Pathology Retreat (2012, June)

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See detailRelease and Innate detection of host cell DNA mediates the adjuvant effects of aluminum salts on adaptive responses
Marichal, Thomas ULg; Ohata, Keichii; Bedoret, Denis et al

in Proceedings of the 1St Winter School Immunology (2012, January)

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See detailL'ADN du soi, allie du systeme immunitaire pour la fonction adjuvante de l'alun
Marichal, Thomas ULg; Bureau, Fabrice ULg; Desmet, Christophe ULg

in Medecine Sciences : M/S (2012), 28(1), 31-3

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See detailResident CD11b(+)Ly6C(-) Lung Dendritic Cells Are Responsible for Allergic Airway Sensitization to House Dust Mite in Mice.
Mesnil, Claire ULg; Sabatel, Catherine ULg; Marichal, Thomas ULg et al

in PLoS ONE (2012), 7(12), 53242

Conventional dendritic cells (DCs) are considered to be the prime initiators of airway allergy. Yet, it remains unclear whether specific DC subsets are preferentially involved in allergic airway ... [more ▼]

Conventional dendritic cells (DCs) are considered to be the prime initiators of airway allergy. Yet, it remains unclear whether specific DC subsets are preferentially involved in allergic airway sensitization. Here, we systematically assessed the respective pro-allergic potential of individually sorted lung DC subsets isolated from house dust mite antigen (HDM)-treated donor mice, following transfer to naive recipients. Transfer of lung CD11c(+)CD11b(+) DCs, but not CD11c(+)CD11b(-)CD103(+) DCs, was sufficient to prime airway allergy. The CD11c(+)CD11b(+) DC subpopulation was composed of CD11c(+)CD11b(+)Ly6C(+) inflammatory monocyte-derived cells, whose numbers increase in the lungs following HDM exposure, and of CD11c(+)CD11b(+)Ly6C(-) DCs, which remain stable. Counterintuitively, only CD11c(+)CD11b(+)Ly6C(-) DCs, and not CD11c(+)CD11b(+)Ly6C(+) DCs, were able to convey antigen to the lymph nodes and induce adaptive T cell responses and subsequent airway allergy. Our results thus support that lung resident non-inflammatory CD11c(+)CD11b(+)Ly6C(-) DCs are the essential inducers of allergic airway sensitization to the common aeroallergen HDM in mice. [less ▲]

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See detailNew models for analyzing mast cell functions in vivo.
Marichal, Thomas ULg; Reber, Laurent L; Galli, Stephen J.

in Trends in Immunology (2012), 33(12), 613-25

In addition to their well-accepted role as critical effector cells in anaphylaxis and other acute IgE-mediated allergic reactions, mast cells (MCs) have been implicated in a wide variety of processes that ... [more ▼]

In addition to their well-accepted role as critical effector cells in anaphylaxis and other acute IgE-mediated allergic reactions, mast cells (MCs) have been implicated in a wide variety of processes that contribute to disease or help to maintain health. Although some of these roles were first suggested by analyses of MC products or functions in vitro, it is critical to determine whether, and under which circumstances, such potential roles actually can be performed by MCs in vivo. This review discusses recent advances in the development and analysis of mouse models to investigate the roles of MCs and MC-associated products during biological responses in vivo, and comments on some of the similarities and differences in the results obtained with these newer versus older models of MC deficiency. [less ▲]

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See detailDNA released from dying host cells mediates aluminum adjuvant activity
Marichal, Thomas ULg; Ohata, Keiichi; Bedoret, Denis et al

in Nature Medicine (2011), 17

Aluminum-based adjuvants (alum) are widely used in human vaccination, although little is understood of their mechanisms of action. Here, we report that, in mice, alum causes the release of host cell DNA ... [more ▼]

Aluminum-based adjuvants (alum) are widely used in human vaccination, although little is understood of their mechanisms of action. Here, we report that, in mice, alum causes the release of host cell DNA, which acts as a potent endogenous immunostimulatory signal mediating alum adjuvant activity. Furthermore, we propose that host DNA signaling differentially regulates IgE and IgG1 production upon alum immunization. Indeed, we support that host DNA induces primary B cell responses, including IgG1 production, through Interferon Response Factor (Irf) 3-independent mechanisms, and 'canonical' type 2 T cell responses associated with IgE isotype switching and peripheral effector responses through Irf3-dependent mechanisms. The finding that host cell DNA is a damage-associated molecular pattern relaying alum adjuvant activity may thus help in the comprehension of the mechanisms of action of current vaccines and in the design of novel adjuvants. [less ▲]

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See detailRole de l'ADN endogène et d'Interferon Response Factor-3 dans l'induction des réponses immunitaires médiées par les lymphocytes T auxiliaires de type 2.
Marichal, Thomas ULg

Doctoral thesis (2011)

Adaptative type 2 helper T cell (Th2) responses represent an important component of adaptative immunity and are implicated in various (patho)physiological processes such as allergic diseases, host defense ... [more ▼]

Adaptative type 2 helper T cell (Th2) responses represent an important component of adaptative immunity and are implicated in various (patho)physiological processes such as allergic diseases, host defense against helminths and artificially adjuvanted vaccination. Induction of adaptative T responses occurs with the help of innate immune cells, especially dendritic cells (DCs). These DCs make the link between innate and adaptative immunity by taking up antigens in peripheral tissues, migrating to lymphoïd organs and presenting antigens to T lymphocytes. Direct or indirect activation of these cells depends on the interaction between exogenous or endogenous danger signals and conserved innate immune receptors, mainly represented by Pattern Recognition Receptors (PRRs). Despite the importance of Th2 responses, the innate immune mechanisms leading to their activation remain partially unknown. For this reason, we have been interested in immune mechanisms underlying the induction of Th2 responses in two major Th2-dependent immunological processes : airway allergy and vaccination with aluminium hydroxides (alum). Airway allergy, of which the most severe manifestation is allergic ashma, is a constantly increasing disease in developped countries. It appears clearly that the stimulation of PRRs by allergens or immunostimulatory molecules plays a key role in the pathophysiology of airway allergy. In addition, PRRs transduce the signal though a limited number of signaling pathways and the role of Interferon Response Factor (IRF)-3 and IRF-7, two important transcription factors downstream of various PRRs, in the pathogenesis of allergic asthma, remains unknown. Therefore, we have investigated their potentiel implication in this disease. We have discovered that IRF-3, but not IRF-7, plays an essential role in allergic airway sensitization against house dust mite antigens, the main allergen source in humans. We have further demonstrated that IRF-3 was intrinsically required in lung DCs for their proallergic function. The IRF-3-dependent effects were independent of type I interferons, the main target genes of IRF-3. Alum is the most widely used artificial adjuvant in human and animal vaccination. Yet, little is known about its mechanism of action, in particular regarding the nature of signals and signaling pathways promoting Th2 responses. We have postulated that alum, like any other efficient adjuvant, must be expected to stimulate innate immunity. On one hand, alum does not contain any molecular pattern that is recognized by PRRs and, on the other hand, alum is known to be cytotoxic. Therefore, we hypothetised that alum-induced endogenous danger signals could play a role in its adjuvant activity. Here, we report that alum induces cell death and subsequent DNA release. This DNA acts as a endogenous immunostimulatory signal relaying alum adjuvant activity on adaptative responses. Furthermore, we propose that host DNA differentially regulates IgG1 and IgE production following alum immunization. Indeed, an IRF-3-dependent DNA signaling pathway plays a role in the activation of inflammatory DCs, the subsequent induction of Th2 response and IgE isotype switching, whereas DNA also induces IgG1 production through IRF-3- independent mechanisms. The finding that host cell endogenous DNA is a damageassociated molecular pattern relaying alum adjuvant activity may thus help in the comprehension of the mechanisms of action of current vaccines and in the design of novel adjuvants. In conclusion, this work has identified a previously unappreciated role for IRF-3, a transcription factor downstream of various PRRs primarily implicated in antiviral responses, in two Th2-dependent immunological processes: allergic asthma and alum-based vaccination. In these models, we have shown that IRF-3 was intrinsically required in professional antigen presenting cells, namely DCs, in order to activate them, a precondition for the priming of adaptative Th2 responses. In addition, we also discovered that host DNA released upon alum treatment acts as an endogenous danger signal mediating the adjuvant activity of alum. [less ▲]

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See detailInterferon Response Factor-3 is essential for house dust mite-induced airway allergy
Marichal, Thomas ULg; Bedoret Denis; Mesnil Claire et al

in Proceedings of the Belgian Thoracic Society Annual Meeting (2011, May 23)

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See detailInterferon Response Factor 3 is essential for house dust mite-induced airway allergy
Marichal, Thomas ULg; Bedoret, Denis; Mesnil, Claire et al

Conference (2011, May)

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See detailIRF3 is essential for house dust mite-induced airway allergy in mice
Marichal, Thomas ULg; Bedoret, Denis; Mesnil, Claire ULg et al

in Proceedings GIGA-Day 2011 (2011, May)

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See detailSirtuin 1 Promotes Th2 Responses and Airway Allergy by Repressing Peroxisome Proliferator-Activated Receptor-γ Activity in Dendritic Cells
Legutko, Agnieszka; Marichal, Thomas ULg; Fievez, Laurence ULg et al

in Journal of Immunology (2011), 187(9), 4517-4529

Sirtuins are a unique class of NAD+-dependent deacetylases that regulate diverse biological functions such as aging, metabolism, and stress resistance. Recently, it has been shown that sirtuins may have ... [more ▼]

Sirtuins are a unique class of NAD+-dependent deacetylases that regulate diverse biological functions such as aging, metabolism, and stress resistance. Recently, it has been shown that sirtuins may have anti-inflammatory activities by inhibiting proinflammatory transcription factors such as NF-κB. In contrast, we report in this study that pharmacological inhibition of sirtuins dampens adaptive Th2 responses and subsequent allergic inflammation by interfering with lung dendritic cell (DC) function in a mouse model of airway allergy. Using genetic engineering, we demonstrate that sirtuin 1 represses the activity of the nuclear receptor peroxisome proliferator-activated receptor-γ in DCs, thereby favoring their maturation toward a pro-Th2 phenotype. This study reveals a previously unappreciated function of sirtuin 1 in the regulation of DC function and Th2 responses, thus shedding new light on our current knowledge on the regulation of inflammatory processes by sirtuins. [less ▲]

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