Mast Cells Regulate the Magnitude and the Cytokine Microenvironment of the Contact Hypersensitivity Response

Norman, M. Ursula; Hwang, John M.; Hulliger, Sara; Bonder, Claudine S.; Yamanouchi, Jun; Santamaría, Pere; Kubes, Paul

doi:10.2353/ajpath.2008.070559

Cited by 45 publications

(41 citation statements)

References 40 publications

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“…Although some accumulation of mast cells was observed on challenge of the footpad, cell recruitment was irrespective of antigen presence or selectin-ligand expression (unpublished data). A recent study by Norman and colleagues 40 showed that the presence of mast cells affects the differentiation of T cells in a contact hypersensitivity reaction. Considering the missing effect of mast cells in our model that relies on the in vitro differentiation of Th1 cells the Ϫ/Ϫ ϫ DO11.10 mice were transferred into WT and FucT-VII Ϫ/Ϫ mice, respectively.…”

Section: Cellular Players In a Dthmentioning

confidence: 99%

Cellular Players and Role of Selectin Ligands in Leukocyte Recruitment in a T-Cell-Initiated Delayed-Type Hypersensitivity Reaction

Doebis

Siegmund

Loddenkemper

et al. 2008

The American Journal of Pathology

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Delayed-type hypersensitivity (DTH) reactions are characterized by a strong cellular infiltrate , including neutrophils , macrophages , and T lymphocytes. In all these cell types , both E-and P-selectin-dependent adhesion pathways play a significant role in recruitment into the inflamed skin. Accordingly , inhibition of selectin-mediated interactions (eg, by antibodies) results in impairment of acute DTH reactions. However, whether inhibition of a specific cell type is responsible for the anti-inflammatory effect or whether all leukocytes are affected remains unclear. To address this question, we used fucosyltransferase-VII knockout mice that lack functional selectin ligands as either donors or recipients in a DTH model elicited by Th1 cell and antigen transfer. We found that selectin-mediated adhesion is required by Th1 effector cells to enter the DTH reaction site and , additionally , to elicit the DTH reaction. On the other hand , elimination of selectin binding in the recipient's neutrophils and macrophages by use of fucosyltransferase-deficient mice receiving wild-type Th1 effector cells resulted in a strongly reduced infiltration of neutrophils and macrophages but unimpaired footpad swelling. These findings demonstrate a major role for both E-and P-selectin in the recruitment of different leukocyte cell types. However, only the presence of selectin ligands on T cells was critical for the inflammatory reaction. These findings reveal T cells as the predominant targets for selectin blockade that aim to suppress skin

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Section: Cellular Players In a Dthmentioning

confidence: 99%

Cellular Players and Role of Selectin Ligands in Leukocyte Recruitment in a T-Cell-Initiated Delayed-Type Hypersensitivity Reaction

Doebis

Siegmund

Loddenkemper

et al. 2008

The American Journal of Pathology

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“…28,29 As TNCB-induced CHSRs thus share most of the mechanisms characterized for conventional DTHRs, we studied the role of TNFR1 in response to TNCB, using the TNCB-induced CHSR as a model for the DTHR that provides the unique possibility to individually investigate antigen presentation, priming, and differentiation of CD4 and CD8 T cells, cell migration, T cell-mast cell interactions, and mast cell-endothelia interactions with the help of mast cell knock-in experiments. 20,27,[30][31][32] Importantly, it allows the study of these effects largely independently of phenomena, such as antigen processing by APCs. Here, we show that TNFR1 signaling is neither needed for in vivo priming nor for the induction of Th1 cells capable of inducing severe DTHRs.…”

mentioning

confidence: 99%

“…In contrast to DTHR induced by TNCB, IL-4 seems to play a role in the generation of DTHR induced by Oxazolon. 24,26,27 A third frequently used hapten is dinitroflourobenzene (DNFB). DNFB exerts the strongest toxic reactions.…”

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confidence: 99%

Direct crosstalk between mast cell–TNF and TNFR1-expressing endothelia mediates local tissue inflammation

Kneilling

Mailhammer

Hültner

et al. 2009

Blood

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Signaling through tumor necrosis factor receptor 1 (TNFR1) controls bacterial infections and the induction of inflammatory Th1 cell-mediated autoimmune diseases. By dissecting Th1 cell-mediated delayed-type hypersensitivity responses (DTHRs) into single steps, we localized a central defect to the missing TNFR1 expression by endothelial cells (ECs). Adoptive transfer and mast cell knockin experiments into Kit(W)/Kit(W-v), TNF(-/-), and TNFR1(-/-) mice showed that the signaling defect exclusively affects mast cell-EC interactions but not T cells or antigen-presenting cells. As a consequence, TNFR1(-/-) mice had strongly reduced mRNA and protein expression of P-selectin, E-selectin, ICAM-1, and VCAM-1 during DTHR elicitation. In consequence, intravital fluorescence microscopy revealed up to 80% reduction of leukocyte rolling and firm adhesion in TNFR1(-/-) mice. As substitution of TNF(-/-) mice with TNF-producing mast cells fully restored DTHR in these mice, signaling of mast cell-derived TNF through TNFR1-expressing ECs is essential for the recruitment of leukocytes into sites of inflammation.

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“…Indeed, at least in the Kit W/W-v model, it has been shown that the doses of adjuvant or peptide in immunization protocols can drastically affect MC involvement in the disease under investigation, as emerged in experimental models of asthma 23 and contact hypersensitivity. 24 The aim of our study was to unravel the contribution of MCs to EAE in both Kit W-sh/W-sh and Kit W/W-v strains by using different protocols of immunization, in order to evaluate if disease outcome was affected by different experimental settings. In this study, we report that, under three different immunization conditions, Kit W-sh/W-sh mice develop a more severe EAE and an increased immune response against myelin than Kit þ / þ animals.…”

mentioning

confidence: 99%

Exacerbated experimental autoimmune encephalomyelitis in mast-cell-deficient KitW-sh/W-sh mice

Piconese

Costanza

Musio

et al. 2011

Laboratory Investigation

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Mast cell (MC)-deficient c-Kit mutant Kit W/W-v mice are protected against experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis, suggesting a detrimental role for MCs in this disease. To further investigate the role of MCs in EAE, we took advantage of a recently characterized model of MC deficiency, Kit W-sh/W-sh . Surprisingly, we observed that myelin oligodendrocyte glycoprotein (MOG) 35-55 -induced chronic EAE was exacerbated in Kit W-sh/W-sh compared with Kit þ / þ mice. Kit W-sh/W-sh mice showed more inflammatory foci in the central nervous system (CNS) and increased T-cell response against myelin. To understand whether the discrepant results obtained in Kit W-sh/W-sh and in Kit W/W-v mice were because of the different immunization protocols, we induced EAE in these two strains with varying doses of MOG and adjuvants. Although Kit W-sh/W-sh mice exhibited exacerbated EAE under all immunization protocols, Kit W/W-v mice were protected from EAE only when immunized with high, but not low, doses of antigen and adjuvants. Kit W-sh/W-sh mice reconstituted systemically, but not in the CNS, with bone marrow-derived MCs still developed exacerbated EAE, indicating that protection from disease could be exerted by MCs mainly in the CNS, and/or by other cells possibly dysregulated in Kit W-sh/W-sh mice. In summary, these data suggest to reconsider MC contribution to EAE, taking into account the variables of using different experimental models and immunization protocols. MCs are key factors in IgE-associated immediate hypersensitivity reactions, during which they release a wide spectrum of inflammatory mediators in response to IgE and antigen (Ag) stimulation. 1 However, recent findings have pointed out that MCs may exert also important effector and/or immunomodulatory functions in other physiopathological conditions as venom detoxification, pathogen clearance, tumor growth, contact hypersensitivity, allograft acceptance and autoimmunity. 2 Most of these studies have assessed the in vivo role of MCs by the use of mouse models carrying spontaneous mutations in c-Kit receptor (WBB6F 1 -Kit W/W-v or C57BL/6-Kit W-sh/W-sh mice) or c-Kit ligand (WCB6F 1 -Kitl Sl /Kitl Sl-d ), which show severe deficiency of MC populations. 3,4 MCs may either enhance or suppress the inflammation associated to different types of autoimmune diseases. MC-deficient Kit W/W-v and Kitl Sl/Sl-d mice are protected from autoantibodymediated models of rheumatoid arthritis and bullous pemphigoid, inflammatory disorders affecting, respectively, the joint and the skin. Reconstitution of Kit W/W-v mice with bone marrow derived, in vitro cultured MCs (BMMCs) restores complete disease susceptibility in both conditions, thus indicating a proinflammatory role of these cells in such diseases. 5,6 Conversely, MCs seem to exert a protective function in experimental autoimmune glomerulonephritis, by limiting clinical and histological glomerular pathology and mortality. 7,8 However, recent work has shown that, unlike Kit W/W-v , Ki...

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Mast Cells Regulate the Magnitude and the Cytokine Microenvironment of the Contact Hypersensitivity Response

Cited by 45 publications

References 40 publications

Cellular Players and Role of Selectin Ligands in Leukocyte Recruitment in a T-Cell-Initiated Delayed-Type Hypersensitivity Reaction

Cellular Players and Role of Selectin Ligands in Leukocyte Recruitment in a T-Cell-Initiated Delayed-Type Hypersensitivity Reaction

Direct crosstalk between mast cell–TNF and TNFR1-expressing endothelia mediates local tissue inflammation

Exacerbated experimental autoimmune encephalomyelitis in mast-cell-deficient KitW-sh/W-sh mice

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