A prominent feature of sensitizing environmental compounds that cause allergic contact dermatitis is the rapid induction of an innate inflammatory response that seems to provide danger signals for efficient T cell priming. We generated mouse models of mast cell deficiency, mast cell-specific gene inactivation, and mast cell reporter mice for intravital imaging and showed that these adjuvant effects of contact allergens are mediated by mast cells and histamine. Mast cell deficiency resulted in impaired emigration of skin DCs to the lymph node and contact hypersensitivity was dramatically reduced in the absence of mast cells. In addition, mast cell-specific inactivation of the Il10 gene did not reveal any role for mast cell-derived IL-10 in the regulation of contact allergy. Collectively, we demonstrate that mast cells are essential promoters of contact hypersensitivity, thereby highlighting their potential to promote immune responses to antigens entering via the skin.
Mast cells are important effectors of type I allergy but also essential regulators of innate and adaptive immune responses. The aim of this study was to develop a Cre recombinase-expressing mouse line that allows mast cell-specific inactivation of genes in vivo. Following a BAC transgenic approach, Cre was expressed under the control of the mast cell protease (Mcpt) 5 promoter. Mcpt5-Cre transgenic mice were crossed to the ROSA26-EYFP Cre excision reporter strain. Efficient Cre-mediated recombination was observed in mast cells from the peritoneal cavity and the skin while only minimal reporter gene expression was detected outside the mast cell compartment. Our results show that the Mcpt5 promoter can drive Cre expression in a mast cell-specific fashion. We expect that our Mcpt5-Cre mice will be a useful tool for the investigation of mast cell biology.
Signaling through the receptor tyrosine kinase kit controls proliferation and differentiation of hematopoietic precursor cells and mast cells. Somatic point mutations of the receptor that constitutively activate kit signaling are associated with mastocytosis and various hematopoietic malignancies. We generated a Cre/loxP-based bacterial artificial chromosome transgenic mouse model that allows conditional expression of a kit gene carrying the kitD814V mutation (the murine homolog of the most common mutation in human mastocytosis, kitD816V) driven by the kit promoter. Expression of the mutant kit in cells of adult mice, including hematopoietic precursors, caused severe mastocytosis with 100% penetrance at young age frequently associated with additional hematopoietic (mostly B lineagederived) neoplasms and focal colitis. Restriction of transgene expression to mature mast cells resulted in a similar mast cell disease developing with slower IntroductionMast cells are best known for their effector function in type I allergic responses 1,2 but were recently shown to be important initiators and effectors also of innate immunity as well as modulators of adaptive immune responses. 3,4 Differentiation and homeostasis of mast cells are dependent on signaling through the transmembrane receptor tyrosine kinase kit, the receptor for stem cell factor (SCF). 5,6 In addition, mast cell migration and several proinflammatory mast cell functions are regulated by SCF-kit signaling. 7 The kit gene is a proto-oncogene that was originally discovered as the cellular homolog (c-kit) of the feline sarcoma virus oncogene v-kit. 8 Binding of SCF to the kit receptor activates various signaling cascades, including the phosphoinositide 3-kinases, protein kinase C, mitogen-activated protein kinase, and janus kinase/signal transducers and activators of transcription pathways to control hematopoiesis, lymphopoiesis, and gametogenesis. 9 The human disease mastocytosis is characterized by abnormal numbers of mast cells accumulating in skin and/or various other organs. The patients may have inadequate release of mast cell mediators causing anaphylactoid symptoms with potentially fatal outcome. The condition is associated with gain-of-function mutations of kit, which result in uncontrolled autophosphorylation of the kit receptor with ligand-independent, constitutive signaling. [10][11][12][13] The majority of mastocytosis patients carry one particular activating point mutation in exon 17 (D816V). 10,14 The kitD816V protein was shown to enhance the proliferation of human cells in vitro and to transform murine cells in vivo under certain conditions that allow proper processing of the protein despite the cross-species situation. 15 Clinical manifestations of mastocytosis associated with the kitD816V gain-of-function mutation can differ dramatically from patient to patient. 11,14,[16][17][18] In a disease subset designated "cutaneous mastocytosis," the abnormal mast cell accumulation is restricted to the skin. Cutaneous mastocytosis with onset in childho...
The immunoglobulin E (IgE)-mediated mast cell (MC) response is central to the pathogenesis of type I allergy and asthma. IκB kinase 2 (IKK2) was reported to couple IgE-induced signals to MC degranulation by phosphorylating the SNARE protein SNAP23. We investigated MC responses in mice with MC-specific inactivation of IKK2 or NF-κB essential modulator (NEMO), or animals with MC-specific expression of a mutant, constitutively active IKK2. We show that the IgE-induced late-phase cytokine response is reduced in mice lacking IKK2 or NEMO in MCs. However, anaphylactic in vivo responses of these animals are not different from those of control mice, and in vitro IKK2-deficient MCs readily phosphorylate SNAP23 and degranulate similarly to control cells in response to allergen or calcium ionophore. Constitutive overactivation of the NF-κB pathway has only slight effects on allergen-triggered MC responses. Thus, IKK2 is dispensable for MC degranulation, and the important question how IgE-induced signals trigger MC vesicle fusion remains open.
The role of mast cells (MCs) in autoimmunity is the matter of an intensive scientific debate. Based on observations in different MC-deficient mouse strains, MCs are considered as fundamental players in autoimmune diseases. However, most recent data suggest that the outcome of such diseases is strongly affected by the individual mouse strain used. By the use of two c-Kit mutant MC-deficient mouse strains and one c-Kit-independent strain, we here investigated the role of MCs in a systemic Ab transfer model of epidermolysis bullosa acquisita, a subepidermal autoimmune blistering skin disease characterized by autoantibodies against type VII collagen. While C57BL/6J-Kit W-sh/W-sh mice developed an unexpected increased blistering phenotype, no significant differences to WT controls were seen in WBB6F 1 -Kit W/W-v or the novel Mcpt5-Cre iDTR animals. Interestingly, in a local Ab transfer model, which induces a localized disease, we showed that application of high concentrations of anti-COL7 (where COL7 is type VII collagen) Abs induced MC activation and MC-dependent edema formation that did, however, not contribute to blister induction. Our results indicate that in the autoimmune disorder epidermolysis bullosa acquisita MCs do not contribute to the immune-mediated tissue injury. Modern c-Kit mutant-independent MC-deficient mouse strains will help to further redefine the role of MCs in autoimmunity.Keywords: Animal models r autoimmunity r conditional depletion r epidermolysis bullosa acquisita r mast cellsAdditional supporting information may be found in the online version of this article at the publisher's web-site IntroductionAutoimmune bullous dermatoses represent a group of organspecific autoimmune diseases with autoantibodies targeting Correspondence: Prof. Frank Petersen e-mail: fpetersen@fz-borstel.de desmosomal and hemidesmosomal structural proteins of skin and mucous membranes. Within this group, epidermolysis bullosa acquisita (EBA) represents a subepidermal blistering disorder characterized by circulating and tissue-bound autoantibodies (mostly of the IgG subclass) against type VII collagen (COL7), a major component of anchoring fibrils essential for the attachment of epidermis and dermis [1,2]. The pathogenicity of anti-COL7C 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu Eur. J. Immunol. 2015. 45: 1462-1470 Innate immunity 1463Abs in EBA has been well documented, both in vitro and in vivo [3]. Studies in men and mice revealed that the deposition of anti-COL7 IgG at the dermal-epidermal junction results in complement activation predominantly via the alternative pathway and subsequent neutrophil infiltration into the dermis of the skin. By releasing ROS and proteases, activated neutrophils are thought to destroy the basement membrane zone and mediate dermal-epidermal separation and blister formation [4,5]. Thus, patients with EBA mainly suffer from fragile skin, blistering, and scarring with milia formation [6]. Although therapeutic approaches include systemic corticosteroids, immunosuppre...
Background The Amref Alternative Rites of Passage (ARP) model was initiated in 2009. To date, about 20,000 girls have been supported by their communities to denounce female genital mutilation/cutting (FGM/C) and graduate into ‘maturity’ through ARP. While this intervention has been implemented for decades, there is limited evidence of its effectiveness in ending FGM/C. In order to ascertain the effectiveness of this intervention, Amref has developed a digital tracking tool to follow up on girls who have and haven’t gone through the ARP. The key research question is: what effect does ARP have on incidences of FGM/C, teenage pregnancy and child, early and forced marriages among adolescent girls and young women? Methods The study will adopt a stepped-wedge cluster randomised controlled trial design to assess the effectiveness of the ARP model on the incidence of FGM/C; teenage pregnancy; child, early and forced marriage; and educational attainment. We selected one cluster in Kajiado County where recent ARPs have been conducted as the intervention site at the beginning of the study and 3 wards/clusters in Narok County as control sites. Approximately 604 girls aged 10-18 years who reside in selected sites/clusters in Kajiado and Narok counties will be recruited and followed up for 3 years post-exposure. Quantitative data analysis will be conducted at bivariate and multivariate levels. Content/thematic analysis approach will be used to analyse qualitative data. Ethics and dissemination The study obtained ethical approval from the Amref Ethics and Scientific Review Committee (AMREF-ESRC P1051-2021). The findings of this study will be shared with local, national and regional stakeholders working in ending FGM/C, teenage pregnancy, and child, early and forced marriages. Registration – Pan-African Clinical Trials Registry (PACTR202208731662190).
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