Conditional depletion of mast cells has no impact on the severity of experimental epidermolysis bullosa acquisita

Abstract

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...

Pathways of immediate hypothermia and leukocyte infiltration in an adjuvant-free mouse model of anaphylaxis

“…While most of the literature on the roles of MCs in experimental anaphylaxis is based on data obtained using Kit mutant genetically MC-deficient mice, several new models have been developed in which the MC deficiency is not dependent on mutations affecting c- kit structure or expression 24, 30–32, 46–49 . While discordant findings have been reported in some disease models in newer versus older MC-deficient strains 30, 46, 47, 50, 51 , the importance of MCs to both IgE-mediated PSA 24, 47, 52 and peanut-induced ASA 19 has been confirmed using multiple MC-deficient mouse strains. In agreement with these findings, we demonstrate here that both Kit W-sh/W-sh mice and Kit -independent Cpa3-Cre; Mcl-1 fl/fl MC-deficient mice developed reduced immediate hypothermia reactions and diminished numbers of late phase intra-peritoneal leukocytes in our adjuvant-free ASA model (Fig 5 & 7).…”

Ablation of a small subpopulation of diabetes-specific bone marrow-derived cells in mice protects against diabetic neuropathy

“…We took advantage of the DT ablation strategy (3) by generating transgenic mice with insulin promoter-driven DT receptor (DTR) expression to confer hyperglycemia-dependent DTR expression in these mice. The analogous strategy had previously been used successfully to selectively ablate B cells (5), dendritic cells (13), mast cells (7,15), and macrophages (10) in mice. Because we used the insulin promoter for creating the DTR mice, we had to circumvent the production of DTR by pancreatic ␤-cell by using these mice as BMT donors.…”

CD11b‐deficient mice exhibit an increased severity in the late phase of antibody transfer‐induced experimental epidermolysis bullosa acquisita

“…[7] Several mouse models have been established either by immunising mice with recombinant murine COL7 [8] or passively by transferring autoantibodies against murine COL7 into mice. [9,10] In this study, we aimed at investigating the role of CD11b in experimental EBA. Due to the MHC restriction in the development of immunisation-induced EBA, we investigated whether CD11b plays a role in antibody transferinduced experimental EBA.…”

“…Here, mice start to exert disease symptoms already 24 hours after injection. [9] The different kinetics of disease development in the two models suggest differences in their underlying pathomechanisms. Therefore, we investigated the role of CD11b deficiency in both, systemic and local antibody transfer-induced EBA.…”