Reduced Skin Blistering in Experimental Epidermolysis Bullosa Acquisita After Anti-TNF Treatment

Hirose, Misa; Kasprick, Anika; Beltsiou, Foteini; Dieckhoff, Katharina Schulze; Schulze, Franziska; Samavedam, Unni K. J. S. R. L.; Hundt, Jennifer E.; Pas, Hendrikus; Jonkman, Marcel F.; Schmidt, Enno; Kalies, Kathrin; Zillikens, Detlef; Ludwig, Ralf J.; Bieber, Katja

doi:10.2119/molmed.2015.00206

Cited by 28 publications

(25 citation statements)

References 51 publications

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“…Using two different murine EBA models mimicking the human inflammatory disease, we showed that oral administration of calcitriol can cause a considerable regulation of EBA development. Compared with control mice, animals treated with calcitriol showed milder skin lesions in a dosedependent fashion and less-intense dermal neutrophil infiltration, whereas the amount of other pathophysiologically relevant myeloid cells, that is, macrophages (Hirose et al, 2016), was unchanged in the skin. Our data are in agreement with previous observations in animal models of, and patients with, other autoimmune diseases, such as multiple sclerosis, type 1 diabetes mellitus, and systemic lupus erythematosus, in which systemic calcitriol treatment efficiently improved the disease course.…”

Section: Discussionmentioning

confidence: 84%

“…Supplementing vitamin D to raise the 25-hydroxyvitamin D status and potentially the end-organ availability of calcitriol in these patients could possibly lead to both better disease control and alleviation of potential bone metabolism problems resulting from conventional immunosuppressive medication and/or the autoimmune condition itself. It can be hypothesized that calcitriol is capable of exerting additive or synergistic effects (e.g., by shifting the ratio from autoreactive to regulatory B cells) when combined with conventional or potential future targeted EBA therapies (e.g., neutralizing antibodies against Fcg receptor IIIA, GM-CSF, or TNF-a) (Hirose et al, 2016;Kasperkiewicz et al, 2016), thus helping to overcome the frequently observed recalcitrance of the patients' disease. However, although only the prophylactic, and not therapeutic, potential of calcitriol has been examined in this study, our results at least indirectly indicate that treatment with vitamin D derivatives could possibly decrease the risk of disease progression or relapse when applied therapeutically or prophylactically during the active and remission stage of the patients, respectively.…”

Section: Discussionmentioning

confidence: 99%

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Calcitriol Treatment Ameliorates Inflammation and Blistering in Mouse Models of Epidermolysis Bullosa Acquisita

Tukaj

Bieber

Witte

et al. 2018

Journal of Investigative Dermatology

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A link between hypovitaminosis D and development of autoimmune bullous disorders has been suggested recently, but this association has not been elaborated experimentally. Here, the role of vitamin D was investigated in epidermolysis bullosa acquisita (EBA), an anti-type VII collagen autoantibody-induced blistering skin disease. Oral administration of the hormonally active vitamin D metabolite calcitriol ameliorated clinical disease severity and dermal neutrophil infiltration in both an antibody transfer- and immunization-induced EBA mouse model. Mechanistically, calcitriol hindered immune effector cell activation as evidenced by increased L-selectin expression on Gr-1 cells in calcitriol-treated mice with antibody transfer-induced EBA, as well as suppressed in vitro immune complex-induced reactive oxygen species production in calcitriol-treated murine neutrophils. Additionally, calcitriol administration was associated with an increase of regulatory T (CD4FoxP3) and B (CD19IL10) cells as well as reduction of pro-inflammatory T helper 17 (CD4IL-17) cells in mice with immunization-induced EBA. In line, levels of circulating anti-type VII collagen autoantibodies were lower in mice that received calcitriol compared to solvent-treated animals. Together with the observed state of hypovitaminosis D in most cases of an analyzed EBA patient cohort, the results of this study support the use of vitamin D derivatives or analogs for patients with EBA and related diseases.

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Section: Discussionmentioning

confidence: 84%

Section: Discussionmentioning

confidence: 99%

Calcitriol Treatment Ameliorates Inflammation and Blistering in Mouse Models of Epidermolysis Bullosa Acquisita

Tukaj

Bieber

Witte

et al. 2018

Journal of Investigative Dermatology

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“…To address the first possibility, chemokine and cytokine expression in lesional skin of wild-type or DEREG mice after experimental BP and EBA was evaluated (for comparison to healthy skin see Table S1 in Supplementary Material). Interestingly, the expression of innate cytokines, such as TNF , known as prominent cytokines in PD skin lesions ( 13 , 27 ), did only slightly differ between wild-type and DEREG mice and was not significant in BP skin lesions (Tables 1 and 2 ). Of note, the Th2 cytokines IL-4, IL-10 , and IL-13 were significantly higher expressed in lesional DEREG skin (Tables 1 and 2 ).…”

Section: Resultsmentioning

confidence: 99%

“…By activating specific Fc gamma receptors, myeloid cells bind to skin-bound ICs, get activated and ultimately release reactive oxygen species (ROS) and proteases, leading to inflammation and blistering ( 9 – 12 ). The involvement of macrophages/monocytes was shown in ex vivo assays of human skin ( 13 ), but not in vivo . Regarding cell types besides myeloid cells, mast cells are required to induce the PD bullous pemphigoid [BP, mediated by autoantibodies against type XVII collagen (COL17)] ( 14 ), while in the PD epidermolysis bullosa acquisita [EBA, mediated by autoantibodies against type VII collagen (COL7)], mast cells were activated, but dispensable for inflammation and blistering ( 15 ).…”

Section: Introductionmentioning

confidence: 99%

Regulatory T Cells Suppress Inflammation and Blistering in Pemphigoid Diseases

et al. 2017

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Regulatory T cells (Tregs) are well known for their modulatory functions in adaptive immunity. Through regulation of T cell functions, Tregs have also been demonstrated to indirectly curb myeloid cell-driven inflammation. However, direct effects of Tregs on myeloid cell functions are insufficiently characterized, especially in the context of myeloid cell-mediated diseases, such as pemphigoid diseases (PDs). PDs are caused by autoantibodies targeting structural proteins of the skin. Autoantibody binding triggers myeloid cell activation through specific activation of Fc gamma receptors, leading to skin inflammation and subepidermal blistering. Here, we used mouse models to address the potential contribution of Tregs to PD pathogenesis in vivo. Depletion of Tregs induced excessive inflammation and blistering both clinically and histologically in two different PD mouse models. Of note, in the skin of Treg-depleted mice with PD, we detected increased expression of different cytokines, including Th2-specific IL-4, IL-10, and IL-13 as well as pro-inflammatory Th1 cytokine IFN-γ and the T cell chemoattractant CXCL-9. We next aimed to determine whether Tregs alter the migratory behavior of myeloid cells, dampen immune complex (IC)-induced myeloid cell activation, or both. In vitro experiments demonstrated that co-incubation of IC-activated myeloid cells with Tregs had no impact on the release of reactive oxygen species (ROS) but downregulated β2 integrin expression. Hence, Tregs mitigate PD by altering the migratory capabilities of myeloid cells rather than their release of ROS. Modulating cytokine expression by administering an excess of IL-10 or blocking IFN-γ may be used in clinical translation of these findings.

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“…[150][151][152][153] In the circulation, FcRn protects circulating IgG antibodies from clearance. 153,154 In autoimmune blistering Table 3 Prospective targets for epidermolysis bullosa acquisita patients currently being investigated in experimental mice models [223][224][225][226][227][228][229][230] Targets in epidermolysis bullosa acquisita demonstrated in mouse models © 2019 European Academy of Dermatology and Venereology disease, circulating autoantibodies ultimately lead to disease. As such, FcRn inhibition has the potential to decrease MHC antigen presentation to T cells and survival of autoantibodies in the circulation, the two fundamental forces in disease pathogenesis.…”

Section: Inhibitory Antibodiesmentioning

confidence: 99%

From bench to bedside: evolving therapeutic targets in autoimmune blistering disease

Kridin

Kowalski

Kneiber

et al. 2019

Acad Dermatol Venereol

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Autoimmune blistering diseases comprise a group of heterogenous conditions characterized by the loss of tolerance and subsequent development of autoantibodies targeting epidermal and subepidermal adhesion proteins. Blisters and erosions form on the skin and mucous membranes leading to significant morbidity and mortality. Traditional therapies rely on systemic immunosuppression. Advancements in our understanding of the pathophysiology of pemphigus and pemphigoid have led to the development of molecules which target specific pathways involved in induction and perpetuation of disease. In this review, we outline the novel therapeutic strategies including B‐cell depletion, T‐regulatory cell repletion, cell signalling inhibitors and small molecular inhibitors, inhibitory monoclonal antibodies, as well as complement inhibition. We additionally review their current level of clinical evidence. We lastly review therapeutics targets gleaned from the experimental epidermolysis bullosa acquisita mouse model. These emerging treatments offer an exciting progression from basic science discoveries that have the potential to transform the treatment paradigm in autoimmune blistering diseases.

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Reduced Skin Blistering in Experimental Epidermolysis Bullosa Acquisita After Anti-TNF Treatment

Abstract: (227 words)Epidermolysis bullosa acquisita (EBA) is a difficult-to-treat subepidermal autoimmune blistering skin disease (AIBD) with circulating and tissue-bound anti-type VII collagen

Cited by 28 publications

References 51 publications

Calcitriol Treatment Ameliorates Inflammation and Blistering in Mouse Models of Epidermolysis Bullosa Acquisita

Calcitriol Treatment Ameliorates Inflammation and Blistering in Mouse Models of Epidermolysis Bullosa Acquisita

Regulatory T Cells Suppress Inflammation and Blistering in Pemphigoid Diseases

From bench to bedside: evolving therapeutic targets in autoimmune blistering disease

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