<scp>CD</scp>11b‐deficient mice exhibit an increased severity in the late phase of antibody transfer‐induced experimental epidermolysis bullosa acquisita

Deng, Fengyuan; Yan, Chen; Zheng, Jiangjun; Huang, Qiaoniang; Cao, Xuetao; Zillikens, Detlef; Petersen, Frank; Yu, Xinhua

doi:10.1111/exd.13434

Cited by 8 publications

(10 citation statements)

References 13 publications

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“…In experimental EBA, the crucial CD18-dependent myeloid extravasation into the skin is partially driven by IL-8 mouse homolog cytokines and the complement cascade component, C5a ( 36 , 37 ). We, therefore, next evaluated the effect of LAS191954 on human PMN migration induced by fMLP, IL-8, or C5a.…”

Section: Resultsmentioning

confidence: 99%

Therapeutic Effect of a Novel Phosphatidylinositol-3-Kinase δ Inhibitor in Experimental Epidermolysis Bullosa Acquisita

et al. 2018

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Epidermolysis bullosa acquisita (EBA) is a rare, but prototypical, organ-specific autoimmune disease, characterized and caused by autoantibodies against type VII collagen (COL7). Mucocutaneous inflammation, blistering, and scarring are the clinical hallmarks of the disease. Treatment of EBA is difficult and mainly relies on general immunosuppression. Hence, novel treatment options are urgently needed. The phosphatidylinositol-3-kinase (PI3K) pathway is a putative target for the treatment of inflammatory diseases, including EBA. We recently discovered LAS191954, an orally available, selective PI3Kδ inhibitor. PI3Kδ has been shown to be involved in B cell and neutrophil cellular functions. Both cell types critically contribute to EBA pathogenesis, rendering LAS191954 a potential drug candidate for EBA treatment. We, here, demonstrate that LAS191954, when administered chronically, dose-dependently improved the clinical phenotype of mice harboring widespread skin lesions secondary to immunization-induced EBA. Direct comparison with high-dose corticosteroid treatment indicated superiority of LAS191954. Interestingly, levels of circulating autoantibodies were unaltered in all groups, indicating a mode of action independent of the inhibition of B cell function. In line with this, LAS191954 also hindered disease progression in antibody transfer-induced EBA, where disease develops dependent on myeloid, but independent of B cells. We further show that, in vitro, LAS191954 dose-dependently impaired activation of human myeloid cells by relevant disease stimuli. Specifically, immune complex-mediated and C5a-mediated ROS release were inhibited in a PI3Kδ-dependent manner. Accordingly, LAS191954 also modulated the dermal–epidermal separation induced in vitro by co-incubation of immune complexes with polymorph nuclear cells, thus pointing to an important role of PI3Kδ in EBA effector functions. Altogether, these results suggest a new potential mechanism for the treatment of EBA and potentially also other autoimmune bullous diseases.

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Section: Resultsmentioning

confidence: 99%

Therapeutic Effect of a Novel Phosphatidylinositol-3-Kinase δ Inhibitor in Experimental Epidermolysis Bullosa Acquisita

et al. 2018

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“…Unexpectedly, in the antibody transfer-induced model of EBA, CD11b-deficient mice develop more severe disease symptoms than wild-type mice in the late phase of the disease. Furthermore, compared to wild-type controls, CD11b-deficient mice express increased levels of circulating IFN-γ and IL-4, suggesting an anti-inflammatory role for CD11b in the resolution phase of experimental autoimmune diseases, such as EBA (237).…”

Section: The Resolution Phase Of Ebamentioning

confidence: 99%

Epidermolysis Bullosa Acquisita: The 2019 Update

et al. 2019

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Epidermolysis bullosa acquisita (EBA) is an orphan autoimmune disease. Patients with EBA suffer from chronic inflammation as well as blistering and scarring of the skin and mucous membranes. Current treatment options rely on non-specific immunosuppression, which in many cases, does not lead to a remission of treatment. Hence, novel treatment options are urgently needed for the care of EBA patients. During the past decade, decisive clinical observations, and frequent use of pre-clinical model systems have tremendously increased our understanding of EBA pathogenesis. Herein, we review all of the aspects of EBA, starting with a detailed description of epidemiology, clinical presentation, diagnosis, and current treatment options. Of note, pattern analysis via direct immunofluorescence microscopy of a perilesional skin lesion and novel serological test systems have significantly facilitated diagnosis of the disease. Next, a state-of the art review of the current understanding of EBA pathogenesis, emerging treatments and future perspectives is provided. Based on pre-clinical model systems, cytokines and kinases are among the most promising therapeutic targets, whereas high doses of IgG (IVIG) and the anti-CD20 antibody rituximab are among the most promising “established” EBA therapeutics. We also aim to raise awareness of EBA, as well as initiate basic and clinical research in this field, to further improve the already improved but still unsatisfactory conditions for those diagnosed with this condition.

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“…Similarly, a local antibody transfer-induced mouse model of EBA can be established, when the rabbit anti-murine COL7 IgG are transferred into mice via intradermal injection. In this experimental setting, IgG are injected intradermally into the base of the ear of adult mice, and the mice develop skin symptoms at the injection site within 48 h after the antibody application ( 17 , 22 ). Thus, these experimental settings present acute and local antibody transfer-induced mouse models of BP and EBA.…”

Section: Mcs In Mouse Models Of Aibdmentioning

confidence: 99%

The Role of Mast Cells in Autoimmune Bullous Dermatoses

Kasprick

Hartmann

et al. 2018

Front. Immunol.

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Skin mast cells (MCs), a resident immune cell type with broad regulatory capacity, play an important role in sensing danger signals as well as in the control of the local immune response. It is conceivable to expect that skin MCs regulate autoimmune response and are thus involved in autoimmune diseases in the skin, e.g., autoimmune bullous dermatoses (AIBD). Therefore, exploring the role of MCs in AIBD will improve our understanding of the disease pathogenesis and the search for novel therapeutic targets. Previously, in clinical studies with AIBD, particularly bullous pemphigoid, patients’ samples have demonstrated that MCs are likely involved in the development of the diseases. However, using MC-deficient mice, studies with mouse models of AIBD have obtained inconclusive or even discrepant results. Therefore, it is necessary to clarify the observed discrepancies and to elucidate the role of MCs in AIBD. Here, in this review, we aim to clarify discrepant findings and finally elucidate the role of MCs in AIBD by summarizing and discussing the findings in both clinical and experimental studies.

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

Cited by 8 publications

References 13 publications

Therapeutic Effect of a Novel Phosphatidylinositol-3-Kinase δ Inhibitor in Experimental Epidermolysis Bullosa Acquisita

Therapeutic Effect of a Novel Phosphatidylinositol-3-Kinase δ Inhibitor in Experimental Epidermolysis Bullosa Acquisita

Epidermolysis Bullosa Acquisita: The 2019 Update

The Role of Mast Cells in Autoimmune Bullous Dermatoses

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