The Experts below are selected from a list of 49842 Experts worldwide ranked by ideXlab platform
Ethan M. Shevach - One of the best experts on this subject based on the ideXlab platform.
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cd4 cd25 t cells prevent the development of organ specific Autoimmune Disease by inhibiting the differentiation of autoreactive effector t cells
Journal of Immunology, 2005Co-Authors: Richard J Dipaolo, Deborah D Glass, Karen E Bijwaard, Ethan M. ShevachAbstract:Thymic-derived, naturally occurring, CD4 + CD25 + regulatory T cells (nTreg) are potent suppressors of immune responses. A detailed understanding of which components of the development and activation of pathogenic effector T cells are inhibited by nTreg during the course of T cell-mediated, Organ-Specific autoimmunity is as yet unknown. We have analyzed the effects of polyclonal nTreg on the development of Autoimmune gastritis. The nTreg inhibited the development of Disease, but failed to inhibit the migration of effector cells into the gastric lymph node or stomach. Notably, nTreg did not inhibit the expansion of autoreactive T cells in the gastric lymph node. The primary effect of nTreg appeared to be inhibition of differentiation of autoantigen-specific T cells to Th1 effector cells, as reflected by a decrease in Ag-stimulated IFN-γ production and a reduction in T-bet expression.
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cutting edge depletion of cd4 cd25 regulatory t cells is necessary but not sufficient for induction of organ specific Autoimmune Disease
Journal of Immunology, 2002Co-Authors: Rebecca S Mchugh, Ethan M. ShevachAbstract:Thymectomy of BALB/c mice on day 3 of life results in the development of Autoimmune gastritis (AIG) due to the absence of CD4+CD25+ regulatory T cells. However, depletion of CD4+CD25+ T cells by treatment with anti-CD25 rarely resulted in AIG. Depletion was efficient, as transfer of splenocytes from depleted mice induced AIG in nu/nu mice. One explanation for this result is that CD4+CD25− T cells upon transfer to nude recipients undergo lymphopenia-induced proliferation, providing a signal for T cell activation. Cotransfer of CD25+ T cells did not inhibit initial proliferation but did suppress AIG. Surprisingly, immunization with the AIG target Ag, H/K ATPase, in IFA failed to induce Disease in normal animals but induced severe AIG in CD25-depleted mice. These results demonstrate that second signals (nonspecific proliferation, TCR activation, or inflammation) are needed for induction of autoimmunity in the absence of CD25+ regulatory T cells.
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certified professionals cd4 cd25 suppressor t cells
Journal of Experimental Medicine, 2001Co-Authors: Ethan M. ShevachAbstract:Although negative selection in the thymus and induction of anergy in the periphery have been widely accepted as mechanisms for controlling autoreactivity, much less attention has been devoted to the role of suppressor T cells in mediating dominant immunologic self-tolerance. In 1995, Sakaguchi et al. 12 made the seminal observation that the transfer of CD4+ T cells which had been depleted of the minor subpopulation (10%) of cells that coexpressed the IL-2 receptor (IL-2R) α-chain (CD25) to nu/nu recipients induced Organ-Specific Autoimmune Disease in the majority of recipients. Cotransfer of CD4+CD25+ cells with the CD4+CD25− cells prevented the development of Disease. The CD4+CD25+ population was also shown to be solely responsible for the prevention of autoimmunity observed after mice are thymectomized on the third day of life 3. Rapid progress in the analysis of the regulatory function of the CD4+CD25+ T cell population was made by the development of in vitro model systems that mimicked the function of these cells in vivo 456. Although minor differences were observed in the results obtained by the different groups, it is widely accepted that these cells are both hyporesponsive and suppressive. Further studies demonstrated that the CD4+CD25+ T cells act through an APC-independent mechanism (7, and unpublished observations). Induction of suppressor activity requires that the CD4+ CD25+ cells be activated through their TCR, but once activated, they suppress T cell activation in an antigen-independent manner without a requirement for reactivation through their TCR. Therefore, we proposed 4 that CD4+ CD25+ cells represent a unique lineage of CD4+ T cells that function as “professional suppressor cells.” The publication in this issue of four papers dealing with different aspects of the function of CD4+CD25+ T cells clearly indicates that they have now received their “professional certification.”
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suppressor effector function of cd4 cd25 immunoregulatory t cells is antigen nonspecific
Journal of Immunology, 2000Co-Authors: Angela M Thornton, Ethan M. ShevachAbstract:CD4 + CD25 + T cells represent a unique population of “professional” suppressor T cells that prevent induction of Organ-Specific Autoimmune Disease. In vitro, CD4 + CD25 + cells were anergic to simulation via the TCR and when cultured with CD4 + CD25 − cells, markedly suppressed polyclonal T cell proliferation by specifically inhibiting the production of IL-2. Suppression was cytokine independent, cell contact dependent, and required activation of the suppressors via their TCR. Further characterization of the CD4 + CD25 + population demonstrated that they do not contain memory or activated T cells and that they act through an APC-independent mechanism. CD4 + CD25 + T cells isolated from TCR transgenic (Tg) mice inhibited responses of CD4 + CD25 − Tg T cells to the same Ag, but also inhibited the Ag-specific responses of Tg cells specific for a distinct Ag. Suppression required that both peptide/MHC complexes be present in the same culture, but the Ags could be presented by two distinct populations of APC. When CD4 + CD25 + T cells were cultured with anti-CD3 and IL-2, they expanded, remained anergic, and in the absence of restimulation via their TCR, suppressed Ag-specific responses of CD4 + CD25 − T cells from multiple TCR transgenics. Collectively, these data demonstrate that CD4 + CD25 + T cells require activation via their TCR to become suppressive, but once activated, their suppressor effector function is completely nonspecific. The cell surface molecules involved in this T-T interaction remain to be characterized.
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cd4 cd25 immunoregulatory t cells suppress polyclonal t cell activation in vitro by inhibiting interleukin 2 production
Journal of Experimental Medicine, 1998Co-Authors: Angela M Thornton, Ethan M. ShevachAbstract:Peripheral tolerance may be maintained by a population of regulatory/suppressor T cells that prevent the activation of autoreactive T cells recognizing tissue-specific antigens. We have previously shown that CD4+CD25+ T cells represent a unique population of suppressor T cells that can prevent both the initiation of Organ-Specific Autoimmune Disease after day 3 thymectomy and the effector function of cloned autoantigen-specific CD4+ T cells. To analyze the mechanism of action of these cells, we established an in vitro model system that mimics the function of these cells in vivo. Purified CD4+CD25+ cells failed to proliferate after stimulation with interleukin (IL)-2 alone or stimulation through the T cell receptor (TCR). When cocultured with CD4+CD25− cells, the CD4+CD25+ cells markedly suppressed proliferation by specifically inhibiting the production of IL-2. The inhibition was not cytokine mediated, was dependent on cell contact between the regulatory cells and the responders, and required activation of the suppressors via the TCR. Inhibition could be overcome by the addition to the cultures of IL-2 or anti-CD28, suggesting that the CD4+CD25+ cells may function by blocking the delivery of a costimulatory signal. Induction of CD25 expression on CD25− T cells in vitro or in vivo did not result in the generation of suppressor activity. Collectively, these data support the concept that the CD4+CD25+ T cells in normal mice may represent a distinct lineage of “professional” suppressor cells.
Cassian Sitaru - One of the best experts on this subject based on the ideXlab platform.
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granulocyte dependent autoantibody induced skin blistering
Journal of Visualized Experiments, 2012Co-Authors: Kinga Csorba, Sebastian Sitaru, Cassian SitaruAbstract:Autoimmune phenomena occur in healthy individuals, but when self-tolerance fails, the Autoimmune response may result in specific pathology. According to Witebsky's postulates, one of the criteria in diagnosing a Disease as Autoimmune is the reproduction of the Disease in experimental animals by the passive transfer of autoantibodies. For epidermolysis bullosa acquisita (EBA), a prototypic Organ-Specific Autoimmune Disease of skin and mucous membranes, several experimental models were recently established. In the animal model described in our present work, purified IgG antibodies against a stretch of 200 amino acids (aa 757-967) of collagen VII are injected repeatedly into mice reproducing the blistering phenotype as well as the histo- and immunopathological features characteristic to human EBA 1. Full-blown widespread Disease is usually seen 5-6 days after the first injection and the extent of the Disease correlates with the dose of the administered collagen VII-specific IgG. The tissue damage (blister formation) in the experimental EBA is depending on the recruitment and activation of granulocytes by tissue-bound autoantibodies 2,-4. Therefore, this model allows for the dissection of the granulocyte-dependent inflammatory pathway involved in the Autoimmune tissue damage, as the model reproduces only the T cell-independent phase of the efferent Autoimmune response. Furthermore, its value is underlined by a number of studies demonstrating the blister-inducing potential of autoantibodies in vivo and investigating the mechanism of the blister formation in EBA 1,3,-6. Finally, this model will greatly facilitate the development of new anti-inflammatory therapies in autoantibody-induced Diseases. Overall, the passive transfer animal model of EBA is an accessible and instructive Disease model and will help researchers to analyze not only EBA pathogenesis but to answer fundamental biologically and clinically essential autoimmunity questions.
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t cells are required for the production of blister inducing autoantibodies in experimental epidermolysis bullosa acquisita
Journal of Immunology, 2010Co-Authors: Ana Gabriela Sitaru, Cassian Sitaru, Detlef Zillikens, Alina Sesarman, Sidonia Mihai, Mircea T Chiriac, Per Hultman, Werner SolbachAbstract:Epidermolysis bullosa acquisita is a prototypical Organ-Specific Autoimmune Disease caused by autoantibodies against type VII collagen of the dermal-epidermal junction. Although mechanisms of autoantibody-induced blister formation were extensively characterized, the initiation of autoantibody production in Autoimmune blistering Diseases is still poorly defined. In the current study, we addressed the role of T cells for the production of blister-inducing autoantibodies in mice immunized with type VII collagen. To detect autoreactive type VII collagen-specific T cells, lymph node cells from immunized SJL mice were stimulated in vitro with recombinant Ag, and their proliferation was measured by radioactive thymidine incorporation and flow cytometry analysis of CFSE-labeled cells. Interestingly, using synthetic peptides of the immunogen, partly different T and B cell epitopes in mice immunized with type VII collagen were demonstrated. In contrast to wild-type mice, immunization with type VII collagen of SJL athymic nude mice lacking T cells did not induce an Autoimmune response and blistering phenotype. Importantly, SJL nude mice repleted with T cells from immunized wild-type mice showed a robust and durable autoantibody production resulting in subepidermal blistering Disease in the recipients. Our present results demonstrate that T cells are required for the initiation of autoimmunity against type VII collagen in experimental epidermolysis bullosa acquisita and provide a basis for developing T cell-directed immunomodulatory strategies for this and related Autoimmune Diseases.
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experimental models of epidermolysis bullosa acquisita
Experimental Dermatology, 2007Co-Authors: Cassian SitaruAbstract:Epidermolysis bullosa acquisita (EBA) is an Organ-Specific Autoimmune Disease with a well-defined antigen-autoantibody system. Recently, mutually complementary ex vivo and animal models were developed for this Disease. The blister formation of EBA can be reproduced by passively transferring antibodies against type VII collagen into mice. In addition, the Fc-dependent interaction of autoantibodies with granulocytes resulting in dermal-epidermal separation can be studied using patient autoantibodies and leukocytes from healthy donors in cryostat sections of normal human skin. Finally, the Autoimmune response and the active blistering Disease are replicated by immunizing mice with autologous type VII collagen. The results obtained using these experimental systems provided conclusive evidence that EBA is an antibody-mediated Autoimmune Disease. In addition, these models represent powerful new tools for understanding EBA pathophysiology and will likely offer unique opportunities to investigate the molecular mechanisms of antibody-mediated Autoimmune Diseases in general. Thus, due to improved Disease modelling, EBA emerges as an exquisitely instructive model Disease to study fundamental, biologically and clinically crucial aspects of antibody-mediated Organ-Specific Autoimmune Diseases that extend well beyond the limits of autoimmunity against type VII collagen. The new mechanistic insights gained from investigating EBA pathogenesis will facilitate the design of immunomodulatory interventions for this and other pathogenetically related Organ-Specific, antibody-dependent Autoimmune Diseases.
Detlef Zillikens - One of the best experts on this subject based on the ideXlab platform.
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therapeutic effect of a novel phosphatidylinositol 3 kinase δ inhibitor in experimental epidermolysis bullosa acquisita
Frontiers in Immunology, 2018Co-Authors: Hiroshi Koga, Detlef Zillikens, Ralf Ludwig, Katja Bieber, Anika Kasprick, Rosa Lopez, Mariona Auli, Merce Pont, Nuria Godessart, Cristina BalagueAbstract: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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image_3_Therapeutic Effect of a Novel Phosphatidylinositol-3-Kinase δ Inhibitor in Experimental Epidermolysis Bullosa Acquisita.TIF
2018Co-Authors: Hiroshi Koga, Detlef Zillikens, Katja Bieber, Anika Kasprick, Rosa Lopez, Mariona Auli, Merce Pont, Nuria Godessart, Ralf J. Ludwig, Cristina BalagueAbstract: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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epidermolysis bullosa acquisita from pathophysiology to novel therapeutic options
Journal of Investigative Dermatology, 2016Co-Authors: Michael Kasperkiewicz, Enno Schmidt, Detlef Zillikens, Christian D Sadik, Katja Bieber, Saleh M Ibrahim, Rudolf A Manz, Ralf LudwigAbstract:Epidermolysis bullosa acquisita (EBA) is a prototypic Organ-Specific Autoimmune Disease induced by autoantibodies to type VII collagen causing mucocutaneous blisters. In the inflammatory (bullous pemphigoid-like) EBA variant, autoantibody binding is followed by a lesional inflammatory cell infiltration, and the overall clinical picture may be indistinguishable from that of bullous pemphigoid, the latter being the most common Autoimmune bullous Disease. The last decade witnessed the development of several mouse models of inflammatory EBA that facilitated the elucidation of the pathogenesis of autoantibody-induced, cell-mediated subepidermal blistering Diseases and identified new therapeutic targets for these and possibly other autoantibody-driven disorders.
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gm csf modulates autoantibody production and skin blistering in experimental epidermolysis bullosa acquisita
Journal of Immunology, 2014Co-Authors: Unni Krishna S R L Samavedam, Susen Muller, Franziska S Schulze, Enno Schmidt, Detlef Zillikens, Andreas Recke, Hiroaki Iwata, Ralf LudwigAbstract:GM-CSF activates hematopoietic cells and recruits neutrophils and macrophages to sites of inflammation. Inhibition of GM-CSF attenuates Disease activity in models of chronic inflammatory Disease. Effects of GM-CSF blockade were linked to modulation of the effector phase, whereas effects on early pathogenic events, for example, Ab production, have not been identified. To evaluate yet uncharacterized effects of GM-CSF on early pathogenic events in chronic inflammation, we employed immunization-induced epidermolysis bullosa acquisita (EBA), an Autoimmune bullous Disease caused by autoantibodies to type VII collagen. Compared to wild-type mice, upon immunization, GM-CSF−/− mice produced lower serum autoantibody titers, which were associated with reduced neutrophil numbers in draining lymph nodes. The same effect was observed in neutrophil-depleted wild-type mice. Neutrophil depletion in GM-CSF−/− mice led to a stronger inhibition, indicating that GM-CSF and neutrophils have additive functions. To characterize the contribution of GM-CSF specifically in the effector phase of EBA, Disease was induced by transfer of anti–type VII collagen IgG into mice. We observed an increased GM-CSF expression, and GM-CSF blockade reduced skin blistering. Additionally, GM-CSF enhanced reactive oxygen species release and neutrophil migration in vitro. In immunization-induced murine EBA, treatment with anti–GM-CSF had a beneficial effect on established Disease. We demonstrate that GM-CSF modulates both autoantibody production and skin blistering in a prototypical Organ-Specific Autoimmune Disease.
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t cells are required for the production of blister inducing autoantibodies in experimental epidermolysis bullosa acquisita
Journal of Immunology, 2010Co-Authors: Ana Gabriela Sitaru, Cassian Sitaru, Detlef Zillikens, Alina Sesarman, Sidonia Mihai, Mircea T Chiriac, Per Hultman, Werner SolbachAbstract:Epidermolysis bullosa acquisita is a prototypical Organ-Specific Autoimmune Disease caused by autoantibodies against type VII collagen of the dermal-epidermal junction. Although mechanisms of autoantibody-induced blister formation were extensively characterized, the initiation of autoantibody production in Autoimmune blistering Diseases is still poorly defined. In the current study, we addressed the role of T cells for the production of blister-inducing autoantibodies in mice immunized with type VII collagen. To detect autoreactive type VII collagen-specific T cells, lymph node cells from immunized SJL mice were stimulated in vitro with recombinant Ag, and their proliferation was measured by radioactive thymidine incorporation and flow cytometry analysis of CFSE-labeled cells. Interestingly, using synthetic peptides of the immunogen, partly different T and B cell epitopes in mice immunized with type VII collagen were demonstrated. In contrast to wild-type mice, immunization with type VII collagen of SJL athymic nude mice lacking T cells did not induce an Autoimmune response and blistering phenotype. Importantly, SJL nude mice repleted with T cells from immunized wild-type mice showed a robust and durable autoantibody production resulting in subepidermal blistering Disease in the recipients. Our present results demonstrate that T cells are required for the initiation of autoimmunity against type VII collagen in experimental epidermolysis bullosa acquisita and provide a basis for developing T cell-directed immunomodulatory strategies for this and related Autoimmune Diseases.
Ralf Ludwig - One of the best experts on this subject based on the ideXlab platform.
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therapeutic effect of a novel phosphatidylinositol 3 kinase δ inhibitor in experimental epidermolysis bullosa acquisita
Frontiers in Immunology, 2018Co-Authors: Hiroshi Koga, Detlef Zillikens, Ralf Ludwig, Katja Bieber, Anika Kasprick, Rosa Lopez, Mariona Auli, Merce Pont, Nuria Godessart, Cristina BalagueAbstract: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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epidermolysis bullosa acquisita from pathophysiology to novel therapeutic options
Journal of Investigative Dermatology, 2016Co-Authors: Michael Kasperkiewicz, Enno Schmidt, Detlef Zillikens, Christian D Sadik, Katja Bieber, Saleh M Ibrahim, Rudolf A Manz, Ralf LudwigAbstract:Epidermolysis bullosa acquisita (EBA) is a prototypic Organ-Specific Autoimmune Disease induced by autoantibodies to type VII collagen causing mucocutaneous blisters. In the inflammatory (bullous pemphigoid-like) EBA variant, autoantibody binding is followed by a lesional inflammatory cell infiltration, and the overall clinical picture may be indistinguishable from that of bullous pemphigoid, the latter being the most common Autoimmune bullous Disease. The last decade witnessed the development of several mouse models of inflammatory EBA that facilitated the elucidation of the pathogenesis of autoantibody-induced, cell-mediated subepidermal blistering Diseases and identified new therapeutic targets for these and possibly other autoantibody-driven disorders.
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gm csf modulates autoantibody production and skin blistering in experimental epidermolysis bullosa acquisita
Journal of Immunology, 2014Co-Authors: Unni Krishna S R L Samavedam, Susen Muller, Franziska S Schulze, Enno Schmidt, Detlef Zillikens, Andreas Recke, Hiroaki Iwata, Ralf LudwigAbstract:GM-CSF activates hematopoietic cells and recruits neutrophils and macrophages to sites of inflammation. Inhibition of GM-CSF attenuates Disease activity in models of chronic inflammatory Disease. Effects of GM-CSF blockade were linked to modulation of the effector phase, whereas effects on early pathogenic events, for example, Ab production, have not been identified. To evaluate yet uncharacterized effects of GM-CSF on early pathogenic events in chronic inflammation, we employed immunization-induced epidermolysis bullosa acquisita (EBA), an Autoimmune bullous Disease caused by autoantibodies to type VII collagen. Compared to wild-type mice, upon immunization, GM-CSF−/− mice produced lower serum autoantibody titers, which were associated with reduced neutrophil numbers in draining lymph nodes. The same effect was observed in neutrophil-depleted wild-type mice. Neutrophil depletion in GM-CSF−/− mice led to a stronger inhibition, indicating that GM-CSF and neutrophils have additive functions. To characterize the contribution of GM-CSF specifically in the effector phase of EBA, Disease was induced by transfer of anti–type VII collagen IgG into mice. We observed an increased GM-CSF expression, and GM-CSF blockade reduced skin blistering. Additionally, GM-CSF enhanced reactive oxygen species release and neutrophil migration in vitro. In immunization-induced murine EBA, treatment with anti–GM-CSF had a beneficial effect on established Disease. We demonstrate that GM-CSF modulates both autoantibody production and skin blistering in a prototypical Organ-Specific Autoimmune Disease.
Katja Bieber - One of the best experts on this subject based on the ideXlab platform.
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therapeutic effect of a novel phosphatidylinositol 3 kinase δ inhibitor in experimental epidermolysis bullosa acquisita
Frontiers in Immunology, 2018Co-Authors: Hiroshi Koga, Detlef Zillikens, Ralf Ludwig, Katja Bieber, Anika Kasprick, Rosa Lopez, Mariona Auli, Merce Pont, Nuria Godessart, Cristina BalagueAbstract: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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image_3_Therapeutic Effect of a Novel Phosphatidylinositol-3-Kinase δ Inhibitor in Experimental Epidermolysis Bullosa Acquisita.TIF
2018Co-Authors: Hiroshi Koga, Detlef Zillikens, Katja Bieber, Anika Kasprick, Rosa Lopez, Mariona Auli, Merce Pont, Nuria Godessart, Ralf J. Ludwig, Cristina BalagueAbstract: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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t cells mediate autoantibody induced cutaneous inflammation and blistering in epidermolysis bullosa acquisita
Scientific Reports, 2016Co-Authors: Katja Bieber, Mareike Witte, Shijie Sun, Jennifer E Hundt, Kathrin Kalies, Soren Drager, Anika Kasprick, Trix TwelkmeyerAbstract:T cells are key players in Autoimmune Diseases by supporting the production of autoantibodies. However, their contribution to the effector phase of antibody-mediated Autoimmune dermatoses, i.e., tissue injury and inflammation of the skin, has not been investigated. In this paper, we demonstrate that T cells amplify the development of autoantibody-induced tissue injury in a prototypical, Organ-Specific Autoimmune Disease, namely epidermolysis bullosa acquisita (EBA) – characterized and caused by autoantibodies targeting type VII collagen. Specifically, we show that immune complex (IC)-induced inflammation depends on the presence of T cells – a process facilitated by T cell receptor (TCR)γδ and NKT cells. Because tissue damage in IC-induced inflammation is neutrophil-dependent, we further analyze the interplay between T cells and neutrophils in an experimental model of EBA. We demonstrate that T cells not only enhance neutrophil recruitment into the site of inflammation but also interact with neutrophils in lymphatic organs. Collectively, this study shows that T cells amplify the effector phase of antibody-induced tissue inflammation.
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epidermolysis bullosa acquisita from pathophysiology to novel therapeutic options
Journal of Investigative Dermatology, 2016Co-Authors: Michael Kasperkiewicz, Enno Schmidt, Detlef Zillikens, Christian D Sadik, Katja Bieber, Saleh M Ibrahim, Rudolf A Manz, Ralf LudwigAbstract:Epidermolysis bullosa acquisita (EBA) is a prototypic Organ-Specific Autoimmune Disease induced by autoantibodies to type VII collagen causing mucocutaneous blisters. In the inflammatory (bullous pemphigoid-like) EBA variant, autoantibody binding is followed by a lesional inflammatory cell infiltration, and the overall clinical picture may be indistinguishable from that of bullous pemphigoid, the latter being the most common Autoimmune bullous Disease. The last decade witnessed the development of several mouse models of inflammatory EBA that facilitated the elucidation of the pathogenesis of autoantibody-induced, cell-mediated subepidermal blistering Diseases and identified new therapeutic targets for these and possibly other autoantibody-driven disorders.