Multiple Modes of Action Mediate the Therapeutic Effect of Intravenous IgG in Experimental Epidermolysis Bullosa Acquisita

Pipi, Elena; Kasprick, Anika; Iwata, Hiroaki; Goletz, Stephanie; Hundt, Jennifer E.; Sadeghi, Hengameh; Schmidt-Jiménez, Leon F.; Schmidt, Enno; Sjögren, Jonathan; Zillikens, Detlef; Ludwig, Ralf J.; Collin, Mattias; Bieber, Katja

doi:10.1016/j.jid.2021.08.448

Cited by 4 publications

(5 citation statements)

References 67 publications

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“…To exclude that parsaclisib acts as a ROS scavenger, a cell-free ROS release assay was employed as previously reported ( 29 ). In brief, human myeloperoxidase (MPO; Enzo Life Sciences, Lörrach, Germany), catalase (CAT; Sigma-Aldrich), and glucose oxidase (GOX; Sigma-Aldrich) were mixed at final concentrations of 10 mU/mL, 2 U/mL, and 0.5 U/mL, respectively.…”

Section: Methodsmentioning

confidence: 99%

Cutaneous kinase activity correlates with treatment outcomes following PI3K delta inhibition in mice with experimental pemphigoid diseases

Ghorbanalipoor

Emtenani²,

Parker³

et al. 2022

Front. Immunol.

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Chronic blistering at the skin and/or mucous membranes, accompanied by a varying degree of inflammation, is the clinical hallmark of pemphigoid diseases that impose a major medical burden. Pemphigoid diseases are caused by autoantibodies targeting structural proteins of the epithelial basement membrane. One major pathogenic pathway of skin blistering and inflammation is activation of myeloid cells following Fc gamma receptor-dependent binding to the skin-bound immune complexes. This process requires activation of specific kinases, such as PI3Kδ, which have emerged as potential targets for the treatment of pemphigoid diseases. Yet, it is unknown if global cutaneous kinase activity present in lesional pemphigoid disease correlates with therapeutic effects following treatment with a given target-selective kinase inhibitor. To address this, we here first determined the kinase activity in three different mouse models of pemphigoid diseases: Antibody transfer-induced mucous membrane pemphigoid (MMP), antibody transfer-induced epidermolysis bullosa acquisita (EBA) and immunization-induced EBA. Interestingly, the kinome signatures were different among the three models. More specifically, PI3Kδ was within the kinome activation network of antibody transfer-induced MMP and immunization-induced EBA, but not in antibody transfer-induced EBA. Next, the therapeutic impact of the PI3Kδ-selective inhibitor parsaclisib was evaluated in the three model systems. In line with the kinome signatures, parsaclisib had therapeutic effects in antibody transfer-induced MMP and immunization-induced EBA, but not in autoantibody-induced EBA. In conclusion, kinase activation signatures of inflamed skin, herein exemplified by pemphigoid diseases, correlate with the therapeutic outcomes following kinase inhibition, demonstrated here by the PI3Kδ inhibitor parsaclisib.

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Section: Methodsmentioning

confidence: 99%

Cutaneous kinase activity correlates with treatment outcomes following PI3K delta inhibition in mice with experimental pemphigoid diseases

Ghorbanalipoor

Emtenani²,

Parker³

et al. 2022

Front. Immunol.

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“…This neutralization mechanism would explain the impact on complement activation in several of the analyzed diseases, which in turn prevents complement-mediated tissue damage (100). Evidence supports the relevance of complement activation inhibition by IVIg in the therapeutic efficacy in autoimmune dermatological conditions, reinforce the relevance of this mechanism within IVIg therapeutic effects (101). In contrast, no common B cell-related targets were found, probably due to the great complexity of B cell pathological role in autoimmune conditions (e.g., autoantibodies production, cytokines release, autoantigens presentation to T cells) (102).…”

Section: Discussionmentioning

confidence: 81%

“…Finally, although we reviewed all available information at the time of the study for identification of direct IVIg targets, including FcgR and non-receptor protein targets, the extreme complexity of IVIg, due to its multi-target feature at the molecular and cellular level, could have led us to underestimate the potential impact of IVIg by including an incomplete list of targets because of a dearth of evidence. Indeed, a recent study by Pipi et al (2021) (101) unraveled potential non-receptor-mediated antioxidative mechanism for high-dose IgG, as neutrophil elastase substrate and through ROS scavenging, potentially involved in the treatment of skin autoimmunity; however, for the latter they did not detail the mechanism nor specified the direct IVIg protein target, which was a requirement for our approach. Also, considering only direct IVIg targets might have oversimplified the model, hindering the detection of effects over immune components indirectly affected by IVIg; and categorizing the identified targets in discrete function compartments, which might have oversimplified the IVIg mechanisms explored in the ANN analysis on overall processes.…”

Section: Discussionmentioning

confidence: 99%

Systems biology and artificial intelligence analysis highlights the pleiotropic effect of IVIg therapy in autoimmune diseases with a predominant role on B cells and complement system

Segú-Vergés

Caño²,

Calderón–Gómez

et al. 2022

Front. Immunol.

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Intravenous immunoglobulin (IVIg) is used as treatment for several autoimmune and inflammatory conditions, but its specific mechanisms are not fully understood. Herein, we aimed to evaluate, using systems biology and artificial intelligence techniques, the differences in the pathophysiological pathways of autoimmune and inflammatory conditions that show diverse responses to IVIg treatment. We also intended to determine the targets of IVIg involved in the best treatment response of the evaluated diseases. Our selection and classification of diseases was based on a previously published systematic review, and we performed the disease characterization through manual curation of the literature. Furthermore, we undertook the mechanistic evaluation with artificial neural networks and pathway enrichment analyses. A set of 26 diseases was selected, classified, and compared. Our results indicated that diseases clearly benefiting from IVIg treatment were mainly characterized by deregulated processes in B cells and the complement system. Indeed, our results show that proteins related to B-cell and complement system pathways, which are targeted by IVIg, are involved in the clinical response. In addition, targets related to other immune processes may also play an important role in the IVIg response, supporting its wide range of actions through several mechanisms. Although B-cell responses and complement system have a key role in diseases benefiting from IVIg, protein targets involved in such processes are not necessarily the same in those diseases. Therefore, IVIg appeared to have a pleiotropic effect that may involve the collaborative participation of several proteins. This broad spectrum of targets and ‘non-specificity’ of IVIg could be key to its efficacy in very different diseases.

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“…In a nonreceptor-mediated fashion, IVIG showed antioxidative properties by scavenging extracellular ROS ( 20 ). Moreover, IVIG were able to impair complement activation and served as a substrate for proteases – key events in EBA pathogenesis ( 22 ).…”

Section: Discussionmentioning

confidence: 99%

Case Report: Biological treatment of epidermolysis bullosa acquisita: report on four cases and literature review

et al. 2023

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Epidermolysis bullosa acquisita (EBA) is a chronic, recurrent autoimmune subepidermal bullous disease characterized by the presence of autoantibodies targeting type VII collagen -- basement membrane zone antigen. Standard therapy for EBA includes a combination of systemic corticosteroids and dapsone; however, severe cases may require advanced treatment. The current article reports on four EBA cases in which biologics: infliximab, rituximab (Rtx), and intravenous immunoglobulin (IVIG) were applied. All patients fulfilled the clinical and immunological criteria of EBA: they presented tense blisters healing with atrophic scars on the skin on traumatized areas and in mucous membranes. The diagnosis of EBA was established using numerous techniques: direct and indirect immunofluorescence, salt split skin, ELISA, Fluorescence Overlay Antigen Mapping using Laser Scanning Confocal Microscopy. Since all the patients did not achieve long-term remission on standard treatment (prednisone, dapsone) due to ineffectiveness or side effects of drugs, they eventually were treated with biologics leading to extraordinary skin improvement and stopping the disease for 1-3 years. Biologics in all patients were tolerated very well. No side effects were observed during application as well as multi-month follow-up. The presented cases provide a premise that biological drugs can be a valuable component of EBA therapy.

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Multiple Modes of Action Mediate the Therapeutic Effect of Intravenous IgG in Experimental Epidermolysis Bullosa Acquisita

Cited by 4 publications

References 67 publications

Cutaneous kinase activity correlates with treatment outcomes following PI3K delta inhibition in mice with experimental pemphigoid diseases

Cutaneous kinase activity correlates with treatment outcomes following PI3K delta inhibition in mice with experimental pemphigoid diseases

Systems biology and artificial intelligence analysis highlights the pleiotropic effect of IVIg therapy in autoimmune diseases with a predominant role on B cells and complement system

Case Report: Biological treatment of epidermolysis bullosa acquisita: report on four cases and literature review

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