GM-CSF Modulates Autoantibody Production and Skin Blistering in Experimental Epidermolysis Bullosa Acquisita

Samavedam, Unni; Iwata, Hiroaki; Müller, Susen; Schulze, Franziska; Recke, Andreas; Schmidt, Enno; Zillikens, Detlef; Ludwig, Ralf J.

doi:10.4049/jimmunol.1301556

Cited by 39 publications

(42 citation statements)

References 59 publications

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“…Neutrophil activation was assessed by the determination of IC-induced ROS release using a previously published protocol50 with minor modifications. In brief, the mouse femurs were isolated, and the cells were washed out with 10 ml PBS using a 26 G syringe.…”

Section: Methodsmentioning

confidence: 99%

“…Isolated TCRγδ or NKT cells were restimulated for 18 h using 5 μg/ml anti mCD3 (Biolegend, clone 145-2C11). The cultured cells, the supernatant or the combination of both was subsequently co-cultured with freshly isolated murine neutrophils50 in a ratio of 1:4 for additional 4 h. The neutrophils were stained for FACS using CD18-FITC, CD62L-PE-Vio770, Ly6G-APC-Vio770 and CD45-VioGreen (Miltenyi) following standard procedures to evaluate the activation status. Dead cells were excluded using PI.…”

Section: Methodsmentioning

confidence: 99%

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T cells mediate autoantibody-induced cutaneous inflammation and blistering in epidermolysis bullosa acquisita

Bieber

Witte

Sun

et al. 2016

Sci Rep

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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, organspecific autoimmune disease, namely epidermolysis bullosa acquisita ( T cells are essential regulators of host defense and exhibit direct cytotoxic as well as regulatory properties. The presence or absence of pro-inflammatory compared with regulatory T cell subsets affects the development and outcome of inflammatory reactions. Misbalance of T cell populations leads to autoimmune disorders, including systemic lupus erythematosus (SLE), different autoimmune bullous dermatoses (AIBDs) and rheumatoid arthritis (RA) [1][2][3] . In these diseases, the contribution of T cells to antibody production and maintenance of the autoimmune response has clearly been demonstrated 4,5 . In recent decades, the understanding of autoantibody-induced tissue injury has greatly improved. However, the role of T cells during the effector phase of autoimmune skin blistering diseases, i.e., tissue injury and inflammation in the targeted organs, is not completely understood. In this study, we investigated the role of T cells during this phase, using a mouse model of epidermolysis bullosa acquisita (EBA), a prototypical organ-specific autoimmune disease 6,7 . EBA is caused by autoantibodies directed against type VII collagen (COL7), an integral component of anchoring fibrils 8 . Animal models, employing antibody transfer into mice 9,10 , have added to a greater understanding of the mechanisms leading to blistering in EBA 9,11,12 . Based on the current understanding of EBA pathogenesis, the effector phase of EBA is predominantly driven by neutrophils -their depletion leading to a complete absence of experimental EBA 13. With regard to T cell involvement during this phase, in vivo and in vitro data have been contradictory. In vivo data indicated a T cell-independent process: Transfer of total IgG isolated from rabbits that had been immunized with COL7 into T cell-deficient mice induced subepidermal blistering 9 . However, in that study, no wild-type control for evaluation of the extent of blistering was included. In other

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

T cells mediate autoantibody-induced cutaneous inflammation and blistering in epidermolysis bullosa acquisita

Bieber

Witte

Sun

et al. 2016

Sci Rep

Self Cite

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“…In one recent study it was demonstrated that GM-CSF treatment could exacerbate autoantibody production and skin blistering in experimental epidermolysis bullosa acquisita (EBA) through neutrophil activation. Predictively, neutralization of GM-CSF proved to be beneficial in this model (63). However, how GM-CSF affects autoantibody production is not understood.…”

Section: Introductionmentioning

confidence: 97%

“…However, recent evidences suggest the involvement of neutrophils in various autoimmune diseases in human including rheumatoid arthritis (58, 60), systemic lupus erythematosus (61), Bullous pemphigoid (62), Epidermolysis bullosa acquisita (63), multiple sclerosis (64) and anti-neutrophil cytoplasmic autoantibodies-associated vasculitis (65). Neutrophils participate in almost every phase of autoimmune diseases such as immunization, transition and effector phase.…”

Section: Introductionmentioning

confidence: 99%

GM-CSF: An immune modulatory cytokine that can suppress autoimmunity

et al. 2015

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GM-CSF was originally identified as a colony stimulating factor (CSF) because of its ability to induce granulocyte and macrophage populations from precursor cells. Multiple studies have demonstrated that GM-CSF is also an immune-modulatory cytokine, capable of affecting not only the phenotype of myeloid lineage cells, but also T-cell activation through various myeloid intermediaries. This property has been implicated in the sustenance of several autoimmune diseases like arthritis and multiple sclerosis. In contrast, several studies using animal models have shown that GM-CSF is also capable of suppressing many autoimmune diseases like Crohn's disease, Type-1 diabetes, Myasthenia gravis and experimental autoimmune thyroiditis. Knockout mouse studies have suggested that the role of GM-CSF in maintaining granulocyte and macrophage populations in the physiological steady state is largely redundant. Instead, its immune-modulatory role plays a significant role in the development or resolution of autoimmune diseases. This is mediated either through the differentiation of precursor cells into specialized non-steady state granulocytes, macrophages and dendritic cells, or through the modulation of the phenotype of mature myeloid cells. Thus, outside of myelopoiesis, GM-CSF has a profound role in regulating the immune response and maintaining immunological tolerance.

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“…Additional work using an adult mouse model for EBA demonstrated that the alternative complement pathway, [35] neutrophils, CD18, NADPH oxidase, [36] GM-CSF, [37] IL-6, [38] TNF-α, [39] Hsp90, [40] CXCR1/2 [41] and the neonatal Fc-receptor [42] are crucial for the pathogenesis of experimental EBA. To avoid the non-specific effects of high levels of rabbit IgG, this model was refined using affinitypurified IgG.…”

Section: Antibody Transfer-induced Models Of Ebamentioning

confidence: 99%

In vitro and in vivo models to investigate the pathomechanisms and novel treatments for pemphigoid diseases

Bieber

Koga

Nishie

2017

Experimental Dermatology

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Pemphigoid diseases (PD) are a subgroup of rare acute or chronic autoimmune skin disorders characterized and caused by autoantibodies directed against distinct structural components of the dermal-epidermal junction. Binding of autoantibodies to their targets leads to the formation of blisters and erosions in patients. PDs comprise eight disorders for which the molecular target antigens have been identified. First, we review the available in vitro and ex vivo models for analysis of distinct aspects of the pathogenesis of PDs. This includes the binding of autoantibodies to skin sections, the analysis of blister formation capability and skin complement activation as well as investigation of neutrophil and keratinocyte activation. In addition to this, several animal models of PD have been developed during the last decades. These animal models have greatly contributed to our current understanding of the pathogenesis of PDs. We summarize spontaneously arising PD in animals and the induction of PD by transfer of (auto)antibodies, transfer of (auto)-antigen-specific lymphocytes and by immunization.In combined use, these models allow dissecting all aspects of PD pathogenesis, for example loss of tolerance, autoantibody production and inflammatory skin processes that lead to blister formation. Overall, we aimed to foster translational biomedical research, to deepen our understanding of PD pathogenesis and to develop novel treatments for patients suffering from these life-threatening and difficult-to-treat autoimmune diseases. K E Y W O R D Sanimal model, autoimmune bullous dermatoses, autoimmunity, bullous pemphigoid, epidermolysis bullosa acquisita, pemphigoid disease, skin

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GM-CSF Modulates Autoantibody Production and Skin Blistering in Experimental Epidermolysis Bullosa Acquisita

Cited by 39 publications

References 59 publications

T cells mediate autoantibody-induced cutaneous inflammation and blistering in epidermolysis bullosa acquisita

T cells mediate autoantibody-induced cutaneous inflammation and blistering in epidermolysis bullosa acquisita

GM-CSF: An immune modulatory cytokine that can suppress autoimmunity

In vitro and in vivo models to investigate the pathomechanisms and novel treatments for pemphigoid diseases

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