The Sphingosine-1-Phosphate Receptor Modulator Fingolimod Aggravates Murine Epidermolysis Bullosa Acquisita

Thieme, Markus; Bieber, Katja; Sezin, Tanya; Wannick, Melanie; Gupta, Yask; Kalies, Kathrin; Ludwig, Ralf J.; Mousavi, Sadegh; Zillikens, Detlef; Sadik, Christian D.

doi:10.1016/j.jid.2019.03.1159

Cited by 8 publications

(5 citation statements)

References 20 publications

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“…One possibility to observe potential exchanges of Tfh cells between lymph nodes would be treatment with the T cell trafficking blocker FTY720. However, previous studies revealed no effect in this autoimmune mouse model ( Niebuhr et al, 2017 ; Thieme et al, 2019 ). The second major finding of our study is that the PBS group, which received only adjuvant, develops GCs to a similar extent as the Ag group.…”

Section: Discussioncontrasting

confidence: 61%

Receptor repertoires of murine follicular T helper cells reveal a high clonal overlap in separate lymph nodes in autoimmunity

Niebuhr

Belde

Fähnrich

et al. 2021

eLife

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Follicular T helper cells (Tfh) are a specialized subset of CD4 effector T cells that are crucial for germinal center (GC) reactions and for selecting B cells to undergo affinity maturation. Despite this central role for humoral immunity, only few data exist about their clonal distribution when multiple lymphoid organs are exposed to the same antigen (Ag) as it is the case in autoimmunity. Here, we used an autoantibody-mediated disease model of the skin and injected one auto-Ag into the two footpads of the same mouse and analyzed the T cell receptor (TCR)β sequences of Tfh located in GCs of both contralateral draining lymph nodes. We found that over 90% of the dominant GC-Tfh clonotypes were shared in both lymph nodes but only transiently. The initially dominant Tfh clonotypes especially declined after establishment of chronic disease while GC reaction and autoimmune disease continued. Our data demonstrates a dynamic behavior of Tfh clonotypes under autoimmune conditions and emphasizes the importance of the time point for distinguishing auto-Ag-specific Tfh clonotypes from potential bystander activated ones.

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Section: Discussioncontrasting

confidence: 61%

Receptor repertoires of murine follicular T helper cells reveal a high clonal overlap in separate lymph nodes in autoimmunity

Niebuhr

Belde

Fähnrich

et al. 2021

eLife

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“…Recent studies in mouse models of pemphigoid diseases, have highlighted the anaphylatoxin C5a and the eicosanoid leukotriene B 4 as central choreographers of this process on the molecular level (9,11,12). On the cellular level, γδ T cells and T regs have been demonstrated to interact with granulocytes to promote and suppress skin inflammation, respectively, by modulating neutrophil activity in the dermis (13)(14)(15).…”

Section: Introductionmentioning

confidence: 99%

The G Protein-Coupled Receptor (GPR) 15 Counteracts Antibody-Mediated Skin Inflammation

et al. 2020

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The G protein-coupled receptor 15 (GPR15) has recently been highlighted as an important regulator of T cell trafficking into the gut under physiological and pathophysiological conditions. Additionally, circumstantial evidence has accumulated that GPR15 may also play a role in the regulation of chronic inflammation. However, the (patho)physiological significance of GPR15 has, in general, remained rather enigmatic. In the present study, we have addressed the role of GPR15 in the effector phase of autoantibody-mediated skin inflammation, specifically in the antibody transfer mouse model of bullous pemphigoid-like epidermolysis bullosa acquisita (BP-like EBA). Subjecting Gpr15 −/− mice to this model, we have uncovered that GPR15 counteracts skin inflammation. Thus, disease was markedly aggravated in Gpr15 −/− mice, which was associated with an increased accumulation of γδ T cells in the dermis. Furthermore, GPR15L, the recently discovered cognate ligand of GPR15, was markedly upregulated in inflamed skin. Collectively, our results highlight GPR15 as counter-regulator of neutrophilic, antibody-mediated cutaneous inflammation. Enhancing the activity of GPR15 may therefore constitute a novel therapeutic principle in the treatment of pemphigoid diseases, such as BP-like EBA.

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“…Since then, S1P receptors have been studied in relation to pathological mechanisms in various tissues and diseases. In the field of dermatology, S1P receptors have been reported to affect various skin diseases, including wound [27], scleroderma [28], epidermolysis bullosa [29], infection [30,31], and inflammatory skin diseases such as atopic dermatitis [32][33][34][35][36] and psoriasis [37][38][39][40]. Recently, Reines et al reported that the topical application of S1P and S1P modulator, FTY720, which binds to S1PR1 and has mixed agonist-antagonist effects on S1PR1 [41], but also binds to S1PR3-5 as well, attenuated ACD reaction via inhibiting dendritic cell migration [42].…”

Section: Discussionmentioning

confidence: 99%

S. epidermidis Rescues Allergic Contact Dermatitis in Sphingosine 1-Phosphate Receptor 2-Deficient Skin

Masuda-Kuroki,

Alimohammadi,

Di Nardo

2023

IJMS

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Recent studies have identified a subtype of the S1P-receptor family called sphingosine-1-phosphate receptor 2 (S1PR2), which plays a crucial role in maintaining the skin barrier. It has been observed that S1PR2 and Staphylococcus epidermidis (S. epidermidis) work together to regulate the skin barrier. However, the interaction between these two factors is still unclear. To investigate this, a study was conducted on healthy skin and allergic contact dermatitis (ACD) using 3,4-Dibutoxy-3-cyclobutene-1,2-dione (SADBE) on the ears of S1pr2fl/fl and S1pr2fl/flK14-Cre mice and using 1 × 106 CFU of S. epidermidis to examine its effects on the skin. The results showed that in S. epidermidis-conditioned ACD, the ear thickness of S1pr2fl/flK14-Cre mice was lower than that of S1pr2fl/fl mice, and mRNA expressions of Il-1β and Cxcl2 of S1pr2fl/flK14-Cre mice were lower than that of S1pr2fl/fl mice in ACD with S. epidermidis. Furthermore, the gene expression of Claudin-1 and Occludin in S1pr2fl/flK14-Cre mice was higher than that of S1pr2fl/fl mice in ACD with S. epidermidis. The study concludes that S. epidermidis colonization improves the skin barrier and prevents ACD even when S1P signaling malfunctions.

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The Sphingosine-1-Phosphate Receptor Modulator Fingolimod Aggravates Murine Epidermolysis Bullosa Acquisita

Abstract: clear DEAF-1-related (NUDR) protein contains a novel DNA binding domain and represses transcription of the heterogeneous nuclear ribonucleoprotein A2/B1 promoter. J Biol Chem 1999;274:30510e9.

Cited by 8 publications

References 20 publications

Receptor repertoires of murine follicular T helper cells reveal a high clonal overlap in separate lymph nodes in autoimmunity

Receptor repertoires of murine follicular T helper cells reveal a high clonal overlap in separate lymph nodes in autoimmunity

The G Protein-Coupled Receptor (GPR) 15 Counteracts Antibody-Mediated Skin Inflammation

S. epidermidis Rescues Allergic Contact Dermatitis in Sphingosine 1-Phosphate Receptor 2-Deficient Skin

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