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Selected Publication:
Sconocchia, T.
The role of bone morphogenetic protein signaling in the induction and maintenance of peripheral tolerance
PhD-Studium (Doctor of Philosophy); Humanmedizin; [ Dissertation ] Graz Medical University; 2021. pp. 83
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- Authors Med Uni Graz:
- Advisor:
- Eller Kathrin
- Strobl Herbert
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- Abstract:
- Dendritic cells (DCs) are professional antigen presenting cells (APCs) that link the innate and adaptive immunity. DCs play a strong role in immunity by taking up, processing, and presenting antigens to T cells in order to coordinate an immune response against pathogens. DCs can be found in many organs and tissues and are also present in the skin. The epidermis contains a unique DC subset known as Langerhans cell (LC). LCs form a dense cellular network in the epidermis and under steady-state conditions maintain immune tolerance in the skin by expanding tissue resident regulatory T (Treg) cells. LCs are susceptible to programming by factors present in the epidermis. Recently, a member of the TGF-b family known as bone morphogenetic protein (BMP)7 was described to be aberrantly expressed in the epidermis during psoriasis and to differentiate moncytic cells into LCs with characteristics of inflammation-associated LC-like DCs. However, their functional characteristics are still not fully understood. The role of Treg cells during psoriasis has recently gained more importance. In fact, murine studies described that Tregs accumulate in psoriasis-like skin lesions and have a role in limiting the severity of the disease. Given the role of LCs in expanding Tregs in the skin and that the mechanisms mediating Treg accumulation during skin inflammation remain elusive, we investigated within this thesis the role of BMP7 and its receptor BMPR1a in Treg accumulation during skin inflammation. We here described a link between BMP7/BMPR1a signaling, LCs/DCs and Treg accumulation during psoriasis. Immunohistology of psoriasis patients and healthy controls together with the analysis of a psoriasis-like inflammation model in mice lacking BMPR1a described a positive correlation between BMP7 expression intensity in the skin and Treg accumulation in psoriatic lesions. In addition, a portion of FoxP3+ cells in psoriatic lesions exhibited active BMP signaling. Moreover, we described that BMPR1a signaling in inflammation-associated LCs and DCs is associated with lower skin inflammation and that it increases the capacity of LCs/DCs to promote Treg differentiation from naïve CD4+ T cells in a mechanism that is dependent on BMPR-mediated CD25/IL-2 induction. We concluded that BMP signaling plays a regulatory role during psoriasis by limiting the inflammation. We suggest a model in which BMP7 and its downstream signaling pathway are strongly expressed in psoriasis and positively associate with Tregs within the lesions. BMPR1a promotes inflammation-associated LCs/DCs to gain enhance Treg stimulatory abilities and locally secreted BMPs can also promote Treg differentiation in a direct manner.