失養型表皮分解性水泡症(泡泡龍)病患因帶有COL7A1基因上之突變，使皮膚表皮真皮層鍵結力下降而導致皮膚脆弱。考量到失養型泡泡龍是單基因遺傳疾病，目前多數研究致力於利用基因剪輯或/和細胞治療，讓病患能重新製造具有功能之第七型膠原蛋白。雖然這些治療方式正在發展中，臨床上卻仍有許多病患亟需及時的治療緩解其搔癢與發炎症狀，以改善生活品質。透過基因分析資訊，我們得以將老藥新用，改善病患的搔癢及全身性發炎症狀。本研究利用單細胞RNA定序及bulk RNA定序來探討COL7A1突變如何影響顯性遺傳(DDEB)及隱性遺傳(RDEB)失養型泡泡龍病患皮膚的基底層角質細胞與發炎細胞，進而找到相對應的治療標的。在基底層角質細胞部分，我們發現RDEB病患的基底層角質細胞具有第一型干擾素信號的增強，具體表現在由RDEB病患誘導性多能幹細胞分化出的角質細胞中，第一型干擾素誘導基因IFIH1和IRF7的上調，這會向單核細胞來源的巨噬細胞發出信號，促使其在皮膚中表現白血球介素-6 (IL-6)。RDEB病患血中的白血球介素-6濃度和疾病嚴重程度呈正相關(嚴重型：6.56±0.90；中等型：2.98±1.58；健康受試者: 1.55±0.79)。DDEB病患的基底層角質細胞則表現較高的S100A8及S100A9，此兩基因和皮膚駐留型T細胞(skin-resident T cell)的活化相關，特別是活化Th2細胞。透過mRNA及蛋白質的定量發現DDEB病患的皮膚同時也表現有較高的Th2細胞激素。在皮膚免疫細胞的分析中，我們發現RDEB和DDEB病患的M2-like巨噬細胞表現出相反的基因表現模式。RDEB病患的M2-like巨噬細胞缺乏M2相關基因的轉錄活化，而DDEB病患則顯示出M2相關基因程式的轉錄活化。RDEB病患皮膚中的M2-like巨噬細胞表現較低之MRC1基因，此基因和膠原蛋白的降解相關。透過以上研究結果，我們能找出臨床上合適之治療標的。在RDEB中，單核細胞來源的巨噬細胞是引發炎症的主要驅動因素，因為它們分泌IL-6。因此，使用抗IL-6或抗IL-6受體的療法（如tocilizumab）在一項病例研究和我們的初步臨床試驗中顯示出良好的效果（數據尚未報告）。DDEB病患皮膚的發炎與搔癢則是因代謝旺盛之GATA3+細胞引起，因此能透過抑制白血球介素-4/13的單株抗體，如dupilumab，達到止癢之效。臨床上，我們已成功利用dupilumab改善多位DDEB病患的搔癢情形，並促進傷口癒合。本研究不只釐清RDEB與DDEB病患搔癢及發炎的致病機轉，更找到各自合適的治療標的。

Pathogenic mutations in type VII collagen (COL7A1), which exhibit complete penetrance, cause dystrophic epidermolysis bullosa (DEB) leading to skin fragility and poor dermal-epidermal adhesion. Given DEB is a monogenic disorder, research is mostly focused on restoring functional COL7A1 in the skin by gene editing, cell therapy, or a combination of both. While development for these therapies is ongoing, treating DEB complications in patients including inflammation, itch, and pain is vital in maintaining quality of life. The current lack of treatments to target itch and inflammation in DEB can be supplemented by drug repurposing, although robust genomic data is necessary to evidence its use. In this study, we employed single-cell RNA sequencing integrated with bulk RNA expression and protein expression data to determine the impact of nonnative COL7A1 on the state of basal keratinocytes (KCBs) in dominantly-inherited (DDEB) and recessively-inherited dystrophic epidermolysis bullosa (RDEB) and how these effects are propagated to skin-resident immune cells with the goal of identifying gene or protein targets for drug repurposing. Our work on KCBs indicated that differentially expressed genes from these cells can robustly classify inflammatory skin diseases including DDEB and RDEB. We found enrichment for type I interferon signaling in RDEB KCBs, as evidenced by upregulated type I interferon-inducible genes IFIH1 and IRF7 in keratinocytes differentiated from RDEB patient-derived induced pluripotent stem cells, which signals to monocyte-derived macrophages to express interleukin (IL)-6 in the skin. Elevated IL-6 (normalized protein expression) was also found to be associated with severe RDEB sera (6.56±0.90) whereas intermediate RDEB (2.98±1.58) and healthy (1.55±0.79) sera have comparably low levels for this cytokine. In DDEB KCBs, we found significant upregulation of S100A8 and S100A9 which act as damage-associated molecule pattern factors which activated skin-resident T cells, primarily helper T (Th) type 2 cells. This was evidenced by significant upregulation of Th2 cytokines at both the mRNA and protein levels in DDEB skin. Our analysis of immune cell populations also revealed opposing signatures only for M2-like macrophages from RDEB and DDEB skin with the former lacking transcriptional activation of M2-associated gene programs. RDEB M2-like macrophages were also found to have repressed expression of the mannose receptor C type-1 (MRC1) which is responsible for fragmented collagen recognition and degradation. From these, we were able to identify therapeutic targets for drug repurposing. In RDEB, where monocyte-derived macrophages act as the primary driver of inflammation by expressing IL6, the use of anti-IL6 or anti-IL6 receptor (e.g. tocilizumab) has shown promising results in one case study and in our preliminary clinical trial (data unreported). In DDEB, we implicated metabolically active GATA3+ cells to be responsible for itch and inflammation in affected skin, and treatment with the anti-IL4/IL13 signaling drug dupilumab showed significant relief from itch and improved wound healing. Our results have not only provided therapeutic targets for treating DEB-associated complications but have also contributed to the understanding of the pathobiology of itch and inflammation in DDEB and RDEB.

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