{
  "abstract": "Introduction Systemic sclerosis, a complex autoimmune disease, is primarily characterized by fibrosis of skin and internal organs. Among notable cutaneous manifestations of SSc, S&P is characterized by vitiligo-like depigmentation with perifollicular pigment retention in sclerosis region, and is associated with diffuse subtype. Previous study reported immune depositions in depigmented areas of S&P skin, and we have observed S&P in SSc patients triggered by trauma and vaccination, hinting the potential role of aberrant immunity in S&P pathogenesis. However, the underlying mechanisms and molecular traits of melanocyte destruction in S&P remain poorly understood.Material and Methods We collected skin biopsy samples from 2 healthy controls (HC) and 3 diffuse cutaneous SSc (dcSSc) patients and employed the latest Visium HD technology, which provides single-cell level resolution and higher spatial fidelity (figure A). The 16 µm bin size was selected for downstream analysis to balance resolution and gene counts.Results The proportion of melanocytes was markedly reduced in the S&P group compared to HC and non-S&P SSc groups (figure B).To decipher the local microenvironment of melanocytes, we defined melanocyte niche as the spots immediately adjacent to melanocyte spots (figure C). S&P melanocyte niches were functionally enriched in response to oxidative stress and immune chemotaxis compared to SSc (figure D). Consistent with this, keratinocytes in S&P epidermis also showed enrichment of oxidative stress and cytokine-mediated signaling pathways compared with other categories, suggesting inflammatory stimulation and oxidative damage in lesional keratinocytes. Melanocytes reside in the basal layer of epidermis, and keratinocytes have been shown to participate in the regulation of melanocyte function.Strikingly, the differentially expressed genes (DEGs) defining this immune-activated niche were dominated by Interferon-gamma-induced chemokines (CXCL9, CXCL10) and alarmins (S100A8, S100A9) (figure E).Immunofluorescence staining further confirmed increased CXCL9 protein expression in the basal layer of the S&P epidermis (figure F). Spatial gradient analysis in S&P sample demonstrated that the expression of CXCL9, CXCL10, S100A8, and S100A9 peaked within the immediate melanocyte niche and decayed with distance, suggesting a focal hub of immune activation driving melanocyte destruction (figure G-H).Conclusions This is the first report uncovering S&P at single-cell spatial resolution, demonstrating how a permissive microenvironment facilitates melanocyte destruction. We propose that dissecting the local microenvironments of distinct skin signs, such as Gottron papules in dermatomyositis or the malar rash in systemic lupus erythematosus, could reveal novel insights into systemic autoimmunity.Abstract P.205 Figure 1",
  "authors": [
    {
      "affiliations": [
        "Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China"
      ],
      "name": "Zhangyi Zhao"
    },
    {
      "affiliations": [
        "Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China"
      ],
      "name": "Chanhan Jia"
    },
    {
      "affiliations": [
        "Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China"
      ],
      "name": "Wanyi Lin"
    },
    {
      "affiliations": [
        "Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China"
      ],
      "name": "Chaoyu Gu"
    },
    {
      "affiliations": [
        "Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China"
      ],
      "name": "Fenglin Wu"
    },
    {
      "affiliations": [
        "Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China"
      ],
      "name": "Zhe Ding"
    },
    {
      "affiliations": [
        "Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China"
      ],
      "name": "Yuankai Sun"
    },
    {
      "affiliations": [
        "Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China"
      ],
      "name": "Hanlin Yin"
    },
    {
      "affiliations": [
        "Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China"
      ],
      "name": "Liangjing Lu"
    }
  ],
  "title": "P.205 Spatial insights into melanocyte niches in salt-and-pepper dyspigmentation of systemic sclerosis",
  "uid": "2367e7a0-c9c1-5bcf-bf61-94baff9656c2"
}