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Single-Cell Sequencing Uncovers Signaling Pathways Involved in Skin Discoloration Disorder

NEW YORK — A range of signaling pathways are involved in the development of vitiligo, a condition that leads to loss of skin color, a new single-cell RNA sequencing study has found.

Vitiligo, an autoimmune disorder, affects about 1 percent of the human population. Cytokine signaling between keratinocytes and T cells leads CD8+ T cells to target melanocytes for destruction, which then generates patches of skin lacking pigmentation.

By isolating affected and unaffected skin cells from individuals with vitiligo, as well as skin samples from unaffected controls, for RNA sequencing analysis, researchers from the University of Massachusetts Medical School further examined which cells and signaling pathways are involved in disease progression. As they reported Wednesday in Science Translational Medicine, the researchers tied various signaling pathways to vitiligo pathogenesis. In particular, they noted a role for CCL5-CCR5 signaling in its development. At the same time, unaffected skin from individuals with vitiligo may be in a subclinical inflammatory state, they found.

"These new observations promote a comprehensive model for understanding the initiation and progression of vitiligo directly within human skin, as well as new therapeutic opportunities," John Harris, a dermatologist at UMass Med, and his colleagues wrote in their paper.

The researchers used suction blistering to collect skin samples from affected and non-lesional skin from 10 individuals with vitiligo, as well as healthy skin samples from seven unaffected individuals. Following single-cell RNA sequencing, the researchers clustered the cells into 10 groups that represented the five main cell types found in skin, such as melanocytes and keratinocytes as well as lymphocytes, macrophages, and dendritic cells. They further clustered these cells based on cell-type-specific expression markers like CD4 or CD8.

Affected lesional skin from individuals with vitiligo have a high rate of T cell infiltration, the researchers found. Further, they traced the main source of IFN-γ to CD8+ T cells, noting that IFN-γ signaling is known to have a key role in vitiligo pathogenesis. Regulatory T cells, they reported, are the second major producer of IFN-γ in vitiligo lesions, where they adopt a type 1 immune profile and express IFNG, TBX21, CXCR3, and CCR5.

Additional analyses of CD8+ T cells noted increased IFN-γ and T cell activation within non-lesion skin samples from individuals with vitiligo — even with their normal melanocyte levels. The researchers further uncovered increased regulatory T cell activation in non-lesional skin from affected individuals, as compared to healthy skin from unaffected individuals. This was then further increased in lesional samples. That plus cell-type-specific IFN-γ responses suggests non-lesional skin is in a subclinical inflammatory state, they added.

To further characterize T-cell recruitment, the researchers examined cell-to-cell signaling events using a database of receptors and ligands. They homed in on CCR5 on regulatory T cells, finding that in patients' skin samples, nearly all of these cells have increased CCR5 expression, though that expression is even higher within vitiligo lesions. CCL5, meanwhile, is a CCR5 ligand and is highly expressed by CD8+ T cells in vitiligo lesions. This suggested to the researchers that CCR5 may enable regulatory T cells to function by positioning them near CD8+ T cells to suppress them.

Since their findings indicate a role for CCR5 in suppressing CD8+ T cells, the researchers noted that treatments that spare CCR5 signaling while still blocking effector pathways might serve as a viable approach. "These observations may apply to autoimmune diseases in other organs characterized by type 1 inflammation as well, such as type 1 diabetes; however, focused studies in these patients will be important to confirm this," they added.