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dc.contributor.advisorJohn E. Harris
dc.contributor.authorStrassner, James P.
dc.date2022-08-11T08:08:38.000
dc.date.accessioned2022-08-23T16:01:58Z
dc.date.available2022-08-23T16:01:58Z
dc.date.issued2019-04-07
dc.date.submitted2019-05-15
dc.identifier.doi10.13028/1swp-p534
dc.identifier.urihttp://hdl.handle.net/20.500.14038/31242
dc.description.abstractVitiligo is an autoimmune disease in which CD8+ T cells selectively destroy melanocytes, leading to a patchy, disfiguring depigmentation of the skin. Our group and others have highlighted the central role of IFN-γ-dependent chemokines in the progression of disease; however, IFN-γ is also reported to have pleiotropic effects on melanocyte biology. We examined whether IFN-γ has a direct role in melanocyte killing. We tested the T-cell effector functions IFN-γ, Fas ligand and perforin by deleting them from autoreactive T cells used to induce vitiligo in mice. We found that disease incidence, disease severity and T cell accumulation in the skin was reduced in mice receiving adoptive transfer of either IFN-γ deficient or Fas ligand deficient gp100-specific T cells; however, perforin was dispensable and led to increased disease scores and T cell accumulation. To determine how melanocytes are affected by IFN-γ signaling during vitiligo, we performed single-cell RNA-sequencing on suction blister biopsies obtained from vitiligo and healthy subjects. We discovered that integrin expression and TGFb2 signaling was decreased only in lesional melanocyte transcriptomes. Moreover, melanocytes appear to participate in their own demise by increasing HLA expression and recruiting effector cells through the chemotactic ligand CCL18. The loss of melanocyte retention factors may explain their clean disappearance from the skin during keratinocyte turnover. Taken together, we believe IFN-γ production by autoreactive T cells in the skin leads to clean loss of melanocytes by downregulation of melanocyte retention factors and by increasing their potential to be detected by effector cells during vitiligo.
dc.language.isoen_US
dc.rightsCopyright is held by the author, with all rights reserved.
dc.subjectVitiligo
dc.subjectautoimmunity
dc.subjectbiomarker
dc.subjectsingle-cell RNA-sequencing
dc.subjectT cell
dc.subjectmelanocyte
dc.subjectT-cell effector functions
dc.subjectBioinformatics
dc.subjectDermatology
dc.subjectImmune System Diseases
dc.subjectImmunity
dc.subjectSkin and Connective Tissue Diseases
dc.subjectTranslational Medical Research
dc.titleThe Role of Interferon Gamma in Melanocyte Clearance During Vitiligo
dc.typeDoctoral Dissertation
dc.identifier.legacyfulltexthttps://escholarship.umassmed.edu/cgi/viewcontent.cgi?article=2034&context=gsbs_diss&unstamped=1
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/gsbs_diss/1023
dc.legacy.embargo2021-05-10T00:00:00-07:00
dc.identifier.contextkey14502978
refterms.dateFOA2022-08-28T02:57:42Z
html.description.abstract<p>Vitiligo is an autoimmune disease in which CD8+ T cells selectively destroy melanocytes, leading to a patchy, disfiguring depigmentation of the skin. Our group and others have highlighted the central role of IFN-γ-dependent chemokines in the progression of disease; however, IFN-γ is also reported to have pleiotropic effects on melanocyte biology. We examined whether IFN-γ has a direct role in melanocyte killing. We tested the T-cell effector functions IFN-γ, Fas ligand and perforin by deleting them from autoreactive T cells used to induce vitiligo in mice. We found that disease incidence, disease severity and T cell accumulation in the skin was reduced in mice receiving adoptive transfer of either IFN-γ deficient or Fas ligand deficient gp100-specific T cells; however, perforin was dispensable and led to increased disease scores and T cell accumulation. To determine how melanocytes are affected by IFN-γ signaling during vitiligo, we performed single-cell RNA-sequencing on suction blister biopsies obtained from vitiligo and healthy subjects. We discovered that integrin expression and TGFb2 signaling was decreased only in lesional melanocyte transcriptomes. Moreover, melanocytes appear to participate in their own demise by increasing HLA expression and recruiting effector cells through the chemotactic ligand CCL18. The loss of melanocyte retention factors may explain their clean disappearance from the skin during keratinocyte turnover. Taken together, we believe IFN-γ production by autoreactive T cells in the skin leads to clean loss of melanocytes by downregulation of melanocyte retention factors and by increasing their potential to be detected by effector cells during vitiligo.</p>
dc.identifier.submissionpathgsbs_diss/1023
dc.contributor.departmentDermatology
dc.description.thesisprogramMD/PhD
dc.identifier.orcid0000-0002-0632-1169


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