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Human and Murine Evidence for Myeloid Cells As Early Drivers of Photosensitive Skin Disease in Systemic Lupus Erythematosus
Human and Murine Evidence for Myeloid Cells As Early Drivers of Photosensitive Skin Disease in Systemic Lupus Erythematosus
상세정보
- 자료유형
- 학위논문 서양
- 최종처리일시
- 20260202105633
- ISBN
- 9798297644687
- DDC
- 610
- 서명/저자
- Human and Murine Evidence for Myeloid Cells As Early Drivers of Photosensitive Skin Disease in Systemic Lupus Erythematosus
- 발행사항
- [Sl] : University of Michigan, 2024
- 발행사항
- Ann Arbor : ProQuest Dissertations & Theses, 2024
- 형태사항
- 170 p
- 주기사항
- Source: Dissertations Abstracts International, Volume: 87-04, Section: B.
- 주기사항
- Advisor: Kahlenberg, J. Michelle.
- 학위논문주기
- Thesis (Ph.D.)--University of Michigan, 2024.
- 초록/해제
- 요약Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disorder characterized by sensitivity to ultraviolet (UV) light and overproduction of type I interferons (IFNs). Up to 70% of SLE patients experience skin lesions, called cutaneous lupus erythematosus (CLE). Flares of cutaneous and systemic disease can be triggered by exposure to UV light in a process called photosensitivity, which affects over 90% of patients with lupus. Though photosensitivity is a well-known phenomenon in SLE and CLE, mechanisms that drive UV-mediated inflammation in lupus are poorly understood and represent a critically important area of research for the prevention of photosensitive disease. This dissertation was focused on the precise dissection of early innate inflammatory responses to UVB light in both murine lupus models and human lupus in an effort to better understand mechanisms that drive the initial response to UV in lupus skin and uncover mechanisms that link UV-induced inflammation with the development of cutaneous lesions in lupus. Specifically, we focus on effects downstream of type I IFN signaling, as type I IFNs have been shown to correlate with increased lupus disease activity and severity, contribute to enhanced apoptosis, and are overexpressed in lesional and nonlesional skin of SLE patients compared with healthy controls. In chapter 2, we utilize murine models of lupus to assess the differential transcriptional and immune-cell recruitment effects of acute and chronic UVB exposure. Additionally, we leverage lupus-prone mice with a type I IFN receptor knockout to assess the effects of type I IFNs on these findings. Using bulk RNA sequencing and flow cytometric analysis of acutely and chronically UVB irradiated lupus and wild-type murine skin, we determined that inflammatory pathways and gene signatures related to neutrophils and monocyte-derived dendritic cells are upregulated in acute and chronic UV-exposed murine lupus skin relative to wild-type in a type I IFN-dependent fashion. Taken together, these data indicate a skewed IFN-driven inflammatory response to both acute and chronic UVB exposure in lupus-prone skin dominated by myeloid cells, suggesting both the importance of type I IFNs and myeloid cells as therapeutic targets for photosensitive patients and highlighting the risks of even moderate UV exposure in this patient population. In chapter 3, we further explore the aberrant cutaneous inflammatory response to UVB exposure using single-cell RNA sequencing technologies to investigate transcriptional differences between UV-exposed and -unexposed skin of SLE and healthy control subjects. Interestingly, in both healthy control and lupus skin, we identify the recruitment of a population of monocyte-derived dendritic cells (moDCs) to the dermo-epidermal junction in UV-treated skin. However, lupus moDCs appear to be derived from different circulating monocyte precursors and further demonstrate hyperinflammatory responses compared to healthy control. We identify several nodes of dysregulation in lupus skin which may contribute to these findings. First, we show dysregulation of epidermal responses to UVB in lupus, identifying an inflammatory population of basal keratinocytes as important mediators of UVB-driven inflammation in lupus skin. We also demonstrate that stromal cell responses in the dermis are skewed likely secondary to inflammatory signals derived from these keratinocytes, which contributes to production of inflammatory cytokines and chemokines that skew lupus moDCs toward hyperinflammatory responses. Finally, we demonstrate that UV-recruited moDCs in lupus are transcriptionally related to lesional CD16+ DCs, identifying a novel link between UV responses and the development of cutaneous lesions.
- 일반주제명
- Medicine
- 일반주제명
- Health sciences
- 일반주제명
- Immunology
- 일반주제명
- Cellular biology
- 키워드
- Photosensitivity
- 기타저자
- University of Michigan Immunology PhD
- 기본자료저록
- Dissertations Abstracts International. 87-04B.
- 전자적 위치 및 접속
- 로그인 후 원문을 볼 수 있습니다.
MARC
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■020 ▼a9798297644687
■035 ▼a(MiAaPQ)AAI32364334
■035 ▼a(MiAaPQ)umichrackham006550
■040 ▼aMiAaPQ▼cMiAaPQ
■0820 ▼a610
■1001 ▼aMaz, Mitra Padideh.
■24510▼aHuman and Murine Evidence for Myeloid Cells As Early Drivers of Photosensitive Skin Disease in Systemic Lupus Erythematosus
■260 ▼a[Sl]▼bUniversity of Michigan▼c2024
■260 1▼aAnn Arbor▼bProQuest Dissertations & Theses▼c2024
■300 ▼a170 p
■500 ▼aSource: Dissertations Abstracts International, Volume: 87-04, Section: B.
■500 ▼aAdvisor: Kahlenberg, J. Michelle.
■5021 ▼aThesis (Ph.D.)--University of Michigan, 2024.
■520 ▼aSystemic lupus erythematosus (SLE) is a heterogeneous autoimmune disorder characterized by sensitivity to ultraviolet (UV) light and overproduction of type I interferons (IFNs). Up to 70% of SLE patients experience skin lesions, called cutaneous lupus erythematosus (CLE). Flares of cutaneous and systemic disease can be triggered by exposure to UV light in a process called photosensitivity, which affects over 90% of patients with lupus. Though photosensitivity is a well-known phenomenon in SLE and CLE, mechanisms that drive UV-mediated inflammation in lupus are poorly understood and represent a critically important area of research for the prevention of photosensitive disease. This dissertation was focused on the precise dissection of early innate inflammatory responses to UVB light in both murine lupus models and human lupus in an effort to better understand mechanisms that drive the initial response to UV in lupus skin and uncover mechanisms that link UV-induced inflammation with the development of cutaneous lesions in lupus. Specifically, we focus on effects downstream of type I IFN signaling, as type I IFNs have been shown to correlate with increased lupus disease activity and severity, contribute to enhanced apoptosis, and are overexpressed in lesional and nonlesional skin of SLE patients compared with healthy controls. In chapter 2, we utilize murine models of lupus to assess the differential transcriptional and immune-cell recruitment effects of acute and chronic UVB exposure. Additionally, we leverage lupus-prone mice with a type I IFN receptor knockout to assess the effects of type I IFNs on these findings. Using bulk RNA sequencing and flow cytometric analysis of acutely and chronically UVB irradiated lupus and wild-type murine skin, we determined that inflammatory pathways and gene signatures related to neutrophils and monocyte-derived dendritic cells are upregulated in acute and chronic UV-exposed murine lupus skin relative to wild-type in a type I IFN-dependent fashion. Taken together, these data indicate a skewed IFN-driven inflammatory response to both acute and chronic UVB exposure in lupus-prone skin dominated by myeloid cells, suggesting both the importance of type I IFNs and myeloid cells as therapeutic targets for photosensitive patients and highlighting the risks of even moderate UV exposure in this patient population. In chapter 3, we further explore the aberrant cutaneous inflammatory response to UVB exposure using single-cell RNA sequencing technologies to investigate transcriptional differences between UV-exposed and -unexposed skin of SLE and healthy control subjects. Interestingly, in both healthy control and lupus skin, we identify the recruitment of a population of monocyte-derived dendritic cells (moDCs) to the dermo-epidermal junction in UV-treated skin. However, lupus moDCs appear to be derived from different circulating monocyte precursors and further demonstrate hyperinflammatory responses compared to healthy control. We identify several nodes of dysregulation in lupus skin which may contribute to these findings. First, we show dysregulation of epidermal responses to UVB in lupus, identifying an inflammatory population of basal keratinocytes as important mediators of UVB-driven inflammation in lupus skin. We also demonstrate that stromal cell responses in the dermis are skewed likely secondary to inflammatory signals derived from these keratinocytes, which contributes to production of inflammatory cytokines and chemokines that skew lupus moDCs toward hyperinflammatory responses. Finally, we demonstrate that UV-recruited moDCs in lupus are transcriptionally related to lesional CD16+ DCs, identifying a novel link between UV responses and the development of cutaneous lesions.
■590 ▼aSchool code: 0127.
■650 4▼aMedicine
■650 4▼aHealth sciences
■650 4▼aImmunology
■650 4▼aCellular biology
■653 ▼aSystemic lupus erythematosus
■653 ▼aPhotosensitivity
■653 ▼aUltraviolet light
■653 ▼aType I interferons
■653 ▼aCutaneous lupus erythematosus
■690 ▼a0982
■690 ▼a0564
■690 ▼a0566
■690 ▼a0379
■71020▼aUniversity of Michigan▼bImmunology PhD.
■7730 ▼tDissertations Abstracts International▼g87-04B.
■790 ▼a0127
■791 ▼aPh.D.
■792 ▼a2024
■793 ▼aEnglish
■85640▼uhttp://www.riss.kr/pdu/ddodLink.do?id=T17360885▼nKERIS▼z이 자료의 원문은 한국교육학술정보원에서 제공합니다.
