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- Chen, J. Y., et al.
(författare)
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High-resolution 3D imaging uncovers organ-specific vascular control of tissue aging
- 2021
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Ingår i: Science Advances. - : American Association for the Advancement of Science (AAAS). - 2375-2548. ; 7:6
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Tidskriftsartikel (refereegranskat)abstract
- Blood vessels provide supportive microenvironments for maintaining tissue functions. Age-associated vascular changes and their relation to tissue aging and pathology are poorly understood. Here, we perform 3D imaging of young and aging vascular beds. Multiple organs in mice and humans demonstrate an age-dependent decline in vessel density and pericyte numbers, while highly remodeling tissues such as skin preserve the vasculature. Vascular attrition precedes the appearance of cellular hallmarks of aging such as senescence. Endothelial VEGFR2 loss-of-function mice demonstrate that vascular perturbations are sufficient to stimulate cellular changes coupled with aging. Age-associated tissue-specific molecular changes in the endothelium drive vascular loss and dictate pericyte to fibroblast differentiation. Lineage tracing of perivascular cells with inducible PDGERB and NG2 Cre mouse lines demonstrated that increased pericyte to fibroblast differentiation distinguishes injury-induced organ fibrosis and zymosan-induced arthritis. To spur further discoveries, we provide a freely available resource with 3D vascular and tissue maps.
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| 2. |
- Cheuk, Stanley Sing Hoi
(författare)
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Resident T cells in human skin : functional heterogeneity and clinical implications
- 2016
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The skin forms a critical barrier against the external environment and is therefore frequently challenged by infections and subjected to immune-mediated diseases as well as malignancies. The Tissue-Resident Memory T (TRM) cell is a subset of T cells that resides at sites of previous infection in the skin and other epithelial tissues. Upon re-activation, TRM cells provide rapid, robust and localized adaptive immune defence against re-infection. The role of TRM cells in different human diseases is increasingly appreciated. This thesis aims to explore the functional capacity and regulatory mechanisms of resident T cells in human skin and their potential roles in two different immune-mediated skin diseases, vitiligo and psoriasis. PAPER I: Human skin contains heterogeneous populations of T cells. CD49a expression marks a functionally distinct subpopulation of epidermal CD8 TRM cells that are highly poised towards IFN-γ production and cytolytic function, whereas CD49a- TRM cells preferentially produced IL-17. The cytotoxic potential of CD49a+ TRM cell was specifically unleashed by IL-15 stimulation. In vitiligo, an acquired chronic depigmenting disorder of the skin, CD49a+ TRM cells accumulated in both epidermis and dermis in lesions implicating a pathogenic role of CD49a+ TRM cells. PAPER II: In psoriasis, a common chronic inflammatory skin disease, a large proportion of epidermal T cells, but not dermal T cells, expressed the pathogenic cytokines IL-17 and IL-22 during active disease (PAPER II). Upon clinical remission, T cells with pathogenic capacity were retained in the epidermis of resolved lesions. Upon reactivation, CD4 T cells responded with IL-22 production, whereas CD8 T cells with TRM cell phenotypes responded with IL-17. A model of localized disease memory based on TRM cells in resolved psoriasis was proposed. PAPER III: CD8 T cells in active psoriasis lesions expressed granzyme A, but not granzyme B or perforin. In vitro experiments showed that granzyme A specifically promotes chemokine expression in IL-17 stimulated keratinocytes. Thus, granzyme A expression in skin-resident CD8 T cells may provide proinflammatory signals in psoriasis. PAPER IV: In cohorts of Caucasian psoriasis patients and healthy controls, genetic association of variants within IL22 promoter is confined to patients with disease on-set before puberty. The risk haplotype of the IL22 promoter led to higher transcriptional activity and higher IL-22 production in CD4 T cells from psoriasis patients, underscoring the impact of genetic heterogeneity and their functional consequences in immune-mediated skin diseases. Through characterization of resident T cells in human skin in healthy and inflammatory conditions, this thesis demonstrates the functional heterogeneity of skin-resident T cells in healthy skin, vitiligo and psoriasis. Further understanding of the formation, homeostatic, regulatory and effector mechanisms of TRM cell may unveil novel therapeutic strategies and improve disease management in a wide range of skin conditions.
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| 6. |
- Handel, Adam E, et al.
(författare)
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Developmental dynamics of the neural crest-mesenchymal axis in creating the thymic microenvironment.
- 2022
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Ingår i: Science advances. - : American Association for the Advancement of Science (AAAS). - 2375-2548. ; 8:19
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Tidskriftsartikel (refereegranskat)abstract
- The thymic stroma is composed of epithelial and nonepithelial cells providing separate microenvironments controlling homing, differentiation, and selection of hematopoietic precursor cells to functional T cells. Here, we explore at single-cell resolution the complex composition and dynamic changes of the nonepithelial stromal compartment across different developmental stages in the human and mouse thymus, and in an experimental model of the DiGeorge syndrome, the most common form of human thymic hypoplasia. The detected gene expression signatures identify previously unknown stromal subtypes and relate their individual molecular profiles to separate differentiation trajectories and functions, revealing an unprecedented heterogeneity of different cell types that emerge at discrete developmental stages and vary in their expression of key regulatory signaling circuits and extracellular matrix components. Together, these findings highlight the dynamic complexity of the nonepithelial thymus stroma and link this to separate instructive roles essential for normal thymus organogenesis and tissue maintenance.
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| 7. |
- Nikamo, Pernilla, et al.
(författare)
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Genetic variants of the IL22 promoter associate to onset of psoriasis before puberty and increased IL-22 production in T cells.
- 2014
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Ingår i: Journal of Investigative Dermatology. - : Elsevier BV. - 0022-202X .- 1523-1747. ; 134:6, s. 1535-1541
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Tidskriftsartikel (refereegranskat)abstract
- Most psoriasis susceptibility genes were identified in cohorts of mixed clinical phenotypes and the exploration of genes in clinical subtypes is scarce. IL-22 has an established role in host defense and in psoriasis skin pathology, reflecting the delicate balance between control of infection and immunopathology. In a case-control study, we compared the genetic association to IL22 in psoriasis onset in patients between 0-9 (n=207), 10-20 (n=394), and 21-40 (n=468) years with healthy controls (n=1,529). Logistic regression analysis revealed association to regulatory elements in the IL22 promoter confined to onset of psoriasis before puberty (odds ratio=1.45, P<0.0007). The associated variants contain putative binding sites for AhR, a potent inducer of IL-22 expression. In a luciferase assay, transcriptional activity of a high-risk gene variant resulted in 80% higher promoter activity (P=0.012) compared with a low-risk variant. Ex vivo stimulated T cells from peripheral blood were analyzed with flow cytometry. Children with psoriasis carrying a high-risk variant produced 1.7 times more IL-22 compared with low-risk variants (P=0.042). Our combined genetic and functional data support the notion that a genetic IL22 variant that promotes epithelial barrier defense is preferentially enriched in and may precipitate the onset of psoriasis at an early age.
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| 8. |
- Serezal, I. G., et al.
(författare)
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Cellular scars and local crosstalk in relapsing psoriasis: an example of a skin sticking disease
- 2020
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Ingår i: Scandinavian Journal of Immunology. - : Wiley. - 0300-9475 .- 1365-3083. ; 92:5
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Tidskriftsartikel (refereegranskat)abstract
- Psoriasis is an inflammatory disease that arises in genetically predisposed individuals. Chronic skin lesions that contain activated immune cells can persist for years. Systemic inhibition of TNF, IL-17 and IL-23 cytokines has revolutionized psoriasis care during the recent decades. Unfortunately, local relapse of disease is common at previously inflamed sites after cessation of treatment. This highlights that fundamental pathologic alterations of the affected tissues are not completely resolved during clinical remission. Here, we present arguments for a local disease memory located in both dermis and epidermis in psoriasis skin. We decipher different cellular components and intercellular crosstalk that sustain local disease memory and amplify disease relapse in human psoriasis. Decrypting the mechanisms underlying the establishment and persistence of pathogenic memory cells in resolved psoriasis may provide new therapeutic perspectives aimed at long-term remission of psoriasis.
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