| 1. |
- Baptista, Marisa A. P., et al.
(författare)
-
Deletion of Wiskott-Aldrich syndrome protein triggers Rac2 activity and increased cross-presentation by dendritic cells
- 2016
-
Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 7
-
Tidskriftsartikel (refereegranskat)abstract
- Wiskott-Aldrich syndrome (WAS) is caused by loss-of-function mutations in the WASp gene. Decreased cellular responses in WASp-deficient cells have been interpreted to mean that WASp directly regulates these responses in WASp-sufficient cells. Here, we identify an exception to this concept and show that WASp-deficient dendritic cells have increased activation of Rac2 that support cross-presentation to CD8(+) T cells. Using two different skin pathology models, WASp-deficient mice show an accumulation of dendritic cells in the skin and increased expansion of IFN gamma-producing CD8(+) T cells in the draining lymph node and spleen. Specific deletion of WASp in dendritic cells leads to marked expansion of CD8(+) T cells at the expense of CD4(+) T cells. WASp-deficient dendritic cells induce increased cross-presentation to CD8(+) T cells by activating Rac2 that maintains a near neutral pH of phagosomes. Our data reveals an intricate balance between activation of WASp and Rac2 signalling pathways in dendritic cells.
|
|
| 2. |
- Eidsmo, Liv
(författare)
-
Dysregulation of receptor induced apoptosis during human leishmaniasis : a possible mechanism of skin ulceration
- 2006
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Leishmaniasis is endemic in 88 countries and 12 million people per year have been estimated to be at risk of infection. The causative agent, the protozoan Leishmania, is spread by sand-flies and infects macrophages in the mammalian host. Leishmaniasis in humans form a spectrum of clinical presentations. In cutaneous leishmaniasis (CL) caused by L. major, the infection is localised in the skin and manifests as one or several ulcers that typically spontaneously heal within one year after infection, often leaving marked scarring. In visceral leishmaniasis (VL) caused by L. donovani, infected macrophages are found in liver, spleen, bone marrow and lymph-nodes and the infection leads to hepatosplenomegaly, wasting, fever and if not treated, to death. Systemic T-cell deficiency occurs early during VL and leads to uncontrolled parasite replication. In general, solid immunity upon healing occurs after resolved VL and CL. In this thesis, the hypothesis that alterations of death receptor-mediated apoptosis have an impact on the pathogenesis of human leishmaniasis has been explored. During VL, dysregulation of the Fas/FasL pathway was investigated, both at one site of infection, the spleen, and on circulating lymphocytes from the peripheral blood. In the case of CL the hypothesis was that increased death receptor-mediated apoptosis in the microenvironment surrounding infected macrophages may induce bystandard apoptosis of keratinocytes, leading to skin ulceration. Dysiregulation of the Fas/FasL pathway occured during human VL and CL. Levels of soluble Fas (sFas) and soluble Fas ligand (sFasL) were elevated in plasma of patients with active VL and individuals co-infected with VL-HIV-1 compared to healthy controls, and the levels of sFas and sFasL were normalized 6 months after successful treatment. During active VL, the expression of membrane bound Fas, and to a lower extent Fast., was up-regulated on spleen cells, where parasites multiply. In contrast, expression of Fas and Fast- were not altered on peripheral blood mononuclear cells (PBMC) during VL. Furthermore, in vitro infection of macrophages with L. donovani results in up-regulation of Fas expression on the surface of infected cells and increases the levels of sFasL in supernatants from infected cultures. During active CL caused by L. major, a disease mainly localised to the skin, the Fas and Fast- levels were not altered in serum or on PBMCs analysed ex vivo. However, when CL PBMCs were restimulated with L. major, Fas was up-regulated on effector T-cells and high levels of sFasL were detected in the supernatants as compared to control PBMCs. Keratinocyte apoptosis is altered during CL. Dysregulation of the Fas/FasL pathway in the microenvironment surrounding L. major infected macrophages under the skin was visualised in biopsies collected from CL patients. A substantial number of apoptotic keratinocytes were observed in the epidermis of morphologically active and healing CL skin samples. Fas expression was increased on the epidermis in active CL, whereas FasL expressing macrophages and T-cells were found in the subepidermal infiltrate during active disease. Supernatants from re-stimulated CL-PBMC cultures containing high levels of sFasL induced apoptosis in human keratinocyte cell line (HaCaT), and apoptosis could be inhibited in 213 supernatants by blocking Fas. A commercial apoptosis-specific microarray was used to assess alterations in keratinocyte RNAexpression during exposure to supernatants from L. major infected PBMCs. Fas and TRAIL mRNA and protein expression were significantly up-regulated compared to untreated keratinocytes. Supernatant induced apoptosis of keratinocytes was partly inhibited through blocking Fas or FasL, and more efficiently through inhibition of TRAIL by neutralising antibodies or soluble TRAIL-R. Furthermore, TRAIL expressing keratinocytes were detected in skin biopsies from CL cases. Blocking the Fas/FasL pathway in vivo may reduce ulceration during murine CL. In order to obtain the proof of the concept that Fas/FasL signalling is involved in keratinocyte-apoptosis leading to ulceration in the skin during CL, the Fas/FasL pathway was blocked in a murine model of CL by intraperitoneal treatment with Fast- neutralising antibodies (MFL-4). Skin inflammation, skin ulceration and ulcer size were followed weekly and compared to infected, untreated mice. Our results suggests that blocking Fas/FasL signalling during murine CL lead to less apoptotic keratinocytes and diminished ulceration. During treatment, the number of IFNgammaproducing CD8+CD3+ cells was increased at the site of infection when Fast- was neutralised which is suggestive of efficient parasite eradication. However, there was no reduction of parasite load at the site of infection or in draining lymph nodes and parasite replication was high upon discontinuation of anti-FasL treatment. Conclusion: The Fas/FasL pathway was shown to be dysregulated both in human VL and CL. A possible mechanism of ulcer formation during CL was proposed by apoptotic death of keratinocytes through enhanced Fast- and TRAIL signalling. This data was further strengthened in a treatment experiment in a murine model of CL, where blocking the Fas/FasL system reduced ulcer formation during L. major infection.
|
|
| 3. |
|
|
| 4. |
|
|
| 5. |
|
|
| 6. |
- Landegren, Nils, et al.
(författare)
-
A gene-centric approach to biomarker discovery identifies transglutaminase 1 as an epidermal autoantigen
- 2021
-
Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 118:51
-
Tidskriftsartikel (refereegranskat)abstract
- Autoantigen discovery is a critical challenge for the understanding and diagnosis of autoimmune diseases. While autoantibody markers in current clinical use have been identified through studies focused on individual disorders, we postulated that a reverse approach starting with a putative autoantigen to explore multiple disorders might hold promise. We here targeted the epidermal protein transglutaminase 1 (TGM1) as a member of a protein family prone to autoimmune attack. By screening sera from patients with various acquired skin disorders, we identified seropositive subjects with the blistering mucocutaneous disease paraneoplastic pemphigus. Validation in further subjects confirmed TGM1 autoantibodies as a 55% sensitive and 100% specific marker for paraneoplastic pemphigus. This gene-centric approach leverages the wealth of data available for human genes and may prove generally applicable for biomarker discovery in autoimmune diseases.
|
|
| 7. |
- Li, Dongqing, et al.
(författare)
-
Single-Cell Analysis Reveals Major Histocompatibility Complex II-Expressing Keratinocytes in Pressure Ulcers with Worse Healing Outcomes
- 2022
-
Ingår i: Journal of Investigative Dermatology. - : Elsevier. - 0022-202X .- 1523-1747. ; 142:3, s. 705-716
-
Tidskriftsartikel (refereegranskat)abstract
- Pressure ulcer (PU) is a chronic wound often seen in patients with spinal cord injury and other bed-bound individuals, particularly in the elderly population. Despite its association with high mortality, the pathophysiology of PU remains poorly understood. In this study, we compared single-cell transcriptomic profiles of human epidermal cells from PU wound edges with those from uninjured skin and acute wounds in healthy donors. We identified significant shifts in the cell composition and gene expression patterns in PU. In particular, we found that major histocompatibility complex class II-expressing keratinocytes were enriched in patients with worse healing outcomes. Furthermore, we showed that the IFN-gamma in PU-derived wound fluid could induce major histocompatibility complex II expression in keratinocytes and that these wound fluid-treated keratinocytes inhibited autologous T-cell activation. In line with this observation, we found that T cells from PUs enriched with major histocompatibility complex II+ keratinocytes produced fewer inflammatory cytokines. Overall, our study provides a high-resolution molecular map of human PU compared with that of acute wounds and intact skin, providing insights into PU pathology and the future development of tailored wound therapy.
|
|
| 8. |
- Li, Xi, et al.
(författare)
-
MicroRNA-132 with Therapeutic Potential in Chronic Wounds.
- 2017
-
Ingår i: Journal of Investigative Dermatology. - : Elsevier BV. - 0022-202X .- 1523-1747. ; 137:12, s. 2630-2638
-
Tidskriftsartikel (refereegranskat)abstract
- Chronic wounds represent a major and rising health and economic burden worldwide. There is a continued search toward more effective wound therapy. We found significantly reduced microRNA-132 (miR-132) expression in human diabetic ulcers compared with normal skin wounds and also in skin wounds of leptin receptor-deficient (db/db) diabetic mice compared with wild-type mice. Local replenishment of miR-132 in the wounds of db/db mice accelerated wound closure effectively, which was accompanied by increased proliferation of wound edge keratinocytes and reduced inflammation. The pro-healing effect of miR-132 was further supported by global transcriptome analysis, which showed that several inflammation-related signaling pathways (e.g., NF-κB, NOD-like receptor, toll-like receptor, and tumor necrosis factor signaling pathways) were the top ones regulated by miR-132 in vivo. Moreover, we topically applied liposome-formulated miR-132 mimics mixed with pluronic F-127 gel on human ex vivo skin wounds, which promoted re-epithelialization. Together, our study showed the therapeutic potential of miR-132 in chronic wounds, which warrants further evaluation in controlled clinical trials.
|
|
| 9. |
- Nikamo, Pernilla, et al.
(författare)
-
Genetic variants of the IL22 promoter associate to onset of psoriasis before puberty and increased IL-22 production in T cells.
- 2014
-
Ingår i: Journal of Investigative Dermatology. - : Elsevier BV. - 0022-202X .- 1523-1747. ; 134:6, s. 1535-1541
-
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.
|
|
| 10. |
- Padhi, Avinash, et al.
(författare)
-
IL-22 Downregulates Peptidylarginine Deiminase-1 in Human Keratinocytes : Adding Another Piece to the IL-22 Puzzle in Epidermal Barrier Formation
- 2022
-
Ingår i: Journal of Investigative Dermatology. - : Elsevier. - 0022-202X .- 1523-1747. ; 142:2, s. 333-342.e6
-
Tidskriftsartikel (refereegranskat)abstract
- Increased presence of IL-22(+) cells in the skin is a characteristic finding in skin barrier defects, such as psoriasis and atopic dermatitis. However, mechanistic insight into effects of IL-22 on epidermal functioning is yet to be elucidated. One crucial step during epidermal differentiation is deimination or citrullination. Here, we show reduced levels of peptidylarginine deiminase 1, an enzyme that converts peptidylarginine into citrulline in lesional psoriatic skin. IL-22 signaling through the IL-22 receptor complex was found to suppress expression of peptidylarginine deiminase 1 in epidermal keratinocytes. Subsequently, total peptidylarginine deiminase activity and extent of protein deimination in keratinocytes treated with IL-22 were reduced together with a significant decrease in deimination of keratin 1 and FLG, both important for epidermal differentiation. Vitamin D and acitretin partly restored the peptidylarginine deiminase 1 defect caused by IL-22. Collectively, we show that IL-22 downregulates deimination, thus identifying a potential target for treatment of skin barrier defects.
|
|
