| 1. |
- Almet, Axel A., et al.
(författare)
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A Roadmap for a Consensus Human Skin Cell Atlas and Single-Cell Data Standardization
- 2023
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Ingår i: Journal of Investigative Dermatology. - : Elsevier. - 0022-202X .- 1523-1747. ; 143:9, s. 1667-1677
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Forskningsöversikt (refereegranskat)abstract
- Single-cell technologies have become essential to driving discovery in both basic and translational investigative dermatology. Despite the multitude of available datasets, a central reference atlas of normal human skin, which can serve as a reference resource for skin cell types, cell states, and their molecular signatures, is still lacking. For any such atlas to receive broad acceptance, participation by many investigators during atlas construction is an essential prerequisite. As part of the Human Cell Atlas project, we have assembled a Skin Biological Network to build a consensus Human Skin Cell Atlas and outline a roadmap toward that goal. We define the drivers of skin diversity to be considered when selecting sequencing datasets for the atlas and list practical hurdles during skin sampling that can result in data gaps and impede comprehensive representation and technical considerations for tissue processing and computational analysis, the accounting for which should minimize biases in cell type enrichments and exclusions and decrease batch effects. By outlining our goals for Atlas 1.0, we discuss how it will uncover new aspects of skin biology.
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| 2. |
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| 3. |
- Bivik Eding, Cecilia, et al.
(författare)
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MTH1 Inhibitors for the Treatment of Psoriasis
- 2021
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Ingår i: Journal of Investigative Dermatology. - : ELSEVIER SCIENCE INC. - 0022-202X .- 1523-1747. ; 141:8, s. 2037-2048
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Tidskriftsartikel (refereegranskat)abstract
- Inflammatory diseases, including psoriasis, are characterized by changes in redox regulation. The MTH1 prevents the incorporation of oxidized nucleotides during DNA replication. Using MTH1 small-molecule inhibitors, we found induced apoptosis through 8-oxodeoxyguanosine triphosphate accumulation and DNA double-strand breaks after oxidative stress in normal and malignant keratinocytes. In psoriasis, we detected increased MTH1 expression in lesional skin and PBMCs compared with that in the controls. Using the imiquimod psoriasis mouse model, we found that MTH1 inhibition diminished psoriatic histological characteristics and normalized the levels of neutrophils and T cells in the skin and skin-draining lymph nodes. The inhibition abolished the expression of T helper type 17-associated cytokines in the skin, which was in line with decreased levels of IL-17-producing gd T cells in lymph nodes. In human keratinocytes, MTH1 inhibition prevented the upregulation of IL-17-downstream genes, which was independent of ROS-induced apoptosis. In conclusion, our data support MTH1 inhibition using small molecules suitable for topical application as a promising therapeutic approach to psoriasis.
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| 4. |
- Bzioueche, Hanene, et al.
(författare)
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Analysis of Matched Skin and Gut Microbiome of Patients with Vitiligo Reveals Deep Skin Dysbiosis : Link with Mitochondrial and Immune Changes
- 2021
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Ingår i: Journal of Investigative Dermatology. - : Elsevier. - 0022-202X .- 1523-1747. ; 141:9, s. 2280-2290
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Tidskriftsartikel (refereegranskat)abstract
- Vitiligo is an autoimmune disease characterized by patchy, white skin owing to melanocyte loss. Commensal cutaneous or gut dysbiosis has been linked to various dermatological disorders. In this study, we studied the skin and gut microbiota of patients with vitiligo compared with those of healthy controls. We obtained swabs and biopsies from both lesional and nonlesional skin as well as stool and blood samples from each individual. We detected reduced richness and diversity of microbiota in the stools of subjects with vitiligo compared with the stools of the controls (P < 0.01). Skin swabs had greater α-diversity than biopsies (P < 0.001); swabs from lesional sites were primarily depleted of Staphylococcus compared with those from nonlesional sites (P < 0.02). Sampling deeper layers from the same patients showed differences in both α- and β-diversity between samples with decreased richness and distribution of species (P < 0.01) in the lesional site. Biopsy microbiota from the lesional skin had distinct microbiota composition, which was depleted of protective Bifidobacterium and Bacteroides but was enriched in Proteobacteria, Streptococcus, Mycoplasma, and mtDNA (P < 0.001); the latter increased in the same patients with heightened innate immunity and stress markers in their blood (P < 0.05). These data describe vitiligo-specific cutaneous and gut microbiota and a link between skin dysbiosis, mitochondrial damage, and immunity in patients with vitiligo.
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| 5. |
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| 6. |
- Eriksson, Ida, et al.
(författare)
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Lysosomal Function and Intracellular Position Determine the Malignant Phenotype in Melanoma
- 2023
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Ingår i: Journal of Investigative Dermatology. - : ELSEVIER SCIENCE INC. - 0022-202X .- 1523-1747. ; 143:9, s. 1769-
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Tidskriftsartikel (refereegranskat)abstract
- Lysosomes are central in cell homeostasis and participate in macromolecular degradation, plasma membrane repair, exosome release, cell adhesion/migration, and apoptosis. In cancer, alterations in lysosomal function and spatial distribution may facilitate disease progression. In this study, we show enhanced lysosomal activity in malignant melanoma cells compared with that in normal human melanocytes. Most lysosomes show perinuclear location in melanocytes, while they are more dispersed in melanoma, with retained proteolytic activity and low pH also in the peripheral population. Rab7a expression is lower in melanoma cells than in melanocytes, and by increasing Rab7a, lysosomes are relocated to the perinuclear region in melanoma. Exposure to the lysosome-destabilizing drug L-leucyl-L-leucine methyl ester causes higher damage in the perinuclear subset of lysosomes in melanomas, whereas differences in subpopulation susceptibility cannot be found in melanocytes. Interestingly, melanoma cells recruit the endosomal sorting complex required for transport-III core protein CHMP4B, involved in lysosomal membrane repair, rather than initiate lysophagy. However, when the perinuclear lysosomal position is promoted by Rab7a overexpression or kinesore treatment, lysophagy is increased. In addition, Rab7a overexpression is accompanied by reduced migration capacity. Taken together, the study emphasizes that alterations in lysosomal properties facilitate the malignant phenotype and declares the targeting of lysosomal function as a future therapeutic approach.
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| 9. |
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| 10. |
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| 11. |
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| 12. |
- Li, Dongqing, et al.
(författare)
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miR-19a/b and miR-20a promote wound healing by regulating the inflammatory response of keratinocytes
- 2021
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Ingår i: Journal of Investigative Dermatology. - : Elsevier. - 0022-202X .- 1523-1747. ; 141:3, s. 659-671
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Tidskriftsartikel (refereegranskat)abstract
- Persistent and impaired inflammation impedes tissue healing and is characteristic of chronic wounds. A better understanding of the mechanisms controlling wound inflammation is needed. Here we show that in human wound-edge keratinocytes, the expression of miR-17, miR-18a, miR-19a, miR-19b, and miR-20a, which all belong to the miR-17∼92 cluster, is upregulated during wound repair. However, their levels are lower in chronic ulcers than acute wounds at the proliferative phase. Conditional knockout of miR-17∼92 in keratinocytes as well as injection of miR-19a/b and miR-20a antisense inhibitors into wound-edges enhanced inflammation and delayed wound closure in mice. In contrast, conditional overexpression of the miR-17∼92 cluster or miR-19b alone in mice keratinocytes accelerated wound closure in vivo. Mechanistically, miR-19a/b and miR-20a decreased TLR3-mediated NF-κB activation by targeting SHCBP1 and SEMA7A, respectively, reducing the production of inflammatory chemokines/cytokines by keratinocytes. Thus, as crucial regulators of wound inflammation, lack of miR-19a/b and miR-20a may contribute to sustained inflammation and impaired healing in chronic wounds. In line with this, we show that a combinatory treatment with miR-19b and miR-20a improved wound healing in a mouse model of type 2 diabetes.
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| 13. |
- Li, Dongqing, et al.
(författare)
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Single-Cell Analysis Reveals Major Histocompatibility Complex II-Expressing Keratinocytes in Pressure Ulcers with Worse Healing Outcomes
- 2022
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Ingår i: Journal of Investigative Dermatology. - : Elsevier. - 0022-202X .- 1523-1747. ; 142:3, s. 705-716
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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.
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| 14. |
- Lindberg, I., et al.
(författare)
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Direct healthcare cost of atopic dermatitis in the Swedish population
- 2021
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Ingår i: Journal of Investigative Dermatology. - : Elsevier. - 0022-202X .- 1523-1747. ; 141:5 Suppl., s. S45-S45
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Data quantifying population-based direct healthcare costs (DHCC) for atopic dermatitis (AD) by severity are limited. This study was designed to provide estimates for these costs. Patients were identified at first AD diagnosis in the National Patient Registry (secondary care) or in primary care (national coverage: 31%) (International Classification of Diseases-10 L20) or first dispensation of topical calcineurin inhibitor or topical corticosteroid (Anatomical Therapeutic Chemical code D11AH01/02 once; D07 twice in a year) in the Prescribed Drug Registry in 2007-17 (index) and followed until death, emigration, 31 Dec 2018 or adulthood. Patients without AD diagnosis with a record of diagnoses/treatment for other non-AD skin conditions were excluded. Patients were matched 1:1 on age, gender and region to controls. 1-year DHCC for secondary and primary care visits and filled prescriptions were compared with controls (2020€). Disease severity (mild-to-moderate [M2M] vs severe) using AD treatment and visits as proxies was assessed between index to 30 days after. 187,338 M2M (48% female; mean age 4) and 46,754 severe children (51%; 8), while 445,317 M2M (55%; 55) and 11,640 severe adults (57%; 53) were included. In children vs. controls, 1-year DHCC for secondary care, primary care and medications were respectively €72, €23, €33 million (mn) higher in M2M and €26, €4, €13 mn higher in severe; in adults vs. controls, €353, €68, €182 mn higher in M2M and €21, €2, €17 mn higher in severe (all comparisons significant, p<0.05). On population level, AD is associated with substantial economic burden, which is higher in M2M vs severe AD partially due to higher prevalence of M2M.
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| 15. |
- Lohcharoenkal, Warangkana, et al.
(författare)
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MiR-130a Acts as a Tumor Suppressor MicroRNA in Cutaneous Squamous Cell Carcinoma and Regulates the Activity of the BMP/SMAD Pathway by Suppressing ACVR1
- 2021
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Ingår i: Journal of Investigative Dermatology. - : Elsevier. - 0022-202X .- 1523-1747. ; 141:8, s. 1922-1931
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Tidskriftsartikel (refereegranskat)abstract
- Cutaneous Squamous Cell Carcinoma (cSCC) is a malignant neoplasm of the skin resulting from the accumulation of somatic mutations due to solar radiation. It is one of the fastest increasing malignancies and it represents a particular problem among immunosuppressed individuals. MicroRNAs (miRNAs) are short non-coding RNAs that regulate the expression of protein-coding genes at the posttranscriptional level. Here we identify miR-130a to be downregulated in cSCC compared with healthy skin and with precancerous lesions (actinic keratosis) and demonstrate that it is regulated at the transcriptional level by HRAS and MAPK-signaling. We report that miR-130a suppresses the growth of cSCC xenografts in mice. We demonstrate that overexpression of miR-130a suppresses long-term capacity of growth, cell motility and invasion ability in human cSCC cell lines. Mechanistically, miR-130a directly targets Activin A receptor, type I (ACVR1/ALK2) and changes in miR-130a levels result in the diminished activity of BMP/SMAD1 pathway via ACVR1. These data reveal a link between activated MAPK-signaling and decreased expression of miR-130a, which acts as a tumor suppressor miRNA in cSCC and contributes to a better understanding of molecular processes in malignant transformation of epidermal keratinocytes.
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| 16. |
- Luo, Longlong, et al.
(författare)
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The Long Noncoding RNA LINC00958 Is Induced in Psoriasis Epidermis and Modulates Epidermal Proliferation
- 2023
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Ingår i: Journal of Investigative Dermatology. - : Elsevier. - 0022-202X .- 1523-1747. ; 143:6, s. 999-1010
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Tidskriftsartikel (refereegranskat)abstract
- Psoriasis is a common, immune-mediated skin disease characterized by epidermal hyperproliferation and chronic skin inflammation. Long noncoding RNAs are >200 nucleotide-long transcripts that possess important regulatory functions. To date, little is known about the contribution of long noncoding RNAs to psoriasis. In this study, we identify LINC00958 as a long noncoding RNA overexpressed in keratinocytes (KCs) from psoriasis skin lesions, in a transcriptomic screen performed on KCs sorted from psoriasis and healthy skin. Increased levels of LINC00958 in psoriasis KCs were confirmed by RT-qPCR and single-molecule in situ hybridization. Confocal microscopy and analysis of subcellular fractions showed that LINC00958 is mainly localized in the cytoplasm of KCs. IL-17A, a key psoriasis cytokine, induced LINC00958 in KCs through C/EBP-β and the p38 pathway. The inhibition of LINC00958 led to decreased proliferation as measured by Ki-67 expression, live cell analysis imaging, and 5-ethynyl-2-deoxyuridine assays. Transcriptomic analysis of LINC00958-depleted KCs revealed enrichment of proliferation- and cell cycle‒related genes among differentially expressed transcripts. Moreover, LINC00958 depletion led to decreased basal and IL-17A‒induced phosphorylation of p38. Furthermore, IL-17A‒induced KC proliferation was counteracted by the inhibition of LINC00958. In summary, our data support a role for the IL-17A‒induced long noncoding RNA, LINC00958, in the pathological circuits of psoriasis by reinforcing IL-17A‒induced epidermal hyperproliferation.
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| 17. |
- Narangifard, Ali, et al.
(författare)
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Molecular Reorganization during the Formation of the Human Skin Barrier Studied In Situ
- 2021
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Ingår i: Journal of Investigative Dermatology. - : Elsevier BV. - 0022-202X .- 1523-1747. ; 141:5, s. 1243-1253
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Tidskriftsartikel (refereegranskat)abstract
- In vertebrates, skin upholds homeostasis by preventing body water loss. The skin's permeability barrier is located intercellularly in the stratum corneum and consists of stacked lipid lamellae composed of ceramides, cholesterol, and free fatty acids. We have combined cryo-electron microscopy with molecular dynamics modeling and electron microscopy simulation in our analysis of the lamellae's formation, a maturation process beginning in stratum granulosum and ending in stratum corneum. Previously, we have revealed the lipid lamellae's initial- and end-stage molecular organizations. In this study, we reveal two cryo-electron microscopy patterns representing intermediate stages in the lamellae's maturation process: a single-band pattern with 2.0-2.5 nm periodicity and a two-band pattern with 5.5-6.0 nm periodicity, which may be derived from lamellar lipid structures with 4.0-5.0 nm and 5.5-6.0 nm periodicity, respectively. On the basis of the analysis of the data now available on the four maturation stages identified, we can present a tentative molecular model for the complete skin barrier formation process.
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| 18. |
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| 19. |
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| 20. |
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| 21. |
- Padhi, Avinash, et al.
(författare)
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IL-22 Downregulates Peptidylarginine Deiminase-1 in Human Keratinocytes : Adding Another Piece to the IL-22 Puzzle in Epidermal Barrier Formation
- 2022
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Ingår i: Journal of Investigative Dermatology. - : Elsevier. - 0022-202X .- 1523-1747. ; 142:2, s. 333-342.e6
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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.
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| 22. |
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| 23. |
- Peltonen, Sirkku, 1964, et al.
(författare)
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Celebrating the 50th Anniversary of ESDR.
- 2020
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Ingår i: The Journal of investigative dermatology. - : Elsevier BV. - 1523-1747 .- 0022-202X. ; 140:9S
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
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| 24. |
- Pipi, Elena, et al.
(författare)
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Multiple modes of action mediate the therapeutic effect of IVIg in experimental epidermolysis bullosa acquisita
- 2022
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Ingår i: Journal of Investigative Dermatology. - : Elsevier BV. - 1523-1747 .- 0022-202X. ; 142:6, s. 8-1564
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Tidskriftsartikel (refereegranskat)abstract
- Substitution of IgG in antibody deficiency or application of high-dose intravenous IgG (IVIg) in patients with autoimmunity are well-established treatments. Data on the mode of action of IVIg are, however, controversial and may differ for distinct diseases. In this study, we investigated the impact and molecular mechanism of high-dose IgG treatment in murine autoantibody-induced skin inflammation, namely, epidermolysis bullosa acquisita (EBA). EBA is caused by antibodies directed against type VII collagen (COL7) and is mediated by complement activation, release of reactive oxygen species, and proteases by myeloid cells. In murine experimental EBA the disease can be induced by injection of anti-COL7 IgG. Here, we substantiate that treatment with high-dose IgG improves clinical disease manifestation. Mechanistically, high-dose IgG reduced the amount of anti-COL7 in skin and sera, which is indicative for an FcRn-dependent mode-of-action. Furthermore, in a non-receptor-mediated fashion, high-dose IgG showed antioxidative properties by scavenging extracellular reactive oxygen species. High-dose IgG also impaired complement activation and served as substrate for proteases, both key events during EBA pathogenesis. Collectively, the non-receptor-mediated anti-inflammatory properties of high-dose IgG may explain the therapeutic benefit of IVIg treatment in skin autoimmunity.
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| 25. |
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