Mast cells in systemic and cutaneous lupus erythematosus

Kaczmarczyk-Sekuła, Karolina; Dyduch, Grzegorz; Kostański, Marcin; Wielowieyska-Szybińska, Dorota; Szpor, Joanna; Białas, Magdalena; Okoń, Krzysztof

doi:10.5114/pjp.2015.57253

Cited by 15 publications

(5 citation statements)

References 24 publications

(39 reference statements)

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“…S5C). Consistent with increased mast cell counts in cutaneous lupus erythematosus (31), the number of mast cells in the skin of Foxp3 E2 mice was also significantly increased (fig. S5D).…”

Section: Foxp3 Exon 2 Deletion Results In Altered Immune Homeostasissupporting

confidence: 62%

FOXP3 exon 2 controls T _reg stability and autoimmunity

Wang

Yang

et al. 2022

Sci. Immunol.

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Differing from the mouse Foxp3 gene that encodes only one protein product, human FOXP3 encodes two major isoforms through alternative splicing—a longer isoform (FOXP3 FL) containing all the coding exons and a shorter isoform lacking the amino acids encoded by exon 2 (FOXP3 ΔE2). The two isoforms are naturally expressed in humans, yet their differences in controlling regulatory T cell phenotype and functionality remain unclear. In this study, we show that patients expressing only the shorter isoform fail to maintain self-tolerance and develop immunodeficiency, polyendocrinopathy, and enteropathy X-linked (IPEX) syndrome. Mice with Foxp3 exon 2 deletion have excessive follicular helper T (T FH ) and germinal center B (GC B) cell responses, and develop systemic autoimmune disease with anti-dsDNA and antinuclear autoantibody production, as well as immune complex glomerulonephritis. Despite having normal suppressive function in in vitro assays, regulatory T cells expressing FOXP3 ΔE2 are unstable and sufficient to induce autoimmunity when transferred into Tcrb -deficient mice. Mechanistically, the FOXP3 ΔE2 isoform allows increased expression of selected cytokines, but decreased expression of a set of positive regulators of Foxp3 without altered binding to these gene loci. These findings uncover indispensable functions of the FOXP3 exon 2 region, highlighting a role in regulating a transcriptional program that maintains T reg stability and immune homeostasis.

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Section: Foxp3 Exon 2 Deletion Results In Altered Immune Homeostasissupporting

confidence: 62%

FOXP3 exon 2 controls T _reg stability and autoimmunity

Wang

Yang

et al. 2022

Sci. Immunol.

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“…The counts of two mast cell subtypes were higher in SCLE, and then DLE. 43 Mast cell’s function in allergic immunity and the immune response had been widely acknowledged and more correlated studies should be intended to figure out its role in LE. 44…”

Section: Discussionmentioning

confidence: 99%

Bioinformatic analysis of key biomarkers and immune filtration of skin biopsy in discoid lupus erythematosus

Xiang

Chen

Yang

et al. 2021

Lupus

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Objective Discoid lupus erythematosus (DLE) is the most common category of chronic cutaneous lupus erythematosus, where the pathological process is proved to be closely associated with immunity. This bioinformatic analysis sought to identify key biomarkers and to perform immune infiltration analysis in the skin biopsy samples of DLE. Methods GSE120809, GSE100093, GSE72535, GSE81071 were used as the data source of gene expression profiles, altogether containing 79 DLE samples and 47 normal controls (NC). Limma package was applied to identify differentially expressed genes (DEGs) and additional Gene Ontology (GO) together with The Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were done. Protein-protein interaction network (PPI) was constructed using STRING and Cytoscape. Hub genes were selected by CytoHubba. Finally, immune filtration analysis was finished by the CIBERSORT algorithm, and comparisons between the two groups were accomplished. Results A total of 391 DEGs were identified, which were composed of 57 up-regulated genes and 334 down-regulated genes. GO and KEGG enrichment analyses revealed that DEGs were closely related with different steps in the immune response. Top 10 hub genes included GBP2, HLA-F, IFIT2, RSAD2, ISG15, IFIT1, IFIT3, MX1, XAF1 and IFI6. Immune filtration analysis from CIBERSORT had found that compared with NC, DLE samples had higher percentages of CD8+ T cells, T cells CD4 memory activated, T cells gamma delta, macrophages M1 and lower percentages of T cells regulatory, macrophages M2, dendritic cells resting, mast cells resting, mast cells activated. Conclusion This bioinformatic study selected key biomarkers from the contrast between DLE and NC skin samples and is the first research to analyze immune cell filtration in DLE.

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“…For example, Tregs stimulate mast cells to produce IL-6 via TGF-β1 (Ganeshan and Bryce, 2012), which in turn induces keratinocyte proliferation through the activation of JAK-STAT3 pathway. DLE lesions contain significantly higher numbers of infiltrating mast cells as compared to acute forms of cutaneous lupus (Kaczmarczyk-Sekula et al, 2015). In addition, Tregs suppress antitumor immune responses through the release of cytokines like IL-10 and TGF-β.…”

Section: Discussionmentioning

confidence: 99%

Chronic Inflammation Promotes Skin Carcinogenesis in Cancer-Prone Discoid Lupus Erythematosus

Zaalberg

Tuchayi

Ameri

et al. 2019

Journal of Investigative Dermatology

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High-risk skin cancer is a rare, but severe, complication associated with discoid lupus erythematosus (DLE). Chronic scar, inflammation, UVR, and immunosuppressive medications are proposed explanations for this heightened skin cancer risk; however, the exact mechanism driving skin carcinogenesis in DLE is unknown. The distinct co-localization of multiple independent skin cancers with areas of active inflammation in two DLE patients followed over 8 years strongly suggested that lupus inflammation promotes skin carcinogenesis in DLE. To investigate this clinical observation, we subjected lupus-prone MRL/lpr and control (MRL/n) mice to a skin carcinogenesis protocol. Skin tumors developed preferentially within the cutaneous lupus inflammation without scarring in MRL/lpr mice (P < 0.01). The inflammation in MRL/lpr skin was characterized by the accumulation of regulatory T cells, mast cells, M2 macrophages, and markedly elevated transforming growth factor-β1 and IL-6 levels, which have been linked to tumor promotion. Tacrolimus treatment reduced skin inflammation and blocked cancer development in MRL/lpr mice (P = 0.0195). A similar tumor-promoting immune environment was detected in SCCs and the perilesional skin of cancer-prone DLE patients. Therefore, discoid lupus inflammation promotes skin cancer in high-risk DLE patients, and blocking the inflammation may be critical for preventing this life-threatening complication of DLE.

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Mast cells in systemic and cutaneous lupus erythematosus

Cited by 15 publications

References 24 publications

FOXP3 exon 2 controls T _reg stability and autoimmunity

FOXP3 exon 2 controls T _reg stability and autoimmunity

Bioinformatic analysis of key biomarkers and immune filtration of skin biopsy in discoid lupus erythematosus

Chronic Inflammation Promotes Skin Carcinogenesis in Cancer-Prone Discoid Lupus Erythematosus

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Mast cells in systemic and cutaneous lupus erythematosus

Cited by 15 publications

References 24 publications

FOXP3 exon 2 controls T reg stability and autoimmunity

FOXP3 exon 2 controls T reg stability and autoimmunity

Bioinformatic analysis of key biomarkers and immune filtration of skin biopsy in discoid lupus erythematosus

Chronic Inflammation Promotes Skin Carcinogenesis in Cancer-Prone Discoid Lupus Erythematosus

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FOXP3 exon 2 controls T _reg stability and autoimmunity

FOXP3 exon 2 controls T _reg stability and autoimmunity