Homeostatic tissue responses in skin biopsies from NOMID patients with constitutive overproduction of IL-1β
| Autor: | Jamie L. Harden, Israel Coats, Raphaela Goldbach-Mansky, Chyi-Chia Richard Lee, Jacob D. Estes, Hong-Wei Sun, Leanne M. Johnson-Huang, Joseph G. Dolan, Michelle A. Lowes, Mayte Suárez-Fariñas, Hiroshi Mitsui, Nicole Plass, Inna Novitskaya, Pamela Aubert, Edward W. Cowen, Katherine C. Pierson |
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| Jazyk: | angličtina |
| Rok vydání: | 2012 |
| Předmět: |
Male
Anatomy and Physiology Neutrophils Biopsy T-Lymphocytes Interleukin-1beta Gene Expression Epigenesis Genetic 0302 clinical medicine Immune Physiology Homeostasis Child Tissue homeostasis Skin 0303 health sciences Multidisciplinary integumentary system Allergy and Hypersensitivity Caspase 1 3. Good health 030220 oncology & carcinogenesis Child Preschool Cytokines Medicine Tumor necrosis factor alpha Female medicine.symptom medicine.drug Research Article Signal Transduction Adult Adolescent Immune Cells Inflammatory Diseases Science Antigen presentation CD11c Inflammation Dermatology Biology Autoimmune Diseases 03 medical and health sciences Genetic Mutation Antigens CD medicine Genetics Humans 030304 developmental biology Anakinra Macrophages Immunity Receptors Interleukin-1 HLA-DR Antigens Cryopyrin-Associated Periodic Syndromes CCL20 Interleukin 1 Receptor Antagonist Protein MicroRNAs Langerhans Cells Immunology Genetics of Disease Clinical Immunology CD163 |
| Zdroj: | PLoS ONE, Vol 7, Iss 11, p e49408 (2012) PLoS ONE |
| ISSN: | 1932-6203 |
| Popis: | The autoinflammatory disorder, Neonatal-onset Multisystem Inflammatory Disease (NOMID) is the most severe phenotype of disorders caused by mutations in CIAS1 that result in increased production and secretion of active IL-1β. NOMID patients present with systemic and organ-specific inflammation of the skin, central nervous system and bone, and respond dramatically to treatment with IL-1 blocking agents. We compared the cellular infiltrates and transcriptome of skin biopsies from patients with NOMID (n = 14) before treatment (lesional (LS) and non-lesional (pre-NL) skin) and after treatment (post-NL) with the IL-1 blocker anakinra (recombinant IL-1 receptor antagonist, Kineret®, Swedish Orphan Biovitrum AB, SOBI), to normal skin (n = 5) to assess tissue responses in the context of untreated and treated disease. Abundant neutrophils distinguish LS skin from pre-NL and post-NL skin. CD11c(+) dermal dendritic cells and CD163(+) macrophages expressed activated caspase-1 and are a likely source of cutaneous IL-1 production. Treatment with anakinra led to the disappearance of neutrophils, but CD3(+) T cells and HLA-DR(+) cells remained elevated. Among the upregulated genes IL-6, IL-8, TNF, IL-17A, CCL20, and the neutrophil defensins DEFA1 and DEFA3 were differentially regulated in LS tissues (compared to normal skin). Important significantly downregulated pathways in LS skin included IL-1R/TLR signaling, type I and II cytokine receptor signaling, mitochondrial dysfunction, and antigen presentation. The differential expression and regulation of microRNAs and pathways involved in post-transcriptional modification were suggestive of epigenetic modification in the chronically inflamed tissue. Overall, the dysregulated genes and pathways suggest extensive "adaptive" mechanisms to control inflammation and maintain tissue homeostasis, likely triggered by chronic IL-1 release in the skin of patients with NOMID. |
| Databáze: | OpenAIRE |
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