Abstract
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.
Highlights
The typical lymphocytic or eosinophilic inflammatory infiltrate of classic urticaria was absent in the Neonatal-onset Multisystem Inflammatory Disease (NOMID) skin biopsies, and a superficial and deep perivascular and interstitial infiltrate predominantly composed of neutrophils was present (Fig. 1B) [3,10]
Some of the neutrophils demonstrated string-like, extracellular elastase and DAPI immunofluorescent co-staining in the dermis that could be consistent with neutrophil extracellular traps (NETs, Fig. S2)
In which NET-like structures localized to the epidermis, this staining in NOMID was localized to the dermis
Summary
‘‘Autoinflammatory’’ diseases have recently been categorized as a group of disorders with primary excessive activation of innate immune responses [1] Included in this group are the cryopyrinassociated periodic syndromes (CAPS) that are caused by autosomal dominant mutations in the cold-induced autoinflammatory syndrome 1 (CIAS1) gene, called NLRP3 or NALP3 (NACHT domain-, leucine-rich repeat-, and PYD-containing protein 3). Treatment of NOMID patients is by lifelong injection with recombinant IL-1 receptor antagonist (recombinant IL-1Ra, anakinra, KineretH, Swedish Orphan Biovitrum AB, SOBI) [3]. This promises to help prevent longterm sequelae of inflammation, and studies with additional IL-1blocking agents are ongoing [7]. Pathway analyses suggest extensive regulation of adaptive pathways including the downregulation of proinflammatory cytokine pathways and pathways regulating epigenetic modifications in an attempt to prevent tissue damage and regain tissue homeostasis
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