Identification of Critical Transcriptomic Signaling Pathways in Patients with H Syndrome and Rosai-Dorfman Disease
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ORIGINAL ARTICLE
Identification of Critical Transcriptomic Signaling Pathways in Patients with H Syndrome and Rosai-Dorfman Disease Samuel Lara-Reyna 1,2 & James A. Poulter 1,2 & Elton J.R. Vasconcelos 3 & Mark Kacar 1,4 & Michael F. McDermott 1 & Reuben Tooze 5 & Rainer Doffinger 6 & Sinisa Savic 1,4 Received: 6 October 2020 / Accepted: 18 November 2020 # The Author(s) 2020
Abstract Biallelic mutations in SLC29A3 cause histiocytosis-lymphadenopathy plus syndrome, also known as H syndrome (HS). HS is a complex disorder, with ~ 25% of patients developing autoinflammatory complications consisting of unexplained fevers, persistently elevated inflammatory markers, and unusual lymphadenopathies, with infiltrating CD68+, S100+, and CD1a− histiocytes, resembling the immunophenotype found in Rosai-Dorfman disease (RDD). We investigated the transcriptomic profiles of monocytes, non-activated (M0), classically activated (M1), and alternatively activated macrophages (M2) in two patients with HS, one without autoinflammatory (HS1) and one with autoinflammatory complications (HS2). RNA sequencing revealed a dysregulated transcriptomic profile in both HS patients compared to healthy controls (HC). HS2, when compared to HS1, had several differentially expressed genes, including genes associated with lymphocytic-histiocytic predominance (e.g. NINL) and chronic immune activation (e.g. B2M). The transcriptomic and cytokine profiles of HS patients were comparable to patients with SAID with high levels of TNF. SERPINA1 gene expression was found to be upregulated in all patients studied. Moreover, higher levels of IFNγ were found in the serum of both HS patients when compared to HC. Gene ontology (GO) enrichment analysis of the DEGs in HS patients revealed the terms “type I IFN,” “IFNγ signaling pathway,” and “immune responses” as the top 3 most significant terms for monocytes. Gene expression analysis of lymph node biopsies from sporadic and H syndrome-associated RDD suggests common underlying pathological process. In conclusion, monocytes and macrophages from both HS patients showed transcriptomic profiles similar to SAIDs and also uniquely upregulated IFNγ signature. These findings may help find better therapeutic options for this rare disorder. Keywords H syndrome . systemic autoinflammatory disease . interferon gamma
Key Points • Regulome analysis of monocytes and macrophage subsets in H syndrome patients shows an autoinflammatory phenotype. • Gene expression analysis of lymph node biopsies from sporadic and H syndrome-associated Rosai-Dorfman disease suggests a common underlying pathological process * Sinisa Savic [email protected] 1
Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds LS9 7TF, UK
2
Leeds Institute of Medical Research, University of Leeds, Leeds LS9 7TF, UK
3
Leeds Omics, University of Leeds, Leeds LS2 9JT, UK
4
Department of Clinical Immunology and Allergy, St James’s University Hospital, Leeds LS9 7TF, UK
5
Section of Experimental Haematology, Leeds Institute of Ca
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