Multiple Sclerosis (MS) is caused by a still unknown interplay between genetic and environmental factors. Epigenetics, including DNA methylation, represents a model for environmental factors to ...influence MS risk.
Twenty-six affected and 26 unaffected relatives from 8 MS multiplex families were analysed in a multicentric Italian study using MeDIP-Seq, followed by technical validation and biological replication in two additional families of differentially methylated regions (DMRs) using SeqCap Epi Choice Enrichment kit (Roche®).
Associations from MeDIP-Seq across families were combined with aggregation statistics, yielding 162 DMRs at FDR ≤ 0.1. Technical validation and biological replication led to 2 hypo-methylated regions, which point to NTM and BAI3 genes, and to 2 hyper-methylated regions in PIK3R1 and CAPN13.
These 4 novel regions contain genes of potential interest that need to be tested in larger cohorts of patients.
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•The 233 genetic loci associated with MS explain less than 40% of disease heritability, leaving a role to epigenetics in disease risk•We compared whole-genome methylation profiles in whole blood of affected and unaffected relatives of 8 multiplex MS families•We used MeDIP-seq and technical and biological replication in 2 additional families using a custom panel•Due to the heterogeneity of results in families, we adopted a method which leveraged consistency of signal across families•Filtering criteria lead to 2 hypo- and 2 hyper-methylated DMRs which relate to NTM, BAI3, PIK3R1 and CAPN13 genes•Replication of these signals is needed in additional cohort of MS patients
Abstract
Funding Acknowledgements
Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Ricerca corrente
Introduction
Valve interstitial cells (VICs) are ...heterogeneous fibroblast-like cells populating the aortic valve (AoV), involved in the extracellular matrix homeostasis. Under pathological conditions, VICs acquire the phenotype of calcific cells causing calcific aortic valve disease (CAVD) 1.
Purpose
In order to find distinctive traits of the phenotype in calcific VICs, we employed single cell RNA-sequencing (scRNASeq) to compare the gene expression signatures of VICs from stenotic AoVs (sVICs) vs. valves with insufficiency (iVICs), a pathology characterized by a lower level of calcification.
Methods
Before being used for scRNAseq profiling, VICs from the two pathological settings were amplified for three passages, after which they were loaded into the Drop-seq platform that encapsulated them in oil droplets with lysis buffer and barcoded primer beads. Beads were then subjected to reverse transcription, followed by library preparation. Libraries were sequenced with a coverage ranging from 50,000 to 100,000 reads per cell.
Results
A total of 5844 iVICs and 5610 sVICs were successfully separated and barcoded. Four independent VICs donors/pathology were processed and UMAP representation/clustering of cells coming from the eight samples identified the existence of 8 distinct cellular phenotypes, including embryonic progenitor mesenchymal (EMBVICs), ‘activated’ (ACVICs), ‘osteoblastic’ (OBVICs) and ‘quiescent’ (QVICs). The analysis of the cellular composition did not reveal substantial differences in the abundance of the different phenotypes in the two pathologies. On the other hand, differential gene expression followed by functional pathways enrichment showed a significant upregulation in sVICs vs. iVICs of genes/pathways related to Interferon-I (INF-I) in all the identified cellular phenotypes with the exception of QVICs. These included e.g for ACVICs, IFITM1 (log2FC = 1.76 P=3e-101), IFI6 (log2FC = 2.38; P = 1e-69), IFITM3 (log2FC 0.9 P = 5e-58), ISG15 (log2FC = 1.7 P= 4e-53) and IFI27 (log2FC = 1.54 P = 6e-41) genes.
Conclusions
This study reveals the involvement of the interferon-I pathway signaling in CAVD, supporting an autophagic/inflammatory/senescent phenotype switching in relevant VICs types resident in the human AoV.
Amyloid A nephropathy is a possible complication of chronic inflammatory disease. Proteinuria and kidney failure are the main features of the disease. Tocilizumab (TCZ), an IL6-R antibody approved ...for rheumatoid arthritis, is a promising choice for histologically demonstrated nephropathy. We describe a case of kidney amyloid associated with Sweet syndrome treated with TCZ. The patient was affected by Sweet syndrome associated with proteinuria. Kidney biopsy showed amyloid deposits. During the follow-up, cutaneous and renal findings were refractory to many immunosuppressive regimen (cyclophosphamide, leflunomide, interferon and steroid). After few years, the patient developed rapidly progressive nephropathy associated with nephrotic syndrome (proteinuria up to 6 g/die). A second kidney biopsy was performed and it showed worsening of amyloid nephropathy. Thus, TCZ was administrated (8 mg/kg once a month) and it stabilized kidney function and induced partial remission of the nephrotic syndrome in the following 2 years.
IgG4-Related Disease (IgG4-RD) is a fibroinflammatory condition characterized by a typical histopathological pattern (dense lymphoplasmacytic infiltrate with prevalent IgG4+ plasma cells and ...storiform fibrosis), which may involve the kidney both directly (IgG4-related kidney disease, IgG4-RKD) or indirectly, as a consequence of post-renal ureteral obstruction due to retroperitoneal fibrosis (IgG4-RD RF). The most frequent presentation of IgG4-RKD is IgG4-related tubulointerstitial nephritis (TIN), but a glomerular disease can be present, in most of the cases a membranous nephropathy. Albeit steroid-responsive, in some cases renal manifestations may lead to progressive and permanent organ damage. In this review we describe four clinical cases representative of typical and less typical renal manifestations of IgG4-RD, emphasizing a potential, subclinical, early involvement of the kidney in the disease.
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