miR-146a and miR-146b regulate the expression of ICAM-1 in giant cell arteritis.

Giant cell arteritis (GCA) is an inflammatory disease of large/medium-sized arteries. MiRNAs are small, non-coding RNAs that inhibit gene expression at post-transcriptional level. Several miRNAs have been shown to be dysregulated in temporal artery biopsies (TABs) from GCA patients, but their role is unknown. The aims of the present work were: to gain insight into the link between inflammation and miRNA up-regulation in GCA; to identify the role of miR-146a and miR-146b. Primary cultures from TABs were treated with IL-1ß, IL-6, soluble IL-6R (sIL6R), IL-17, IL-22, IFNγ, LPS and PolyIC. Correlations between cytokine mRNA and miRNA levels were determined in inflamed TABs. Primary cultures from TABs, human aortic endothelial and smooth muscle cells and ex-vivo TAB sections were transfected with synthetic miR-146a and miR-146b to mimic miRNA activities. Cell viability, target gene expression, cytokine levels in culture supernatants were assayed. Treatment of primary cultures from TABs with IL-1ß and IL-17 increased miR-146a expression while IL-1ß, IL-6+sIL6R and IFNγ increased miR-146b expression. IFNγ and IL-1ß mRNA levels correlated with miR-146a/b levels. Following transfection, cell viability decreased only in primary cultures from TABs. Moreover, transfection of miR-146a/b mimics increased ICAM-1 gene expression and production of the soluble form of ICAM-1 by primary cultures from TABs and by ex-vivo TABs. ICAM-1 expression was higher in inflamed than normal TABs and ICAM-1 levels correlated with miR-146a/b levels. Expression of miR-146a and miR-146b in GCA appeared to be driven by inflammatory cytokines (e.g. IL-1ß, IFNγ). miR-146a and miR-146b seem responsible for the increase of soluble ICAM-1.

Genes deregulated in giant cell arteritis by Nanostring nCounter gene expression profiling in temporal artery biopsies.

OBJECTIVE: To identify differentially expressed genes in temporal artery biopsies (TABs) from patients with giant cell arteritis (GCA) with different histological patterns of inflammation: transmural inflammation (TMI) and inflammation limited to adventitia (ILA), compared with normal TABs from patients without GCA. METHODS: Expression of 770 immune-related genes was profiled with the NanoString nCounter PanCancer Immune Profiling Panel on formalin-fixed paraffin-embedded TABs from 42 GCA patients with TMI, 7 GCA patients with ILA and 7 non-GCA controls. RESULTS: Unsupervised clustering of the samples revealed two distinct groups: normal TABs and TABs with ILA in one group, 41/42 TABs with TMI in the other one. TABs with TMI showed 31 downregulated and 256 upregulated genes compared with normal TABs; they displayed 26 downregulated and 187 upregulated genes compared with TABs with ILA (>2.0 fold changes and adjusted p values <0.05). Gene expression in TABs with ILA resembled normal TABs although 38 genes exhibited >2.0 fold changes, but these changes lost statistical significance after Benjamini-Yekutieli correction. Genes encoding TNF superfamily members, immune checkpoints, chemokine and chemokine receptors, toll-like receptors, complement molecules, Fc receptors for IgG antibodies, signalling lymphocytic activation molecules, JAK3, STAT1 and STAT4 resulted upregulated in TMI. CONCLUSIONS: TABs with TMI had a distinct transcriptome compared with normal TABs and TABs with ILA. The few genes potentially deregulated in ILA were also deregulated in TMI. Gene profiling allowed to deepen the knowledge of GCA pathogenesis.

[Superior mesenteric venous thrombosis. Report of 2 cases and review of the literature]. / Trombosi venosa mesenterica superiore. Presentazione di due casi e revisione della letteratura.

Mesenteric venous thrombosis is an uncommon but often fatal form of intestinal ischaemia. The authors present two cases of severe small intestinal ischaemia due to superior mesenteric vein thrombosis, the first associated with oral contraceptive use and a congenital methylene-tetrahydrofolate reductase defect and the second associated with atypical intestinal mycobacterial disease and acquired immunodeficiency syndrome. The authors review the relevant literature using the Medline search facility and comment on the changing aspects of MVT syndrome with regard to aetiological factors, diagnostic approach and surgical or pharmacological therapy.