MicroRNA activation signature in patients with hemophagocytic lymphohistiocytosis and reversibility with disease-specific therapy  Janos Sumegi, MD, PhD, Shawnagay Nestheide, BS, Bruce Aronow, PhD, David Fletcher, BS, Mehdi Keddache, PhD, Joyce Villanueva, BS, Kejian Zhang, MD, Alexandra H. Filipovich, MD  Journal of Allergy and Clinical Immunology  Volume 137, Issue 1, Pages 309-312 (January 2016) DOI: 10.1016/j.jaci.2015.06.006 Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 miRNA expression in healthy control subjects and patients with HLH. A, Heat map of the differentially expressed miRNAs in which red indicates upregulation and yellow indicates downregulation. RPKM, Reads per kilobase per million. B, Quantitative RT-PCR validation of a selected set of differentially expressed miRNAs (8 control subjects and 25 patients with HLH). The insert shows the correlation of expression levels between miRNA sequencing and quantitative RT-PCR. C, miRNA expression in plasma (6 control subjects and 6 patients with HLH). D, Soluble IL-2 receptor (sIL2R) plasma levels of patients with active HLH (red) and remission (green). The yellow field shows the variation of soluble IL-2 receptor levels in control subjects. E, Expression of miRNAs in control subjects (blue, n = 8), patients with active HLH (red, n =10), and patients in remission (green, n = 10). Journal of Allergy and Clinical Immunology 2016 137, 309-312DOI: (10.1016/j.jaci.2015.06.006) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 Gene enrichment analysis of the upregulated miRNA targets in patients with HLH. Violet rectangles and squares on the rightmost indicate miRNAs, and their size reflects the abundance of the individual miRNA (rectangles, >5000 reads per kilobase per million; squares, <5000 reads per kilobase per million). They are connected through red and gray lines to their validated target genes (yellow and red hexagons). Eleven miRNAs (violet rectangles) target all genes but Toll-like receptor 5 in the network (see Fig E1). Yellow squares (at top) are knockout phenotypes from mouse models with indicated phenotypes and connected with green edges to their corresponding genes (yellow hexagons). The features that are also significant for other genes (red hexagons) in the network are connected by gray lines that are not concepts related to the tolerance and autoimmune-associated core genes (yellow hexagons).4 Other phenotypes related to abnormal lymphocyte physiology from mouse models are displayed as light green squares. Dark green squares are concepts related to immune responses. Purple squares on the leftmost indicate pathways. Squares (turquoise) at the lowermost of the figure are gene expression signatures from the Immgen Consortium database (https://www.immgen.org). Journal of Allergy and Clinical Immunology 2016 137, 309-312DOI: (10.1016/j.jaci.2015.06.006) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions