Autoimmune Disease and miRNAs PHM142 Presentation November 28, 2018 Instructor: Dr. J. Henderson Autoimmune Disease and miRNAs Jessica Callaghan, Petar Popov, Ken Shi-Kin Chung, Kishan Rana November 28, 2018

What are microRNAs (miRNAs)? Small, single-stranded RNA molecules Non-coding RNA function in regulation of post-transcriptional gene expression tend to be highly conserved across species highly conserved across species Baulina, N. M., Kulakova, O. G. & Favorova, O. O. MicroRNAs: The Role in Autoimmune Inflammation. Acta Naturae 8, 21–33 (2016).

Canonical vs. non-canonical pathways Primary-miRNA Pre-miRNA miRNA duplex RNA-induced silencing complex (RISC) Baulina, N. M., Kulakova, O. G. & Favorova, O. O. MicroRNAs: The Role in Autoimmune Inflammation. Acta Naturae 8, 21–33 (2016).

Mechanism of gene regulation by miRNAs Baulina, N. M., Kulakova, O. G. & Favorova, O. O. MicroRNAs: The Role in Autoimmune Inflammation. Acta Naturae 8, 21–33 (2016).

Redundancy in mRNA and miRNA controls mRNA expression can be controlled by many miRNAs Conversely, 1 miRNA can control many different mRNAs Baulina, N. M., Kulakova, O. G. & Favorova, O. O. MicroRNAs: The Role in Autoimmune Inflammation. Acta Naturae 8, 21–33 (2016).

miRNA as biomarkers in: Multiple Sclerosis and Rheumatoid Arthritis Neurological auto-immune disease—characterized by inflammation, demyelination of the CNS, resulting in motor, speech, vision disabilities differential expression of certain miRNAs can point to disease progression/severity: miRNA 140-5p: ↓ in the PBMCs of MS patients—also inversely correlated to disease severity can be use as a biomarker for pathogenesis/prognosis of MS as a biomarker of re-myelination from MS: miRNA-572: ↓ in MS, but increased in remitting MS—a good potential biomarker for re-myelination from MS In rheumatoid arthritis: as a biomarker of disease activity/severity: miRNA-223—possibly ↓ serum levels signaling less activity based on recent observational studies = ↓ after early RA therapy Chen, J.-Q., Papp, G., Szodoray, P. & Zeher, M. The role of microRNAs in the pathogenesis of autoimmune diseases. Autoimmun Rev 15, 1171–1180 (2016).

miRNA polymorphisms in risk for auto-immune disease Single nucleotide polymorphisms (SNPs) in miRNA Rheumatoid arthritis risks miRNA-499 gene: rs3746444 (A>G) IL-2, IL-6, IL-17, IL-21, IL-23 miRNA-146a gene: rs2910164 (C>G) NF-kB, TNF-a Latini, A., Ciccacci, C., Novelli, G. & Borgiani, P. Polymorphisms in miRNA genes and their involvement in autoimmune diseases susceptibility. Immunol. Res. 65, 811–827 (2017).

Targeting miRNAs in auto-immune disease gene therapy Rheumatoid Arthritis—dysfunctional apoptosis in synovial cells leads to hyperplasia and inflammation (a) (b) Baier, A., Meineckel, I., Gay, S. & Pap, T. Apoptosis in rheumatoid arthritis. Current Opinion in Rheumatology 15, 274 (2003). Tsujimoto, Y. Role of Bcl-2 family proteins in apoptosis: apoptosomes or mitochondria? Genes Cells 3, 697–707 (1998).

Example miRNA therapy: miRNA-15a RA Treatment Strategy—target Bcl-2 protein that regulates apoptosis using miR-15a (c) Nagata et al. study—2 main findings (c): arthritic mice are able to uptake double-stranded miR-15a Caspase 3 was increased in synovium of experimental mice Multiple Sclerosis—miR-15a also down-regulated in MS patients (d) inhibits apoptotic processes modulating BCL2 gene expression (c) Nagata, Y. et al. Induction of apoptosis in the synovium of mice with autoantibody-mediated arthritis by the intraarticular injection of double-stranded MicroRNA-15a. Arthritis & Rheumatism 60, 2677–2683 (2009). (d) Luo, D. & Fu, J. Identifying characteristic miRNAs-genes and risk pathways of multiple sclerosis based on bioinformatics analysis. Oncotarget 9, 5287–5300 (2018).

Summary miRNAs are non-coding single stranded molecules that inhibit gene expression miRNA bind mRNA to either promote mRNA degradation or translational repression SNPs in miRNA genes pose risk for autoimmune diseases by acquisition of novel targets in the immune system Most common rheumatoid arthritis associated polymorphism include miRNA-499 (acts on IL-17) and miRNA-146a (correlated to TNF-a) miRNA levels can be used as a biomarker in auto-immune disease, for example — estimating disease progression, activity, severity, or remittance (e.g. in RA and MS) miR-15a has therapeutic potential in RA and MS by supressing anti-apoptotic BCL2 to induce apoptosis via the caspase cascade

Citations Baulina, N. M., Kulakova, O. G. & Favorova, O. O. MicroRNAs: The Role in Autoimmune Inflammation. Acta Naturae 8, 21–33 (2016). Chen, J.-Q., Papp, G., Szodoray, P. & Zeher, M. The role of microRNAs in the pathogenesis of autoimmune diseases. Autoimmun Rev 15, 1171–1180 (2016). Latini, A., Ciccacci, C., Novelli, G. & Borgiani, P. Polymorphisms in miRNA genes and their involvement in autoimmune diseases susceptibility. Immunol. Res. 65, 811–827 (2017). Baier, A., Meineckel, I., Gay, S. & Pap, T. Apoptosis in rheumatoid arthritis. Current Opinion in Rheumatology 15, 274 (2003). Tsujimoto, Y. Role of Bcl-2 family proteins in apoptosis: apoptosomes or mitochondria? Genes Cells 3, 697–707 (1998). Nagata, Y. et al. Induction of apoptosis in the synovium of mice with autoantibody-mediated arthritis by the intraarticular injection of double-stranded MicroRNA-15a. Arthritis & Rheumatism 60, 2677–2683 (2009). Luo, D. & Fu, J. Identifying characteristic miRNAs-genes and risk pathways of multiple sclerosis based on bioinformatics analysis. Oncotarget 9, 5287–5300 (2018).