1. 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

2. 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).

3. 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).

4. 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).

5. 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).

6. 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).

7. miRNA polymorphisms in risk for auto-immune disease
Single nucleotide polymorphisms (SNPs) in miRNA
Rheumatoid arthritis risks
miRNA-499 gene: rs (A>G)
IL-2, IL-6, IL-17, IL-21, IL-23
miRNA-146a gene: rs (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).

8. 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).

9. 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).

10. 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

11. 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).