The Role of miRNA in Auto Immune Diseases :

A Promise for Biomarkers and Targeted Therapies

Sofia Mubarika Haryana

FK KMK UGM
Indonesia Academy of Science
Outline

1. Auto Immune disease – polygenic and environment

2. Postgenomic Era and Precision Medicine Era for Autoimmune
a. Functional Genomics to study the clinical gap
b. miRNA as small molecules with big roles
3. miRNA Dysregulation in Autoimmune disease
4. Best practices - miRNA as specific biomarkers and target therapy for
Autoimmune Diseases
5. Take Home Message
 Autoimmune Diseases – Problems and Challenges
• “A condition in which the body's immune
system mistakes its own healthy tissues
as foreign and attacks them “
• 10 highest incidence
• Rheumatoid arthritis
• Systemic lupus erythematosus
• Inflammatory bowel disease (IBD).
• Multiple sclerosis (MS).
• Type 1 diabetes mellitus.
• Guillain-Barre syndrome.
• Chronic inflammatory demyelinating
polyneuropathy.
• Psoriasis.
• Affect approx. 4% population in the
world
• Costly, managed for years
• By the diagnosed – tissue damaged
has occurred
• miRNA – key regulator in Protein
Expressions
• miRNA exosome – cell and tissue
specific
• Potential as Biomarker specific and
targeted therapy for autoimmunity
GWAS – Number of gene mutations in AID’s
Genetic – epigenetic –
environment interactions

Lisa Stuart, 2015 Personalized, epigenetics, 2015

 GWAS
AIDs

Overlap non –
coding>>>> : coding

Schmidt et al, Mol Biol & Evol, 2013 Farh et al, Nature 2014
 Genome and Epigenome Non coding RNA
Coding RNA – 3%
Non Coding RNA – 97%

Naeini et al , Pubmed 2009

Niess et al, 2019
Coding RNA – 2-3 %
• miRNA packed in
Exosome and MVB

• Actively secreted
from every cell
Postgenomic Era – Functional Genomics ?
Level of
Molecular Diagnosis in Post expressions
genomic Era
Metabolo
Compl Function Metabolo me
Genomi etion Databa al mics
Genomics Proteomic Proteome
cs of se genomic
HGP s s
Transcrioto
mics transcripto
Diagnosis Innovativ
me
e
of
Therapie
Infections s mRN
A
Development Predictive
of New medicine
vaccine Micro
Analysi
s
Functional genomics :
miRNA expressions in various AID’s  Sjogren syndrome Osteoarthritis
Activities
SLE

AI Thyroiditis
miRNA – Novel Regulator of Autoimmunity
miRNA – small molecule big roles

Zheng et al, Cell & Mol Immunol 2017 Hecker et al, Intl J Mol. Sci, 2014
Dysregulation of miRNA in Autoimmune diseases

Pauley et al, Autoimmunity 2009

miRNA dysregulation : Epigenetic : miRNA dysregulated AbN expression
Upregulated miRNA
 supress mRNA target

Down regulated miRNA

 activate mRNA target

Loss of Immune
tolerance

AUTO
IMMUNITY
Exosome - in AID
• Exosomes are extracellular microvesicles (30-150 nm) released from
cells that contain proteins, lipids, RNA and DNA.
• Exosome contain bioactive molecules and serve as carriers facilitating
cell-cell communication, such as antigen presentation, inflammatory
activation, autoimmune diseases (AIDs) and tumor metastasis.
• Recently, evidence showed that exosomes involved as immune
regulator in AIDs
• Some studies have shown that exosomes are involved in the
occurrence and development of AITDs,
Zhou et al, Front in Immunol, 2021
Exosome Immunoregulate Innate and Adaptive Immunity

Zhou et al, Front in Immunol 2021

 Exosome – Cargo and Cell Communicators

Exosomes can be loaded. Nano molecules – pass BBB, other barriers

Differs source of
exosomes
Moon et al., Cell 2022
Exosome source –
antigen
presentation
Exosome Isolation
strategy

Patel et al, Scientif. Report, 2019

Clinical
Application ?
Exosome and liquid biopsy

- Diagnosis
- Prognosis
- Follow up
Evidence serum MIRNA as a specific Biomarkers
• N = 154 patients without a history of surgery
(Cohort 1) and
• 75 patients who were to undergo intestinal
resection (Cohort 2).
• Serum samples from Cohort 1 before colonoscopy
and from Cohort 2 before surgery and during post-
operative colonoscopic examination.
• The serum levels of exosomal miR-144-3p were
measured using quantitative reverse-transcription
polymerase chain reaction (PCR).

• Correlations between relative exosome miR-144-3p levels, disease activity, and disease behavior were analysed.
• The area under the receiver-operating characteristic curve (AUC) was used to assess the predictive value of exosomal
miR-144-3p regarding mucosal activity and post-operative recurrence.
Anel et al, Cell, 2019
 Fig.1
Fig 2. Correlations between serum exosome miR-144-3p and CDAI, SES-CD
in patients with CD. (A) Spearman correlation ...

Fig.3
Fig.4 Penetrating Dis Behav Fig.5 ROC

Predictive Power
Biomarker
AUC 0.761
P < 0.001

Gastroenterol Rep (Oxf), Volume 10, , 2022, goab056, https://doi.org/10.1093/gastro/goab056

The content of this slide may be subject to copyright: please see the slide notes for details.
The results indicated
• Serum exosomal miR-144-3p levels may be valuable for monitoring
Crohn Disease (CD).
• Highly elevated exosomal miR-144-3p levels indicate the presence of
penetrating complications.
• This approach is compare to the inflammatory marker CRP for detecting
early recurrence in CD patients after intestinal resection.
• Serum exosome miRNA is stable and easy to detect , non invasive
procedures and therefore useful in clinical practice.
• Further studies are needed to validate these findings
Clinical trial exosome

Lee et al. J. Clin Med, 2021

Exosome-miRNA – biological and
pathogenic

Mirzaei et al,
J.NeuroImmunol,2021
 Prospect for target Therapy ?

TNF-α
IL-1β

IL-6
miRNA 155 in
MS and SLE:
- different targets
MiRNA
dysregulation
in SLE- as a
Basic for
Development
of Target
Therapy
Exosome Therapy in
OA

Anel et al, Cell, 2019

Exosome and miRNA in auto immune
diseases

Mirzaei et al,
J.NeuroImmunol,2021
 Prospect for the future……….
Exosome sources and isolation for biomarkers and therapy in autoimmune
diseases
A

Duan et al, Nature 2019

Hot topic

•.
MSC derived
Exosome for AID
therapy/
Regenerative
therapy

Shen etal, Front in Immunol, 2021

Exosome miRNA for
Target Therapy
Take home message
• Auto Immune disease is an interaction between genetic and
epigenetic and environment
• miRNA regulator protein expression at the posttranscriptional 
dysregulated in Auto immunity
• Potential miRNA as specific biomarker for certain AID
• Exosome and miRNA clinical trial for auto Immune diseases are
underway ( http;//clinicaltrial.gov.therapy