Abstract
Autoimmune diseases (AD) are severe pathophysiological ailments that are
stimulated by an exaggerated immunogenic response towards self-antigens,
which can cause systemic or site-specific organ damage. An array of
complex genetic and epigenetic facets majorly contributes to the
progression of AD, thus providing significant insight into the
regulatory mechanism of microRNA (miRNA). miRNAs are short, non-coding
RNAs that have been identified as essential contributors to the
post-transcriptional regulation of host genome expression and as crucial
regulators of a myriad of biological processes such as immune
homeostasis, T helper cell differentiation, central and peripheral
tolerance, and immune cell development. Pertaining to the differential
expression of miRNA attributed in target tissues and cellular bodies of
innate and adaptive immunity, a paradigm of scientific expeditions
suggests an optimistic correlation between immunogenic dysfunction and
miRNA alterations. Therefore, it is not astonishing that dysregulations
in miRNA expression patterns are now recognized in a wide spectrum of
disorders, establishing themselves as potential biomarkers and
therapeutic targets. Owing to its theranostic potencies, miRNA targets
have been widely utilized in the development of biosensors and other
therapeutic molecules originating from the same. This article tends to
deliberate and conceptualize the brief pathogenesis and pertinent
epigenetic regulatory mechanism as well as miRNA networks majorly
affecting five different ADs namely Rheumatoid Arthritis (RA), Diabetes,
Multiple Sclerosis (MS), Systemic Lupus Erythematosus (SLE) and
Inflammatory Bowel Disorder (IBD) thereby providing novel theranostic
interventions.
Keywords - Autoimmune Diseases, miRNA, Epigenetic Regulation,
Diagnostics, Therapeutics
Introduction
Autoimmune diseases (ADs) are chronic and progressive ailments
designated by an exaggerated self-immunogenic response, accompanied by
the overproduction of self-antibodies leading to an overall systemic
dysfunction and abnormalities in cellular components. Depending on
various biological and physicochemical factors, ADs can bring damage to
a particular organ or other biological systems. The interaction of
environmental factors and genetic anomalies has a key role in showcasing
the pathological effects of ADs . The involvement of B cells in the
progression of ADs displays an array of different biological roles.
These biological roles mainly include the entrenched secretion of
self-antibodies; the presentation of self-antigens and arising
complementary interactions with T cells; the release of cytokines
involved in the inflammatory response; and the development of deranged
specialized microstructure named as germinal centers. With the help of
these cellular processes, autoimmune conditions that are often
categorized as antibody-mediated or as T cell-mediated, both are
considered to be controlled and affected by B cells . The maturation of
T-cells in the thymus is responsible for the elimination of a large
amount of auto-reactive T cells, but a bulk of T cells that have gained
maturity and are able to detect autoantigens can be observed in the
peripheral circulatory system of healthy people along with the people
suffering from AD. While they appear to be responsible for the
pathophysiology of a number of ADs in patients, these auto-reactive
cells are maintained in an unresponsive condition in healthy persons.
CD4+ CD25+ are considered to be T cells possessing a natural regulatory
mechanism and furthermore, it is a population of T cells that have been
recently discovered and is regarded to be predominantly responsible for
the modulation of the activity of these auto-reactive immune cells .
Recent studies suggest that in some types of autoimmunity, the
interaction between the environment and the host is influenced by
epigenetic alterations induced by various environmental factors,
including altered DNA methylation patterns. Due to environmental
factors, it may become difficult for certain cells to maintain
epigenetic homeostasis, which can result in loss of tolerance due to
abnormal expression of genes. These altered cells can subsequently
contribute to the onset of autoimmunity in those with a genetic
predisposition . Expression of genes and cellular processes are altered
by epigenetic changes, but the genomic sequence remains unaffected. The
key epigenetic processes include expression of non-coding RNA,
modification of amino termini of histone proteins by post-translational
alterations, and CpG DNA dinucleotides methylation and/or their
hydroxymethylation. Pathophysiology of ADs has been strongly connected
to disease responsible for triggering gene alterations or a combination
of genetic vulnerability, and epigenetic changes occurring due to the
involvement of various environmental factors. Thus, it is crucial to
understand how some ADs are caused by the concoction of genetic as well
as epigenetic pathways . A new family of noncoding RNA known as long
noncoding RNA (lncRNA) is essential for the control of both autoimmune
and immunological processes, whereas, on the other hand, endogenous
non-coding RNAs (ncRNAs) known as circular RNAs (circRNAs) showcases
itself as the crucial immune system gene modulators and is responsible
for the occurrence and progression of ADs . In addition to this, small,
conserved non-coding RNA molecules called miRNAs target the 3β
untranslated region (UTR) of particular messenger RNAs (mRNAs) and
either promote their destruction or suppress translation. Apoptosis,
differentiation, cell cycle, and immunological activities are the
biological processes that miRNA is known to control. According to recent
studies, miRNAs are essential for the regulatory mechanisms of
immunological processes and play a key role in preventing ADs . The
therapy of ADs has changed little over the past few decades due to
advancements in medicine, and the mechanisms behind many of these
diseases are still unknown. Itβs also important to understand how ADs
initiate, progress, and end. Owing to its unique regulatory properties
and pathogenic contributions, miRNA can legitimately serve as a
potential biomarker candidate to efficaciously diagnose the progression
of AD. Several daunting attempts were actualised to construct a
compendium of biosensors to detect sole pathogenic miRNA candidates
participating in AD pathophysiology. Due to the advent of advancing
progressions in the domain of material sciences and pharmaceutical
interventions, several miRNA encapsulating strategies have been
formulated to enhance site-directed specific drug delivery to curb a
number of ADs. Altered physiological microenvironment and physical
properties are some of the characteristic hallmarks of AD that demand
the application of stimuli-responsive drug delivery platforms to cater a
stimulus specific to the disease. Understanding the methods through
which miRNAs participate in these processes can therefore offer a new
window to advance our knowledge of ADs. This article tends to provide
insight into miRNA regulation and responsiveness towards the
complexities of immunological cascades associated with progressive ADs,
pertaining special emphasis on Rheumatoid arthritis (RA), Diabetes,
Multiple Sclerosis (MS), Systemic Lupus Erythematosus (SLE) and
Inflammatory bowel disorder (IBD), thereby providing optimistic
deliberations on novel theragnostic interventions concerning the same.
Along the same lines, it also heralds to showcase significant epigenetic
modulations for the above-mentioned ADs.
Biogenesis of mi-RNA and its regulatory mechanism on ADs
Small non-coding RNAs (19-21 nucleotides) called miRNAs majorly
influences the post-transcriptional regulation of gene expression by
either limiting messenger RNA (mRNA) translation or encouraging mRNA
degradation. miRNA was first identified in the year 1993 and it remains
conserved among a wide variety of species . miRNAs are the major
contributing factors in the pathophysiology of multiple diseases
including cancer, cardiovascular, metabolic and ADs . Animal miRNAs are
encoded as mono-cistronic (individual genes), poly-cistronic (cluster of
genes), or introns of host genes (intronic). Primary miRNA (pri-miRNA)
transcripts with hairpins and 5β and 3β flanking sequences are produced
by RNA polymerase II . As depicted in Figure 1, the processing is
carried out mainly by Drosha and Dicer, two members of the RNase III
family of enzymes , which work in complexes with dsRNA-binding proteins
(dsRBPs), such as DGCR8 and transactivation-responsive RNA-binding
protein (TRBP) in mammals, to catalyze the two steps of primary
precursor (pre-miRNA) processing in the canonical pathway . The
structural properties of individual pri-miRNA sequences influence the
effectiveness of pri-miRNA processing. Co-transcriptional processing of
pri-miRNAs results in a fast pool of 59-71-nt-long stem-loop pre-miRNAs.
Exportin-5, a member of the karyopherin protein family, exports nascent
pre-miRNAs to the cytoplasm in a GTP-dependent manner . Once in the
cytoplasm, the pre-miRNA is integrated into the RISC Loading Complex
(RLC), where it is processed into a 21-nt-long miRNA/miRNA* duplex by
the type III ribonuclease Dicer . Up to one-third of human mRNAs may be
miRNA targets, and miRNA-mediated gene regulation is essential for
normal physiological processes including the cell cycle,
differentiation, and death. miRNAs are essential for the control of
immunological processes and the avoidance of AD, as stated by the recent
research . There are various checkpoints that guarantee the deletion or
silencing of autoreactive T and B lymphocytes, which are produced
regularly and randomly throughout lymphomagenesis. But occasionally,
self-reactive lymphocytes manage to get past the checkpoints and
continue to live in peripheral lymphoid tissues. When these autoreactive
cells are triggered, they launch a vicious assault against self-tissues
that trigger ADs . miRNAs control autoimmunity by influencing the
formation, differentiation, and function of many cell types, including
innate immune cells (innate immunity), adaptive immune cells (adaptive
immunity), and local resident cells . Toll-like receptors (TLRs), C-type
lectin-like receptors (CLRs), nucleotide-binding oligomerization domain
(NOD)-like receptors, retinoic acid-inducible gene (RIG)-I-like
receptors (RLRs), are all expressed by host cells. These receptors are
capable of recognizing a wide range of pathogen-associated molecular
patterns (PAMPs) . These processes activate intracellular signaling
pathways, resulting in the release of proinflammatory cytokines,
chemokines, and interferons (IFNs) as well as the production of
co-stimulatory molecules. Several investigations have demonstrated that
miRNAs play critical roles in the biological processes of these adaptive
immune cells in autoimmunity, miRNAs also alter/regulate a particular
subgroup of T cells called regulatory T cells (Tregs) are essential for
regulating the immune response, which finally results in the upkeep of
self-tolerance and homeostasis . According to Husakova et al., (2016),
miRNAs have an impact on the development of CD8+ T cells, Th1 cells, Th2
cells, and Thymus by affecting the levels of miRNA-155, miRNA-147, and
miRNA-146a. The in-vivo application of the major miRNAs are already
known. The multi-modal applications of miRNA delves into the
conceptualization and understanding of various novel developmental
strategies for the treatment and prevention of ADs