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 3’ 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. It’s 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 5’ and 3’ 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