Dissecting the theranostic potential of exosomes in autoimmune disorders

The biology of exosomes is a fascinating field of science that has attracted much attention from clinical researchers due to the plethora of associated applications. These biological cargoes serve as a hub of information about the health status of a cell or a group of cells. Recent reports on exosome-derived biomolecules in relation to diseases such as cancer, neurodegenerative diseases, and infectious diseases have spurred interest in exploring their role in the pathogenesis of other debilitating disease conditions. Progressive research into autoimmune disorders (ADs) in relation to exosome biology has identified novel therapeutic leads aiming to improve the life expectancy of individuals suffering from such disorders.¹ One such important, notable contribution was recently shared by Guay et al. and provided concreate evidence on the mechanism of β cell apoptosis induced by the transfer of exosomal miRNAs derived from T cells, which eventually leads to type I diabetes mellitus. The crucial mediators of the process were T-lymphocyte-derived exosomes harboring miR-142-3p, miR-142-5p, and miR-155. Anti-miRs designed to block the interactions of miRNAs with their target genes inside β cells prevented the process of apoptosis, eventually rescuing β cells.² Thus, targeting the mediators of crosstalk or blocking the function of exosomal miRNAs could serve as an interesting therapeutic strategy for type I diabetes mellitus (Fig. 1). Consistent with the above report, this review highlights the contribution of exosomes to the development of autoimmune disorders. In addition, this review also reveals the possible “theranostic” markers (therapeutic and diagnostic biomarkers) associated with ADs.

Fig. 1.

Therapeutic application of anti-miRs to combat exosome-induced apoptosis of beta cells in type I diabetes mellitus²

ADs are caused by an immune response directed against the host’s own cells, thereby damaging tissues and organs. AD is one of the leading causes of worldwide morbidity and mortality due to chronic diseases. AD can present as an organ-specific disorder, as in the case of type I diabetes mellitus and multiple sclerosis (MS), or can result in a systemic ailment such as systemic lupus erythematosus (SLE) or rheumatoid arthritis (RA). Regardless of the type of AD, the outcome of any AD is precipitated by damage to a single organ or multiple organs. Prompt and precise diagnosis of the type of AD aids in the initiation of appropriate treatment for the disease. Exosomes are vesicular bodies of endosomal origin considered to be conveyers of biological information in the form of proteins and RNAs from one cell to another. The content of these vesicles is unique to each cell type and differs significantly between cells under normal physiological conditions and in pathological transformations. Exosomes are derived from different types of calls, including stem cells and tumor cells and are essentially found ubiquitously in body fluids such as saliva, plasma, ascites, breast milk, urine, and cerebrospinal fluid. The stability and array of biological functions exhibited by exosomes make them potential major factors in the diagnosis of ADs.³

The diagnostic potential of exosomes for ADs was documented a few years ago by Ebrahimkhani et al. This team provided the first demonstration of the pool of differentially expressed miRNAs derived from exosomes in relapsing-remitting MS and progressive MS, which is otherwise difficult to classify and diagnose based on clinical parameters. Nine miRNAs, namely, miR-15b-5p, miR-23a-3p, miR-223-3p, miR-374a-5p, miR-30b-5p, miR-433-3p, miR-485-3p, miR-342-3p, and miR-432-5p, were separated from the already identified repertoire of miRNAs and validated in cases of progressive MS. Thus, identification of these exosomal biomarkers is revealed as a “liquid biopsy” approach for the detection and monitoring of MS.⁴ A similar study provided insight into the role of exosomally derived let-7i microRNA in regulating the pathogenesis of MS by interfering with the IGF1R/TGFBR1 pathway. An increase in the level of let-7i, as observed in patients with MS compared to healthy controls, can serve as a potent diagnostic marker.⁵ A high expression level of the long noncoding RNA HOTAIR (lncRNA HOTAIR) derived from peripheral blood mononuclear cells and serum exosomes was found to critically regulate the molecular pathways associated with macrophage migration, implicating this lncRNA as a potent prognostic marker for rheumatoid arthritis.⁶ A comprehensive investigation of the serum exosome protein profile of RA patients revealed several proteins to be highly expressed in patients with active RA, inactive RA and osteoarthritis compared to healthy controls. Interestingly, there was a six-fold increase in the level of Toll-like receptor 3 (TLR3) in active RA patients.

Exosomes are currently used as drug delivery vehicles due to their stability and excellent biocompatibility. The development of exosome bioconjugates with anti-inflammatory properties in addition to remyelination-inducing abilities produced promising results towards reducing the clinical score of MS. LJM-3064, an aptamer conjugated to the surface of exosomes, was tested in both in vitro (in the oligodendroglial cell line OLN93) and in vivo (in female C57BL/6 mice) models with promising results, confirming the clinical utility of the tested strategy.⁷ The therapeutic potential of mesenchymal stem cell-derived miRNA-150-5p, Exo-150, was investigated in a collagen-induced arthritis mouse model. Interestingly, Exo-150 reduced the destruction of joints by blocking angiogenesis and synoviocyte hyperplasia.⁸

Exosome-based nanotherapeutics are in need of development due to the plethora of positive signals accompanied by these drugs. The effectiveness of exosomes derived from interferon gamma-induced mesenchymal stem cells (IFNγ-Exo) in a mouse model of experimental autoimmune encephalomyelitis (EAE) was promising, with effects characterized by reduced demyelination and neuroinflammation and an increased number of regulatory T-cells (Tregs), thereby alleviating conditions of multiple sclerosis. This experimental evidence proves the therapeutic mechanisms of stem cell-derived exosomes as cell-free therapeutics in treating autoimmune disorders.⁹

Exosomes serve as a “theranostic factors” wherein the differentially expressed proteins and nucleic acids serve as diagnostic biomarkers; on the other hand, the unique biomolecules involved in cellular communication or exosome biosynthesis serve as therapeutic leads. The current scenario demands rapid diagnosis of diseases and prompt treatment plans to overcome the burden of debilitating disorders. In-depth probing into exosomal cargoes has identified diagnostic biomarkers, especially for diseases such as cancer,¹⁰ neurodegenerative diseases, and cardiovascular disorders. Prolific research has ensued, resulting in two exosomal biomarker-based diagnostic kits for prostate and lung cancers. Revelations about exosomal contents and their implications in various disease types will aid in the exploration of novel pathways associated with disease progression and pathogenesis, thereby changing perspectives in clinical medicine.

Competing interests

The authors declare no competing interests.