Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are severe inflammatory reactions affecting the skin and mucous membranes. A recent study reveals significant insights about the regulatory role of microRNAs (miRNAs) involved in these conditions, particularly concerning patients experiencing severe ocular complications (SOC).
The study, conducted by researchers at Kyoto Prefectural University of Medicine, aimed to explore how certain miRNAs influence the immune response in cases of SJS/TEN with SOC. The need for such investigation arose from the complex mechanisms underlying these disorders, often triggered by medications, most commonly cold medicines. They are characterized by extensive tissue damage and serious complications, including blindness.
The investigation examined the expression levels of eight specific miRNAs—let-7a-5p, let-7d-3p, let-7e-5p, miR-146a-5p, miR-130a-3p, miR-151a-3p, miR-151a-5p, and miR-27b-3p—comparing plasma samples from 100 patients with chronic SJS/TEN and SOC to those of 92 healthy individuals. Notably, four miRNAs showed significant upregulation, correlatively linked to increased expression of important innate immune genes.
MicroRNAs, by definition, are short, noncoding RNAs roughly composed of 22 nucleotides, acting as regulators of gene expression post-transcriptionally. They can suppress or promote gene expression by binding to target messenger RNA (mRNA) molecules, thereby playing various roles including modulation of immune responses.
MicroRNA let-7a-5p was particularly noteworthy, as it was positively correlated with the regulation of innate immune genes such as Toll-like receptor 3 (TLR3), RIG-I, and MDA5. The researchers associated its upregulation directly with the persistent ocular inflammation observed within SJS/TEN patients. "Our findings demonstrate specific miRNAs are up-regulated in SJS/TEN with SOC and associated with the upregulation of important immune response genes, indicating their role in the disease’s pathogenesis," they state.
Using quantitative RT-PCR methods, the study analyzed immune-related gene expression levels. The researchers found significant increases not only of TLR3 and RIG-I but also of other innate immune genes like AIM2, CXCL10, and IFI44L, which are associated with the immune system’s response to infections and inflammation. This upregulation suggests the immune system’s serious reaction to perceived threats, potentially exacerbated by drug-induced stress.
The findings also indicated the complexity of the immune responses, as some microRNAs displayed opposing regulatory functions. For example, miRNAs such as let-7d-3p appeared to downregulate TLR3 and other immune genes. This discovery highlights how the balance between different miRNAs could significantly influence the severity of ocular complications resulting from SJS/TEN.
The researchers conclude by emphasizing the clinical relevance of these findings, proposing the potential for future therapeutic applications. By developing miRNA-based therapies, it might be possible to control immune responses more effectively, mitigating both ocular and cutaneous complications faced by SJS/TEN patients.
While the study provides valuable insights, it is not without limitations. The sample size, particularly of mononuclear cells from patients, poses challenges to generalizability, and the cross-sectional nature of the research prevents definitive causality from being established. Further research is needed to explore these interactions comprehensively and their direct impacts on clinical outcomes.