Ashley Cullum

Background: Systemic Lupus Erythematosus (SLE) occurs when the body’s immune system erroneously targets its own tissues, causing widespread inflammation and tissue damage systemically. Central to SLE pathogenesis are dysregulated protein kinase pathways, precipitating proliferation of T cells, particularly CD4+ T cells, which promote a cascade of pro-inflammatory cytokines, fostering chronic inflammation and tissue damage. Concurrent T cell activation of B cell differentiation perpetuates autoantibody production, further exacerbating tissue injury. SLE’s etiology is multifactorial, including genetic predisposition, hormonal influences, and environmental triggers. SLE manifestation is diverse, encompassing a plethora of symptoms spanning non-erosive arthritis, arthralgias, fever, and a characteristic butterfly-distributed rash. Additionally, systemic manifestations extend to hematological, renal, respiratory, ocular, and gastrointestinal dysregulation, presenting diagnostic challenges in distinguishing SLE from overlapping conditions. Diagnostic evaluation entails testing for antinuclear antibodies (ANA), alongside elimination of differentials. Therapeutic interventions for SLE predominantly target symptom management, given the absence of a definitive cure. These treatments, ranging from nonsteroidal anti-inflammatory drugs (NSAIDs) to immunosuppressive agents, harbor notable side effects, necessitating individualized approaches tailored to patient-specific manifestations. Amidst this therapeutic landscape, mesenchymal stem cell (MSC) therapy emerges as a promising avenue, leveraging MSCs’ immunoregulatory properties to modulate aberrant immune responses in SLE.^4,5,6

Objective: Through examination of recent research, this presentation unveils MSCs’ potential in modulating the hyper-T cell responses prevalent with SLE.

Search Methods: A PubMed MeSH search was performed using terms: “past 5 years”, “systemic lupus erythematosus”, “therapy”, and “mesenchymal stem cells”.

Results: One study investigated MSCs’ capacity to augment T cell senescence, ultimately mitigating lupus-associated organ damage. Human umbilical cord-derived MSCs (hUC-MSCs) demonstrated the ability to transfer miR-199a-5p, downregulating Sirt1 in CD4+ T cells, consequently promoting T cell senescence through p53/16/21 upregulation. Additionally, systemically infused MSCs showed a profound reduction in lupus-related manifestations in murine models of SLE, including decreased lymph node size, spleen index, and serum autoantibody levels.¹

Moreover, another study highlighted the role of MSCs in upregulating MAP3K1 signaling through the inhibition of mi-320b, which was associated with decreased CD4+ T cell proliferation and heightened MAP3K1 expression.³

Furthermore, MSCs’ have been shown to increase T cell apoptosis and enhance apoptotic cell clearance, thereby attenuating SLE-associated inflammation and autoimmunity. Peripheral blood smear and spleen analysis revealed increased apoptosis upon MSC infusion, possibly through the induction of Fas-mediated apoptosis.² Also, hUC-MSCs possessed the ability to engulf apoptotic cells, contributing to the inhibition of CD4+ T cell hyper-proliferation.⁷

Conclusion: These findings emphasize the therapeutic potential of MSCs in alleviating SLE pathogenesis via CD4+ T cell modulation to decrease inflammatory and auto-antibody response. However, critiques on study methodologies and translational challenges underscore the need for further research. Concerns regarding the translatability and efficacy of murine models to human subjects alongside the accessibility of MSC therapy for economically disadvantaged populations warrant attention. MSC therapy emerges as promising in SLE management, offering insights into disease pathogenesis and therapeutic interventions. Addressing existing challenges and expanding research endeavors will pave the way for personalized and accessible SLE treatments in the future.

Works Cited

• Cheng T, Ding S, Liu S, Li Y, Sun L. Human umbilical cord-derived mesenchymal stem cell therapy ameliorates lupus through increasing CD4+ T cell senescence via MiR-199a-5p/Sirt1/p53 axis. Theranostics. 2021;11(2):893. doi:10.7150/thno.48080
• Huang S, Wu S, Zhang Z, et al. Mesenchymal stem cells induced CD4+ T cell apoptosis in treatment of lupus mice. Biochemical and Biophysical Research Communications. 2018;507(1):30-35. doi:10.1016/j.bbrc.2018.10.133
• Li Z, Wang R, Wang D, et al. Circulating miR-320b Contributes to CD4+ T-Cell Proliferation in Systemic Lupus Erythematosus via MAP3K1. J Immunol Res. 2023;2023:6696967. doi:10.1155/2023/6696967
• Meng K, Li H, Jinjuan Y, et al. Mesenchymal stem cell-derived extracellular vesicles for immunomodulation and regeneration: a next generation therapeutic tool? | Cell Death & Disease. https://www.nature.com/articles/s41419-022-05034-x
• Obrișcă B, Sorohan B, Tuță L, Ismail G. Advances in Lupus Nephritis Pathogenesis: From Bench to Bedside. International Journal of Molecular Sciences. 2021;22(7):3766. doi:10.3390/ijms22073766
• Xie M, Li C, She Z, et al. Human umbilical cord mesenchymal stem cells derived extracellular vesicles regulate acquired immune response of lupus mouse in vitro. Sci Rep. 2022;12:13101. doi:10.1038/s41598-022-17331-8
• Zhang Z, Huang S, Wu S, et al. Clearance of apoptotic cells by mesenchymal stem cells contributes to immunosuppression via PGE2. EBioMedicine. 2019;45:341-350. doi:10.1016/j.ebiom.2019.06.016