Sabina Norova

 Introduction. Systemic lupus erythematosus (SLE) is an autoimmune disorder occurring in 20-150 cases per 100,000 population.¹ SLE is increasingly prevalent in people of African ancestry and it usually affects women of reproductive age, with a female-to-male ratio being 9:1.¹ In SLE, all pathways lead to production of endogenous interferon α (IFN-α), which promotes the maturation of conventional myeloid dendritic cells (DCs).² Mature DCs break self-tolerance while immature DCs promote tolerogenicity.² Current treatments with B cell selective monoclonal antibodies inhibiting T and B lymphocytes are ineffective because they non-specifically suppress the immune system and lead to infections.³ In treating SLE, a disease with autoantigens in several cell types, mesenchymal stem cells (MSCs) can induce DC tolerogenicity.³ Methods. Twenty-one patients refractory to SLE underwent umbilical cord-derived MSC transplantation (UC-MSCT). Peripheral blood mononuclear cells (PBMCs) of SLE patients and healthy controls were isolated to compare conventional DCs (CD1c⁺DCs) using flow cytometry.³ Human Fms-related tyrosine kinase 3-ligand (FLT3L) stimulated with IFN-γ was added to PBMCs and analyzed by PCR.³ Mice with SLE underwent human adipose tissue derived mesenchymal stem cell (ASC) transplantation to measure anti-dsDNA and CD138 levels.⁴ PBMCs from healthy mice treated with FLT3L for 21 days were analyzed using flow cytometry.⁵ Results. Compared to healthy controls, patients with SLE have decreased numbers of CD1c⁺DCs.³ ASCs led to decreased production of anti-dsDNA and CD138.⁴ FLT3L injection in mice resulted in 16 to 234 fold increase in DCs starting on day 5 and peaked on day 14.⁵ In patients with SLE, UC-MSC injected with FLT3L up-regulated CD1c⁺DCs production.³ Stimulation of UC-MSCs with IFN-γ enhanced FLT3L expression via JAK-STAT pathway.³ Furthermore, systemic lupus erythematosus disease activity index (SLEDAI) score was negatively correlated to CD1c⁺DCs.³ Conclusions. MSC transplantation demonstrated therapeutic efficacy in animal models.^4,5 Moreover, MSC transplants were well tolerated by patients and treatment-related mortality or adverse events did not occur.³ Dendritic cell tolerogenicity is critical in treating autoimmunity in SLE by upregulating the expression of immunomodulatory molecules, immunosuppressive cytokines, and regulatory T cells while decreasing the expression of pro-inflammatory cytokines.⁶ Increasing CD1c⁺DCs, which are decreased in SLE patients, is critical via MSC transplantation.³ Stimulating UC-MSCs with IFN-γ enhances production of FLT3L via JAK/STAT pathway.³ Consequently, FLT3L increases production of CD1c⁺DCs, thus promoting DC tolerogenicity and decreasing SLEDAI score.³ These findings demonstrate the MSCs as a promising therapeutic tool to suppress immunity in SLE patients in a more controlled and specific manner.

1. Tsokos, G. Systemic Lupus Erythematosus. The New England Journal of Medicine. 2011; 2110-2121. doi: 10.1056/NEJMra1100359
2. Bertsias, G, Cervera, R, Boumpas, D. Systemic Lupus Erythematosus: Pathogenesis and Clinical Features. Eular textbook on rheumatic diseases. 2012; 476-505.
3. Yuan, X, Qin, X, Wang, D. et al.Mesenchymal stem cell therapy induces FLT3L and CD1c+ dendritic cells in systemic lupus erythematosus patients. Nature Communications. 2019; 10 (2498). https://doi-org.srv-proxy2.library.tamu.edu/10.1038/s41467-019-10491-8
4. Choi, E, Lee, M, Song, J, et al. Mesenchymal stem cell transplantation can restore lupus disease-associated miRNA expression and Th1/Th2 ratios in a murine model of SLE. Scientific Reports. https://doi.org/10.1038/srep38237
5. Breton, G, Lee, J, Zhou, Y, Schreiber, J. Circulating precursors of human CD1c+ and CD141+dendritic cells. Rockefeller University Press. 2015; 212 (3): 401–41. https://doi.org/10.1084/jem.20141441
6. Kaewraemruaen, Ch, Ritprajak, P, Hirankarn, N. Dendritic cells as key players in systemic lupus erythematosus. Asia Pacific Journal of Allergy and Immunology. 2019. Doi: 10.12932/AP-070919-0639