Jessica Quach

 Introduction. Systemic Lupus Erythematosus (SLE) is a chronic autoimmune disease in which the body’s immune system produces autoantibodies against its own cells and tissues, resulting in inflammation and organ damage¹. SLE affects anywhere from 40 to 200 individuals per 100,000². To date, SLE treatment primarily includes the use of nonspecific immunosuppressive or immunomodulatory agents, such as NSAIDs, corticosteroids, antimalarials, and cyclophosphamide. However, these agents have limited effect on more active forms of SLE and produce severe side effects². Current trials focus on targeting plasmacytoid dendritic cells (pDCs), the major producers of IFN-a. Aberrant expression of IFN-a plays a key role in stimulating autoantibody production and facilitating SLE progression. These studies show that there are a number of agents that can target pDCs in a variety of ways. These findings could suggest a potential therapy for SLE with fewer side effects and greater efficacy. Methods.   Four studies that were completed within the past two years involving the targeting of pDCs and their role in the pathogenesis of SLE were analyzed. One study utilized B6.Nba2 mice and measured levels of autoantibodies, expression of IFN-inducible genes, and other parameters to confirm the pathogenesis of pDCs, with a specific focus on Siglec H-positive pDCs³. Another study utilized MRL/lpr mice and measured IFN-a levels and activation of pDCs after the application of FC-99⁴. The third study utilized human Gen2.2 pDCs and healthy donor PBMCs and measured levels of IFN-a and TNF-a after using TSG-6⁵. The final study utilized lupus-prone (NZB x NZW)F1 (NZB/NZW) mice and measured IFN-a production after treatment with Bcl-2 antagonists⁶. Results.   The study that looked at Siglec H-positive pDCs showed that depletion of these particular pDCs exhibited a reduction in many measures of lupus-like disease³. The study that investigated FC-99 proved that FC-99 suppressed the activation of pDCs and reduced IFN-a production and therefore attenuated lupus-like syndrome⁴. The third study demonstrated that treatment with TSG-6 reduced both IFN-a and TNF-a⁵. The final study determined that Bcl-2 antagonists were able to selectively kill pDCs while sparing conventional DCs, decrease IFN-a production, and work with glucocorticoids synergistically to destroy activated pDCs⁶.  Conclusions. Studies have found that targeting pDCs, the main producers of IFN-a, results in a variety of findings that all suggest attenuation of symptoms characteristic of SLE. Utilization of any of these already discovered techniques – depletion of Siglec H-positive pDCs, application of FC-99, TSG-6, or Bcl-2 antagonists – represent novel ways of treating SLE.

1. Rowland S.L., Riggs J.M., Gilfillan S., et al. Early, transient depletion of plasmacytoid dendritic cells ameliorates autoimmunity in a lupus model. The Journal of Experimental Medicine. 2014;211(10):1977-1991.
2. Shaikh, M., Jordan, N., Cruz, D. Systemic lupus erythematosus. Clinical Medicine 2017 Feb 1; 17 (1): 78-83. doi: 10.7861/clinmedicine.17-1-78
3. Davison, L. M., Jørgensen, T. N. Sialic Acid–Binding Immunoglobulin-Type Lectin H–Positive Plasmacytoid Dendritic Cells Drive Spontaneous Lupus-like Disease Development in B6.Nba2 Mice. Arthritis & Rheumatology. 2015; 67(4):1012–1022.
4. Ji J., Fan, H., Li, F, et al. A benzenediamine derivative FC-99 Attenuates Lupus-like Syndrome in MRL/lpr Mice Related to Suppression of pDC Activation. Immunology Letters. 2015; 168(2): 355-365.
5. Kui L, Chan GC, Lee PPW. TSG-6 Downregulates IFN-Alpha and TNF-Alpha Expression by Suppressing IRF7 Phosphorylation in Human Plasmacytoid Dendritic Cells. Mediators of Inflammation. 2017; 2017:7462945.
6. Zhan, Y., Carrington, E. M., Ko, H.-J. Bcl-2 Antagonists Kill Plasmacytoid Dendritic Cells From Lupus-Prone Mice and Dampen Interferon-α Production. Arthritis & Rheumatology. 2015; 67(3): 797–808.