Systemic Lupus Erythematosus (SLE)
Systemic Lupus Erythematosus (SLE) is a long term, autoimmune disorder affecting multiple organ systems and characterized by the breakdown of immune tolerance, inflammation, the production of autoantibodies, and subsequent damage to organs. MyD88-targeted therapy development at Protheragen involves the use of inhibitors to alter MyD88-dependent signaling pathways pertinent to interferon production in SLE and tissue damage.
Introduction to Systemic Lupus Erythematosus
The chronic disorder that is Rheumatoid Arthritis (RA) is distinguished by excessive inflammation of the joints caused by synergistic activity of both the adaptive and innate immune systems. Its prevalence is roughly around 1% on a global scale, and it is more common in women. There is notable evidence of TLR-MyD88 signaling taking part in activation of fibroblasts in the synovium, auto antibody production such as RF and ACPA, and destruction of the joint through Th17 and TNF-alpha.
Pathogenesis of Rheumatoid Arthritis
An autoimmune disease with type I interferon (IFN) systemic response, immune complex buildup, and several affected organs is referred to as heterogenous SLE. Recent epidemiological studies report a global prevalence of 30-150 cases per 100,000, with a 9:1 female-to-male predominance. Emerging evidence underlines the importance of TLR7/9-MyD88 in the control of pathogenic plasmacytoid dendritic cell (pDC) activation and anti-nuclear antibody (ANA) production, which fuels both lupus nephritis and skin-driven symptoms.
Pathogenesis of Systemic Lupus Erythematosus
The combination of genetic factors (such IRF5, STAT4 polymorphisms) and environmental factors (such as exposure to UV light or viral RNA/DNA) leads to a loss of immune tolerance is the primary cause of SLE. Some of the defining factors are:
- B-cell hyperactivation: Self-reactive B cells produce a-range of self-immune antibodies such as anti-dsDNA and anti-Smith and form immune complexes.
- IFNR Type I signature: TLR7/9 dependent MyD88 in pDCs initiates secretion of IFN-α which is the key in fostering effort driven immune response by maturation of dnDCs.
Fig.1 Regulation of IRF5 activity in the TLR7, 8, 9-MyD88 pathway. (Ban, Sato and Tamura, 2018)- Tissue injury: Immune complex deposition in the kidney and skin leads to complement activation and NET formation.
MyD88-Targeted Therapeutic Development for Systemic Lupus Erythematosus
| Therapeutic Strategy | Mechanism of Action | Representative Approaches | Development Stage |
| TLR9-MyD88-NF-κB p65 Axis Inhibition | Block TLR9-MyD88 signaling to reduce NF-κB-driven pro-inflammatory cytokines (IL-6, TNF-α). | TLR9 antagonists (e.g., IMO-3100), MyD88 dimerization inhibitors (e.g., ST2825). | Preclinical |
| miR-152-3p Silencing | Downregulate miR-152-3p to restore DNMT1-mediated MyD88 promoter methylation, suppressing MyD88 expression. | Anti-miR-152-3p oligonucleotides (e.g., locked nucleic acid-LNA). | Preclinical |
| IRF5 Activity Suppression | Inhibit IRF5 activation downstream of TLR-MyD88 to reduce type I interferons and cytokines. | IRF5 small-molecule inhibitors, siRNA targeting IRF5. | Preclinical |
| DNMT1 Modulation | Enhance DNMT1 activity to methylate MyD88 promoter, reducing TLR signaling. | DNMT1 agonists (e.g., decitabine analogs) or miR-152-3p inhibitors to restore DNMT1. | Preclinical |
Disclaimer: Protheragen focuses on providing preclinical research services. This table is for information exchange purposes only. This table is not a treatment plan recommendation. For guidance on treatment options, please visit a regular hospital.
Our Services
Protheragen providesMyD88-targeted therapeutic discovery and advanced disease models development services for systemic lupus erythematosus. Our multi-dimensional disease models facilitate the interfacing of MyD88 signaling modulator screening to accelerate the preclinical intervention development associated with type I interferonopathy and the immune complex mediated tissue destruction.
Therapeutic Discovery Platform for Systemic Lupus Erythematosus
Protheragen offers an integrated platform for the MyD88 targeted SLE therapeutic discovery which simultaneously addresses type I interferonopathy and multiorgan damage. The focus is on bypassing the MyD88 signaling loops through specific pathway disease models designed for preclinical investigation directed at the unrestrained innate immunity activation in systemic autoimmunity whilst exploiting existing therapies.
Disease Models Development for Systemic Lupus Erythematosus
Protheragen offers in vitro & in vivo models for SLE including cell-based models, organoid models, and animal models. These enable longitudinal study of the mechanisms of immune complex deposition, type I interferon signal dysregulation, and multiorgan inflammation to comprehensively evaluate therapeutic strategies aimed at the pathophysiological mechanisms of SLE.
- pDC-B Cell Co-Culture Systems
- Immune Complex-Activated Glomerular Cells
- Lupus Nephritis Kidney-on-a-Chip
- NZB/W F1 Mice
- TLR7tg Mice
- Myd88fl/fl Cd11c-Cre Mice
- Pristane-Induced Lupus
Protheragen has the companywide strategy focuses on setting up and analyzing MyD88 related pathologies that are crafted to be aggressive through developing and executing a holistic approach, and construction of multidisciplinary proposals such as disease model development, pharmacokinetics and drug safety evaluation. Protheragen also provides investigator-initiated trials that focus on shortening the duration of the primary evaluation phase.
If you are interested in our services, please don't hesitate to contact us.
References
- Ban, T., G. R. Sato, and T. Tamura. "Regulation and Role of the Transcription Factor Irf5 in Innate Immune Responses and Systemic Lupus Erythematosus." Int Immunol 30.11 (2018): 529-36.
- Wang, H., et al. "The Effect of Tlr9, Myd88, and Nf-Kappab P65 in Systemic Lupus Erythematosus." Evid Based Complement Alternat Med 2022 (2022): 6830366.
All of our services and products are intended for preclinical research use only and cannot be used to diagnose, treat or manage patients.