In-Depth Interpretation of Core SLE Pathogenic Mechanisms (2025 Latest Consensus)

Research from 2024–2025 has further clarified the multi-pathway synergistic pathogenesis of SLE. The core mechanisms can be summarized into three key stages:

• Upstream Trigger: Nucleic Acid Exposure and IFN-I Storm — Defective clearance of apoptotic/necrotic cells leads to release of nucleic acids (DNA:RNA hybrids, R-loops, oxidized mitochondrial DNA), which activate pDCs via TLRs to produce large amounts of IFN-α, establishing the “IFN signature” and initiating systemic inflammation.
• Midstream Amplification: Abnormal B-Cell Activation and Autoantibody Production — Excessive BAFF/APRIL expression breaks B-cell tolerance, promoting differentiation of autoreactive B cells into long-lived plasma cells that continuously produce antinuclear antibodies, anti-dsDNA antibodies, etc., forming immune complexes deposited in target organs.
• Downstream Damage: Immune Complex Deposition and Tissue Inflammation — Immune complexes deposit in kidneys, skin, blood vessels, and other tissues, activating the complement system, recruiting neutrophils to release NETs, and inducing local inflammation, vascular damage, and fibrosis, ultimately causing multi-organ dysfunction.

Recent research highlights: Age-associated B cells (ABCs) have been confirmed as key precursor cells for autoantibody production; enhanced NETosis forms a positive feedback loop with the IFN-I pathway; gut microbiome dysbiosis contributes to disease initiation through mucosal immune abnormalities, opening new therapeutic targets.

Clarification of Core Pathways and Triggers: The type I interferon (IFN-I) pathway has been confirmed as the central driver of immune dysregulation, closely linked to abnormal B-cell activation and autoantibody production. Real-world data for Anifrolumab (anti-IFNAR mAb) confirm significant efficacy in skin and joint manifestations with good long-term safety.

Pathway Blockade and Innovative Drugs: The Chinese-developed dual-target biologic Telitacicept, which blocks both BLyS and APRIL, significantly improves response rates in moderate-to-severe patients. Drugs targeting the IFN-I receptor (Anifrolumab), TYK2 inhibitors (Deucravacitinib), and new targets such as TLR7 and IRAK4 are entering clinical use, offering new options for patients refractory to conventional therapy.

Cell Therapy Innovations Lowering Barriers: In vivo CAR-T therapy uses LNP vectors to generate CAR-T cells directly in patients without chemotherapy preconditioning, rapidly depleting pathogenic B cells with improved safety. Multiple trials show drug-free remission after deep B-cell depletion, with some patients remaining relapse-free for over two years.

Optimized Clinical Assessment: Revised SRI-4 criteria combined with dynamic monitoring of complement and anti-dsDNA antibodies more accurately reflect treatment response. For target organ involvement such as lupus nephritis, individualized regimens combining biologics and immunosuppressants are emerging, alongside comprehensive management emphasizing sun protection and microbiome modulation to reduce relapse risk.