In a groundbreaking discovery, a research team led by Professor Song Hongmei, Director of Pediatrics at PUMCH, in collaboration with Professor Zhou Qing's team from Zhejiang University, has identified the first case of early-onset systemic lupus erythematosus (SLE) caused by a somatic gain-of-function mutation in the TLR7 gene. Their findings were recently published in the globally prestigious journal Annals of the Rheumatic Diseases (IF=20.3). The study reveals the mechanism behind the TLR7 F506S mutation in disease development, marking the first reported case worldwide of SLE triggered by a somatic TLR7 mutation. This discovery not only explains the pathogenesis of certain refractory SLE cases but also opens up new avenues for treatment.

SLE is a complex autoimmune disease where the immune system mistakenly attacks the body's own organs, leading to symptoms ranging from skin rashes and arthritis to kidney damage and neurological complications. Early-onset SLE is often associated with rare monogenic variants. While over 50 genes have been linked to monogenic SLE or SLE-like syndromes, the genetic cause remains unidentified in most pediatric cases. This has resulted in a “one-size-fits-all” treatment approach relying on steroids and immunosuppressants, which carries significant side effects and severely impacts quality of life.

The case involved a child who experienced recurrent fever and severe thrombocytopenia shortly after birth, with treatments at multiple hospitals proving ineffective over eight years. Through whole exome sequencing, the research team identified a somatic mutation in the TLR7 gene, which is related to immune system function.

In validating the mutation's effects, researchers found that immune cells extracted from the patient's blood showed significantly elevated inflammatory markers when exposed to specific substances, confirming the mutation-induced immune system hyperactivation.

To use an analogy, if the immune system is the body's "security system", TLR7 acts as its "alarm", tasked with detecting viral invaders. The mutation made this patient's TLR7 "hypersensitive", triggering frequent "false alarms" even in the absence of viral invasion, leading to excessive immune responses and self-targeted attacks. This somatic mutation, occurring randomly during early embryonic development like a "minor assembly error", triggered a systemic chain reaction.

Following diagnosis, the patient received targeted combination therapy, resulting in visibly decreased inflammatory markers and gradual improvement in platelet counts.

This globally first discovery of SLE caused by a somatic TLR7 mutation not only illuminates the pathogenic mechanism of certain refractory SLE cases but also suggests new therapeutic directions. TLR7 signaling pathway inhibitors might be a better treatment option with fewer side effects than traditional medications.

In recent years, Professor Song's team has identified several genes associated with SLE-like manifestations and developed an early identification model for monogenic lupus, enhancing clinicians' diagnostic capabilities. According to Professor Song, as more causative genes for early-onset SLE are discovered, our understanding of SLE pathogenesis will continue to expand, potentially leading to more precise targeted therapies.

Written by the Department of Pediatrics