TLR-9 Deletion Not Model Specific
“The fact that TLR-9 deletion across multiple models results in severe nephritis says it is not model specific and that there is a fundamental mechanism in the mouse where TLR-9 suppression suppresses inflammation,” says Dr. Fairhurst. “This pathway probably also exists in humans, but whether TLR-9 plays the dominant role remains to be seen.”
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For SLE patients, many of the existing therapies treat symptomatic effects with limited effectiveness. The researchers think targeting TLR-7 may go to the root cause of SLE by stopping inflammation leading to kidney disease.
“I would hope this stimulates more questions and furthers interest in the mechanism of disease progression,” says Dr. Fairhurst. “Further understanding of immunology helps us understand the disease and perhaps to harness pathways for autoimmunity.”
Jill Buyon, MD, is division director of rheumatology at the New York University School of Medicine. She thinks this well-done study will be useful when considering therapeutic candidates for SLE treatment.
“Previous murine studies have supported a suppressive role for TLR-9 signaling in lupus,” she says. “What the authors have shown, rather elegantly, is that when TLR-9 is knocked out in a lupus-prone mouse, severe autoimmunity develops, characterized by splenomegaly and kidney disease. Importantly, TLR-7 expression was increased in inflammatory cells present in the kidney and this was apparent prior to clinical disease, a finding that may provide insights into early treatments to prevent full-blown lupus nephritis.”
The results suggest the TLR-7 pathway is a key perpetrator of disease and that TLR-9 is important to provide a suppressive influence. TLR-7 seems to be responsible for many autoimmune responses seen in lupus.
“In this mouse model, the autoantibody repertoire was skewed toward RNA‐containing antigens, including anti-Ro and La antibodies as well as anti-Sm antibodies,” says Dr. Buyon. “Often, really elegant research raises new questions, and this work certainly draws attention to antibodies clinicians usually consider less concerning than anti-dsDNA antibodies with regard to renal disease in human lupus.
“But what I take away from this research is that suppression of TLR-7 should be considered early in the course of disease.”
Kurt Ullman has been a freelance writer for more than 30 years and a contributing writer to The Rheumatologist for more than 10 years.
- Celhar T, Yasuga H, Lee HY, et al. Toll-like receptor 9 deficiency breaks tolerance to RNA-associated antigens and up-regulates toll-like receptor 7 protein in Sle1 mice. Arthritis Rheumatol. 2018 Oct;70(10):1597–1609.