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TLR7 gain-of-function genetic variation causes human lupus
Grant J Brown1, Pablo F Cañete1, Hao Wang1
1Centre for Personalised Immunology, Department of Immunology and Infectious Disease, John Curtin School of Medical Research, Australian National University, Canberra, Australian Capital Territory, Australia.
Nature
|April 28, 2022
Summary
A novel Toll-like receptor 7 (TLR7) gene variant causes lupus by enhancing the sensing of self-ligands. This discovery highlights TLR7
Area of Science:
- Immunology
- Genetics
- Rheumatology
Background:
- Circumstantial evidence links enhanced Toll-like receptor 7 (TLR7) signaling to systemic autoimmune diseases.
- Direct evidence for lupus-causing TLR7 gene variants has been lacking.
- TLR7 acts as a sensor for viral RNA and binds to guanosine.
Purpose of the Study:
- To identify and characterize genetic variants in TLR7 associated with human systemic lupus erythematosus (SLE).
- To investigate the functional consequences of a novel TLR7 gain-of-function variant on immune cell activation and autoimmunity.
- To elucidate the role of TLR7 signaling in the pathogenesis of lupus.
Main Methods:
- Identification of a de novo TLR7 missense variant (TLR7Y264H) in a child with severe lupus and in additional lupus patients.
- Functional assays to assess the variant's effect on guanosine and 2',3'-cGMP sensing.
- Introduction of the variant into mice to model lupus and assess autoimmune phenotypes.
- Analysis of B cell and T cell populations, including age-associated B cells and germinal center B cells.
- Assessment of autoimmunity and cellular phenotypes in MyD88-deficient mice.
Main Results:
- A novel TLR7 gain-of-function variant (TLR7Y264H) was identified in patients with lupus.
- The TLR7Y264H variant selectively enhanced the sensing of guanosine and 2',3'-cGMP.
- Transplantation of the variant into mice was sufficient to induce lupus.
- Enhanced TLR7 signaling led to aberrant B cell survival, accumulation of CD11c+ age-associated B cells, and germinal center B cells.
- MyD88 deficiency rescued autoimmunity and all observed cellular and serological phenotypes.
- Autoimmunity was not ameliorated by germinal center deficiency, suggesting an extrafollicular origin of pathogenic B cells.
Conclusions:
- A specific TLR7 gain-of-function variant is causative of human lupus.
- Enhanced TLR7 signaling, driven by self-ligands like guanosine, plays a critical role in lupus pathogenesis.
- Targeting TLR7 or its downstream adaptor MyD88 presents a potential therapeutic strategy for lupus.
