TLR7 gain-of-function genetic variation causes human lupus.

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.