TLR7 – TLR7-Mediated Systemic Lupus Erythematosus

Systemic lupus erythematosus (SLE) is a prototypical systemic autoimmune disease characterized by multi-organ involvement and production of pathogenic autoantibodies. Toll-like receptor 7 (TLR7) is an endosomal sensor of single-stranded RNA and guanosine-containing ligands that drives type I interferon responses and is encoded on the X chromosome (PMID:35477763). Enhanced TLR7 signalling has long been implicated in SLE, but direct genetic proof was lacking until recent monogenic case series.

Rare gain-of-function TLR7 variants cause monogenic SLE. A de novo missense c.790T>C (p.Tyr264His) variant was identified in a child with severe early-onset SLE and selectively increased sensing of guanosine and 2',3'-cGMP in vitro (PMID:35477763). Two additional variants, c.1582C>A (p.Leu528Ile) arising de novo and c.1520T>C (p.Phe507Ser) segregating in three affected relatives in one family, also recapitulated lupus phenotypes in knock-in mice (PMID:38324161). These data support an X-linked dominant inheritance of monogenic lupus due to TLR7 hyperactivation.

Common TLR7 polymorphisms modulate SLE risk across populations. The 3'UTR SNP rs3853839 was associated with increased susceptibility in Danish and Taiwanese cohorts (G vs. C: P = 0.008; PMID:24919757; P = 0.0051; PMID:24445780). A meta-analysis of 11 984 patients and 14 572 controls confirmed associations for rs3853839 and, in specific ethnic groups, rs179008 (TLR7) with SLE risk (OR = 1.414; P = 0.002) (PMID:26762473).

Mechanistic studies demonstrate that TLR7 gain-of-function drives aberrant B cell survival and autoimmunity. Knock-in mice carrying the Y264H or L528I variants developed spontaneous lupus, with expansion of CD11c⁺ age-associated B cells, germinal centre hyperplasia, and elevated follicular helper T cells; MyD88 deficiency fully rescued these phenotypes (PMID:35477763; PMID:38324161). In vitro assays showed mutated TLR7 amplifies NF-κB and interferon signalling, promoting BCR-activated B cell survival.

Conversely, a Spanish case–control study found no significant association for the rs179008 SNP in SLE (P = 0.08; PMID:19473567), indicating ethnic heterogeneity. Moreover, variants in the TLR7 chaperone UNC93B1 selectively dysregulating TLR7 trafficking predispose to childhood-onset SLE, underscoring the specificity of TLR7 hyperactivation in disease pathogenesis (PMID:38831104).

Overall, genetic and experimental data provide a strong clinical validity for TLR7 in SLE. Both rare monogenic gain-of-function variants and common polymorphisms contribute to disease susceptibility. TLR7 is a promising diagnostic marker and therapeutic target, with clear rationale for TLR7 or MyD88 inhibition in SLE management.

References

• Nature • 2022 • TLR7 gain-of-function genetic variation causes human lupus. PMID:35477763
• Journal of clinical immunology • 2024 • Interface Gain-of-Function Mutations in TLR7 Cause Systemic and Neuro-inflammatory Disease. PMID:38324161
• Molecular biology reports • 2014 • Single nucleotide polymorphisms in genes encoding toll-like receptors 7, 8 and 9 in Danish patients with systemic lupus erythematosus. PMID:24919757
• Scientific reports • 2014 • Genetic variations in Toll-like receptors (TLRs 3/7/8) are associated with systemic lupus erythematosus in a Taiwanese population. PMID:24445780
• Lupus • 2016 • Association between toll-like receptor polymorphisms and systemic lupus erythematosus: a meta-analysis update. PMID:26762473
• Clinical and experimental rheumatology • 2009 • Investigation of TLR5 and TLR7 as candidate genes for susceptibility to systemic lupus erythematosus. PMID:19473567
• Nature immunology • 2024 • Genetic variants in UNC93B1 predispose to childhood-onset systemic lupus erythematosus. PMID:38831104

Evidence Based Scoring (AI generated)