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Biological Sciences - Article
Carola Vinuesa
The John Curtin School of Medical Research, The Australian National University
Corresponding Author
ORCiD: https://orcid.org/0000-0001-9799-0298
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While circumstantial evidence supports enhanced TLR7 signaling as a mechanism of human systemic autoimmune disease, we have lacked the proof afforded by lupus-causing TLR7 gene variants. Here we describe monogenic human systemic lupus erythematosus (SLE) caused by TLR7 gain-of-function. We identified a de novo, novel, missense TLR7 Y264H variant in a child with severe lupus and additional novel or rare variants in probands with interferonopathies or systemic autoimmunity (Aicardi Goutieres Sd, SLE, Sjogren’s Sd, and juvenile idiopathic arthritis). The variants increased NF-κB and IFN-β activity and the de novo TLR7 Y264H variant was sufficient to cause lupus when introduced in mice. We show that constitutive TLR7 signaling drives aberrant survival of BCR-activated B cells that would otherwise die, and accumulation of CD11c+ age-associated B cells and germinal center (GC) B cells in a B cell-intrinsic manner. Follicular and extrafollicular helper T-cells were also increased but these phenotypes were cell-extrinsic. MyD88-deficiency rescued autoimmunity, aberrant B cell survival, and all cellular and serological phenotypes. Despite prominent spontaneous GC formation in mice carrying the TLR7 Y264H variant, we show that TLR7-driven lupus was not ameliorated when the TLR7 Y264H mice were made GC-deficient suggesting extrafollicular origin of pathogenic B cells. We establish the importance of TLR7 for human SLE pathogenesis, which paves the way for therapeutic TLR7 or MyD88 inhibition.
Keywords
TLR7 signaling, pathogenesis, human systemic autoimmune disease
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Biological Sciences - Article
Carola Vinuesa
The John Curtin School of Medical Research, The Australian National University
Corresponding Author
ORCiD: https://orcid.org/0000-0001-9799-0298
Badges
Prescreen
This manuscript passed our Prescreen assessment
Complete author information
Appropriate declaration statements
Potential risks to human health
Prescreen
Peer Review Timeline
CURRENT STATUS: Under Review
Version 1
Posted 27 Jan, 2021
Metrics
Comments: 0
PDF Downloads: ...
HTML Views: ...
License:
This work is licensed under a CC BY 4.0 License. Read Full License
While circumstantial evidence supports enhanced TLR7 signaling as a mechanism of human systemic autoimmune disease, we have lacked the proof afforded by lupus-causing TLR7 gene variants. Here we describe monogenic human systemic lupus erythematosus (SLE) caused by TLR7 gain-of-function. We identified a de novo, novel, missense TLR7 Y264H variant in a child with severe lupus and additional novel or rare variants in probands with interferonopathies or systemic autoimmunity (Aicardi Goutieres Sd, SLE, Sjogren’s Sd, and juvenile idiopathic arthritis). The variants increased NF-κB and IFN-β activity and the de novo TLR7 Y264H variant was sufficient to cause lupus when introduced in mice. We show that constitutive TLR7 signaling drives aberrant survival of BCR-activated B cells that would otherwise die, and accumulation of CD11c+ age-associated B cells and germinal center (GC) B cells in a B cell-intrinsic manner. Follicular and extrafollicular helper T-cells were also increased but these phenotypes were cell-extrinsic. MyD88-deficiency rescued autoimmunity, aberrant B cell survival, and all cellular and serological phenotypes. Despite prominent spontaneous GC formation in mice carrying the TLR7 Y264H variant, we show that TLR7-driven lupus was not ameliorated when the TLR7 Y264H mice were made GC-deficient suggesting extrafollicular origin of pathogenic B cells. We establish the importance of TLR7 for human SLE pathogenesis, which paves the way for therapeutic TLR7 or MyD88 inhibition.
Figure 1
Figure 2
Figure 3
Figure 4
There is NO Competing Interest.
This is a list of supplementary files associated with this preprint. Click to download.
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