TLR7 gain-of-function genetic variation causes human lupus

Article

关键词: PLASMACYTOID DENDRITIC CELLS;    RECEPTOR 7;    AUTOANTIBODY PRODUCTION;    B-CELLS;    RNA;    RECOGNITION;    RESPONSES;    SELF;    DNA;    RIBONUCLEOTIDES;   

DOI  :  10.1038/s41586-022-04642-z

来源: SCIE

【 摘 要 】

Although circumstantial evidence supports enhanced Toll-like receptor 7 (TLR7) signalling as a mechanism of human systemic autoimmune disease(1-7), evidence of lupus-causing TLR7gene variants is lacking. Here we describe human systemic lupus erythematosus caused by a TLR7gain-of-function variant. TLR7 is a sensor of viral RNA(8,9) and binds to guanosine(10-12). We identified a de novo, previously undescribed missense TLR7(Y264H) variant in a child with severe lupus and additional variants in other patients with lupus. The TLR7(Y264H )variant selectively increased sensing ofguanosine and 2',3'-cGMP(10-12), and was sufficient to cause lupus when introduced into mice. We showthat enhanced TLR7 signalling drives aberrant survival of B cell receptor (BCR)-activated B cells, and in a cell-intrinsic manner, accumulation of CD11c(+) age-associated B cells and germinal centre B cells. Follicular and extrafollicular helper T cells were also increased but these phenotypes were cell-extrinsic. Deficiency of MyD88 (an adaptor protein downstream of TLR7) rescued autoimmunity, aberrant B cell survival, and all cellular and serological phenotypes. Despite prominent spontaneous germinal-centre formation in Tlr7(Y264H) mice, autoimmunity was not ameliorated bygerminal-centre deficiency, suggesting an extrafollicular origin of pathogenic B cells. We establish the importance of TLR7 and guanosine-containing self-ligands for human lupus pathogenesis, which pavesthe way for therapeutic TLR7 or MyD88 inhibition.

【 授权许可】

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