E-viri
Recenzirano
Odprti dostop
-
Brown, Grant J; Cañete, Pablo F; Wang, Hao; Medhavy, Arti; Bones, Josiah; Roco, Jonathan A; He, Yuke; Qin, Yuting; Cappello, Jean; Ellyard, Julia I; Bassett, Katharine; Shen, Qian; Burgio, Gaetan; Zhang, Yaoyuan; Turnbull, Cynthia; Meng, Xiangpeng; Wu, Phil; Cho, Eun; Miosge, Lisa A; Andrews, T Daniel; Field, Matt A; Tvorogov, Denis; Lopez, Angel F; Babon, Jeffrey J; López, Cristina Aparicio; Gónzalez-Murillo, África; Garulo, Daniel Clemente; Pascual, Virginia; Levy, Tess; Mallack, Eric J; Calame, Daniel G; Lotze, Timothy; Lupski, James R; Ding, Huihua; Ullah, Tomalika R; Walters, Giles D; Koina, Mark E; Cook, Matthew C; Shen, Nan; de Lucas Collantes, Carmen; Corry, Ben; Gantier, Michael P; Athanasopoulos, Vicki; Vinuesa, Carola G
Nature (London), 05/2022, Letnik: 605, Številka: 7909Journal Article
Although circumstantial evidence supports enhanced Toll-like receptor 7 (TLR7) signalling as a mechanism of human systemic autoimmune disease , evidence of lupus-causing TLR7 gene variants is lacking. Here we describe human systemic lupus erythematosus caused by a TLR7 gain-of-function variant. TLR7 is a sensor of viral RNA , and binds to guanosine - . We identified a de novo, previously undescribed missense TLR7 variant in a child with severe lupus and additional variants in other patients with lupus. The TLR7 variant selectively increased sensing of guanosine and 2',3'-cGMP , and was sufficient to cause lupus when introduced into mice. We show that 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 mice, autoimmunity was not ameliorated by germinal-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 paves the way for therapeutic TLR7 or MyD88 inhibition.
Avtor
Vnos na polico
Trajna povezava
- URL:
Faktor vpliva
Dostop do baze podatkov JCR je dovoljen samo uporabnikom iz Slovenije. Vaš trenutni IP-naslov ni na seznamu dovoljenih za dostop, zato je potrebna avtentikacija z ustreznim računom AAI.
Leto | Faktor vpliva | Izdaja | Kategorija | Razvrstitev | ||||
---|---|---|---|---|---|---|---|---|
JCR | SNIP | JCR | SNIP | JCR | SNIP | JCR | SNIP |
Baze podatkov, v katerih je revija indeksirana
Ime baze podatkov | Področje | Leto |
---|
Povezave do osebnih bibliografij avtorjev | Povezave do podatkov o raziskovalcih v sistemu SICRIS |
---|
Vir: Osebne bibliografije
in: SICRIS
To gradivo vam je dostopno v celotnem besedilu. Če kljub temu želite naročiti gradivo, kliknite gumb Nadaljuj.