Endosomal TLR signaling is required for anti-nucleic acid and rheumatoid factor autoantibodies in lupus.
Proc Natl Acad Sci U S A
; 106(29): 12061-6, 2009 Jul 21.
Article
em En
| MEDLINE
| ID: mdl-19574451
ABSTRACT
Using the Unc93b1 3d mutation that selectively abolishes nucleic acid-binding Toll-like receptor (TLR) (TLR3, -7, -9) signaling, we show these endosomal TLRs are required for optimal production of IgG autoAbs, IgM rheumatoid factor, and other clinical parameters of disease in 2 lupus strains, B6-Fas(lpr) and BXSB. Strikingly, treatment with lipid A, an autoAb-inducing TLR4 agonist, could not overcome this requirement. The 3d mutation slightly reduced complete Freund's adjuvant (CFA)-mediated antigen presentation, but did not affect T-independent type 1 or alum-mediated T-dependent humoral responses or TLR-independent IFN production induced by cytoplasmic nucleic acids. These findings suggest that nucleic acid-sensing TLRs might act as an Achilles' heel in susceptible individuals by providing a critical pathway by which relative tolerance for nucleic acid-containing antigens is breached and systemic autoimmunity ensues. Importantly, this helps provide an explanation for the high frequency of anti-nucleic acid Abs in lupus-like systemic autoimmunity.
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Base de dados:
MEDLINE
Assunto principal:
Endossomos
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Fator Reumatoide
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Transdução de Sinais
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Anticorpos Antinucleares
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Receptores Toll-Like
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Lúpus Eritematoso Sistêmico
Tipo de estudo:
Guideline
Limite:
Animals
Idioma:
En
Ano de publicação:
2009
Tipo de documento:
Article