TLR recognition of self nucleic acids hampers glucocorticoid activity in lupus

Cristiana Guiducci, Mei Gong, Zhaohui Xu, Michelle Gill, Damien Chaussabel, Thea Meeker, Jean H. Chan, Tracey Wright, Marilynn Punaro, Silvia Bolland, Vassili Soumelis, Jacques Banchereau, Robert L. Coffman, Virginia Pascual and Franck J. Barrat ()
Additional contact information
Cristiana Guiducci: Dynavax Technologies Corporation, 2929 Seventh Street, Suite 100, Berkeley, California 94710, USA
Mei Gong: Dynavax Technologies Corporation, 2929 Seventh Street, Suite 100, Berkeley, California 94710, USA
Zhaohui Xu: Baylor Institute for Immunology Research, Dallas, Texas 75204, USA
Michelle Gill: Baylor Institute for Immunology Research, Dallas, Texas 75204, USA
Damien Chaussabel: Baylor Institute for Immunology Research, Dallas, Texas 75204, USA
Thea Meeker: Dynavax Technologies Corporation, 2929 Seventh Street, Suite 100, Berkeley, California 94710, USA
Jean H. Chan: Dynavax Technologies Corporation, 2929 Seventh Street, Suite 100, Berkeley, California 94710, USA
Tracey Wright: Texas Scottish Rite Hospital, Dallas, Texas 75219, USA
Marilynn Punaro: Texas Scottish Rite Hospital, Dallas, Texas 75219, USA
Silvia Bolland: Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Maryland 20852, USA
Vassili Soumelis: Institut Curie, 26 rue d’Ulm, 75005 Paris, France
Jacques Banchereau: Baylor Institute for Immunology Research, Dallas, Texas 75204, USA
Robert L. Coffman: Dynavax Technologies Corporation, 2929 Seventh Street, Suite 100, Berkeley, California 94710, USA
Virginia Pascual: Baylor Institute for Immunology Research, Dallas, Texas 75204, USA
Franck J. Barrat: Dynavax Technologies Corporation, 2929 Seventh Street, Suite 100, Berkeley, California 94710, USA

Nature, 2010, vol. 465, issue 7300, 937-941

Abstract: Corticosteroid boost in lupus Systemic lupus erythematosus (SLE) is an autoimmune disease in which innate tolerance to self nucleic acids is broken with devastating consequences. There have been few advances in therapy in recent years, and patients are still treated mostly with strong immunosuppressives such as high-dose glucocorticoids, often causing severe side effects. In fact lupus patients require much higher glucocorticoid doses than needed in other autoimmune diseases such as rheumatoid arthritis. A possible explanation for this low sensitivity to glucocorticoids has now been identified. In SLE patients the Toll-like receptors TLR7 and TLR9, key players in innate immunity, recognize self nucleic acids on B cells and plasmacytoid dendritic cells (PDC). Now it is shown that, in SLE patients and in lupus-prone mouse strains, stimulation of PDCs by TLR7/9 reduces the immuosuppressive potency of glucocorticoids. This suggests that inhibitors of TLR7/9 signalling, such as the novel class of oligonucleotides known as immunoregulatory sequences (IRSs), could prove to be effective corticosteroid-sparing drugs.

Date: 2010
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DOI: 10.1038/nature09102

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