Pharmacological inhibition of TLR9 activation blocks autoantibody production in human B cells from SLE patients
| Autor: | Claudio Sette, Maria M. Rosado, Maria Loiarro, Nicola Fanto, Eleonora Nucera, Elisabetta Cortis, Federica Capolunghi, Grazia Gallo, Barbara Ruggiero, Rita Carsetti, Simona Cascioli, Elia Girolami, Rita De Santis, Antonella Insalaco, Vito Ruggiero, Marina Vivarelli, Silvia Bordasco |
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| Rok vydání: | 2010 |
| Předmět: |
Adult
Male Adolescent Plasma cell medicine.disease_cause Heterocyclic Compounds 2-Ring Peripheral blood mononuclear cell Autoimmunity Pathogenesis Young Adult Rheumatology immune system diseases Humans Lupus Erythematosus Systemic Medicine Spiro Compounds Pharmacology (medical) Antibody-Producing Cells Autoantibodies Autoimmune disease Settore BIO/16 B-Lymphocytes Toll-like receptor business.industry Autoantibody TLR9 medicine.disease medicine.anatomical_structure Case-Control Studies Toll-Like Receptor 9 Antibody Formation Myeloid Differentiation Factor 88 Immunology CpG Islands Female business |
| Zdroj: | Rheumatology. 49:2281-2289 |
| ISSN: | 1462-0332 1462-0324 |
| Popis: | Objectives. Toll-like receptor 9 (TLR9), which recognizes hypomethylated DNA [cytosine-phosphate-guanine (CpG)], plays a role in the maintenance of serological memory and has been recently implicated in the pathogenesis of SLE. We previously reported that in vitro TLR9 triggers memory B-cell differentiation into antibody-producing cells, and that the MyD88-inhibitor ST2825 blocks TLR9-induced plasma cell (PC) generation. Here, we investigated whether memory B cells produce autoantibodies in SLE patients with active disease or in clinical remission, and whether ST2825 could inhibit PC generation in SLE patients. Methods. Peripheral blood mononuclear cells from 10 SLE patients in clinical remission and 2 with active SLE were cultured in the presence of CpG with or without ST2825. Phenotypical analysis of CpG-stimulated cells was performed by flow cytometry. Supernatants were collected to measure antibody production by ELISA and to detect autoantibodies by IF. Results. CpG-induced TLR9 stimulation caused autoantibody secretion in patients with active disease and in the majority of patients in clinical remission. Inhibition of MyD88 completely blocked the de novo generation of PCs and the secretion of autoantibodies. Conclusions. Autoreactive B cells persist in SLE patients during disease remission in the circulating B-cell memory pool. TLR9-dependent activation of memory B cells by pathogens could be one of the mechanisms triggering relapses in SLE. Compounds targeting the TLR/MyD88 pathway may be used as novel therapeutic tools to treat acute disease and to prevent relapses in SLE patients. |
| Databáze: | OpenAIRE |
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