Impaired TLR9 responses in B cells from patients with systemic lupus erythematosus

• Published in: JCI insight 2018-03, Vol.3 (5)
• Main Authors: Gies, Vincent, Schickel, Jean-Nicolas, Jung, Sophie, Joublin, Aurélie, Glauzy, Salomé, Knapp, Anne-Marie, Soley, Anne, Poindron, Vincent, Guffroy, Aurélien, Choi, Jin-Young, Gottenberg, Jacques-Eric, Anolik, Jennifer H, Martin, Thierry, Soulas-Sprauel, Pauline, Meffre, Eric, Korganow, Anne-Sophie
• Format: Article
• Language: English
• Subjects: Adult; Aged; Aged, 80 and over; Antigens, CD19 - immunology; Antigens, CD19 - metabolism; Autoimmunity; B-Lymphocytes - drug effects; B-Lymphocytes - immunology; B-Lymphocytes - metabolism; Cells, Cultured; Cytokines - immunology; Cytokines - metabolism; Dendritic Cells - drug effects; Dendritic Cells - immunology; Dendritic Cells - metabolism; Female; Humans; Immune Tolerance; Immunology; Life Sciences; Lupus Erythematosus, Systemic - blood; Lupus Erythematosus, Systemic - immunology; Male; Middle Aged; Oligodeoxyribonucleotides - pharmacology; Primary Cell Culture; Receptors, Complement 3d - immunology; Receptors, Complement 3d - metabolism; Toll-Like Receptor 9 - agonists; Toll-Like Receptor 9 - immunology; Toll-Like Receptor 9 - metabolism; Up-Regulation; Young Adult
• ISSN: 2379-3708; 2379-3708
• DOI: 10.1172/jci.insight.96795

B cells play a central role in systemic lupus erythematosus (SLE) pathophysiology but dysregulated pathways leading to a break in B cell tolerance remain unclear. Since Toll-like receptor 9 (TLR9) favors the elimination of autoreactive B cells in the periphery, we assessed TLR9 function in SLE by analyzing the responses of B cells and plasmacytoid dendritic cells (pDCs) isolated from healthy donors and patients after stimulation with CpG, a TLR9 agonist. We found that SLE B cells from patients without hydroxychloroquine treatment displayed defective in vitro TLR9 responses, as illustrated by the impaired upregulation of B cell activation molecules and the diminished production of various cytokines including antiinflammatory IL-10. In agreement with CD19 controlling TLR9 responses in B cells, decreased expression of the CD19/CD21 complex on SLE B cells was detected as early as the transitional B cell stage. In contrast, TLR7 function was preserved in SLE B cells, whereas pDCs from SLE patients properly responded to TLR9 stimulation, thereby revealing that impaired TLR9 function in SLE was restricted to B cells. We conclude that abnormal CD19 expression and TLR9 tolerogenic function in SLE B cells may contribute to the break of B cell tolerance in these patients.