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. 2018 Mar 8;3(5):e96795.
doi: 10.1172/jci.insight.96795.

Impaired TLR9 Responses in B Cells From Patients With Systemic Lupus Erythematosus

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Free PMC article

Impaired TLR9 Responses in B Cells From Patients With Systemic Lupus Erythematosus

Vincent Gies et al. JCI Insight. .
Free PMC article

Abstract

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.

Keywords: Autoimmune diseases; Autoimmunity; B cells; Immunology.

Conflict of interest statement

Conflict of interest: The authors have declared that no conflict of interest exists.

Figures

Figure 1
Figure 1. Decreased CD19 and CD21 expression on SLE B cells.
(A) CD19, CD21, CD81, and CD225 mean fluorescence intensity (MFI) ratios of CD19+ B cells from quiescent (n = 22) and active (n = 10) systemic lupus erythematosus (SLE) patients compared with healthy donors (HDs; n = 39). (B) CD19 and CD21 MFI ratios of transitional, mature naive B cells from quiescent (n = 20) and active (n = 10) SLE patients compared with HDs (n = 37). The MFI ratio was determined as follows: (MFI of the considered marker)/(mean of the MFI of the considered marker in the HD group). *P < 0.05, **P < 0.005, ***P < 0.001 by 2-tailed Mann-Whitney U test.
Figure 2
Figure 2. CD19 downregulation appeared concomitantly with CD21 expression on maturing B cells.
CD19 and CD21 mean fluorescence intensity (MFI) of CD19+CD10+IgM pro-B and pre-B cells, CD19+CD10+IgM+CD21CD24++ immature B cells, and CD19+CD10IgM+CD21+ mature B cells from the bone marrow of systemic lupus erythematosus (SLE) patients (n = 6) compared with healthy donors (HDs; n = 4). *P < 0.05 by 2-tailed Wilcoxon’s signed-rank test.
Figure 3
Figure 3. Impaired TLR9 responses in SLE B cells.
Frequency of CD86+CD69+ (A) and TACI+CD25+ (B) in gated CD20+CD27 naive B cells from healthy donors (HDs; n = 19) or systemic lupus erythematosus (SLE) patients without hydroxychloroquine (HCQ) (n = 12) after no stimulation (NS) or in vitro stimulation of B cells with polyclonal F(ab′)2 anti-human IgM, gardiquimod (TLR7 ligand), CpG (TLR9 ligand), or CD40 ligand (CD40L) for 2 days. **P < 0.005 by 2-tailed Mann-Whitney U test.
Figure 4
Figure 4. Altered cytokine secretion after TLR9 stimulation in SLE B cells.
Concentrations of cytokines (IL-6, IL-10, and TNF-α) in culture supernatants, from healthy donors (HDs; n = 15) or systemic lupus erythematosus (SLE) patients without hydroxychloroquine (HCQ) (n = 9), after no stimulation (NS) or in vitro stimulation of B cells with polyclonal F(ab′)2 anti-human IgM, gardiquimod (TLR7 ligand), CpG (TLR9 ligand), or CD40 ligand (CD40L) for 2 days. *P < 0.05 by 2-tailed Mann-Whitney U test.
Figure 5
Figure 5. Unaltered TLR9 responses in pDCs.
(A and B) Frequency of CD86+CD69+ cells and MHCII fold induction after no stimulation (NS) or in vitro stimulation of sorted plasmacytoid dendritic cells (pDCs) from healthy donors (HDs) and untreated systemic lupus erythematosus (SLE) patients with class C CpG (A) (n = 4) or class B CpG (B) (n = 3) for 2 days. Two-tailed Mann-Whitney U test.

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