B cells expressing the transcription factor T-bet drive lupus-like autoimmunity
Kira Rubtsova, … , John W. Kappler, Philippa Marrack
Kira Rubtsova, … , John W. Kappler, Philippa Marrack
Published February 27, 2017
Citation Information: J Clin Invest. 2017;127(4):1392-1404. https://doi.org/10.1172/JCI91250.
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Research Article Autoimmunity Immunology

B cells expressing the transcription factor T-bet drive lupus-like autoimmunity

Abstract

B cells contribute to multiple aspects of autoimmune disorders and may play a role in triggering disease. Thus, targeting B cells may be a promising strategy for treating autoimmune disorders. Better understanding of the B cell subsets that are responsible for the development of autoimmunity will be critical for developing efficient therapies. Here we have reported that B cells expressing the transcription factor T-bet promote the rapid appearance of autoantibodies and germinal centers in spontaneous murine models of systemic lupus erythematosus (SLE). Conditional deletion of T-bet from B cells impaired the formation of germinal centers and mitigated the development of kidney damage and rapid mortality in SLE mice. B cell–specific deletion of T-bet was also associated with lower activation of both B cells and T cells. Taken together, our results suggest that targeting T-bet–expressing B cells may be a potential target for therapy for autoimmune diseases.

Authors

Kira Rubtsova, Anatoly V. Rubtsov, Joshua M. Thurman, Johanna M. Mennona, John W. Kappler, Philippa Marrack

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Figure 2

B cell–specific T-bet expression is responsible for the development of kidney pathology and rapid mortality in lupus-like autoimmunity.

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B cell–specific T-bet expression is responsible for the development of k...
(A) Proteinuria scores of 7-month-old mice (1 = trace, 2 = 30 mg/dl, 3 = 100 mg/dl, 4 ≥ 500 mg/dl). (B–D) Kidney sections from 12-month-old mice were stained with periodic acid–Schiff from SLE × T-betfl/fl × CD19Cre/WT (B), and SLE × T-betfl/fl × CD19WT/WT (C), and C57BL/6 (D) mice. A representative glomerulus is shown in each section. Arrowheads indicate glomeruli. Hypercellularity and endocapillary proliferation were seen in most glomeruli from the SLE × T-betfl/fl × CD19WT/WT mice. Original magnification, ×400. (E) Twenty-five glomeruli for each mouse were evaluated in a blinded analysis in kidney sections. The percentage of affected glomeruli is shown for each individual mouse. (F–H) Five kidneys of 12-month-old mice per genotype were analyzed by immunofluorescence histology (IFH). Representative IFH staining of kidney glomeruli stained with anti-IgG (red) and anti-C3 (green) is shown for: SLE × T-betfl/fl × CD19Cre/WT (F), SLE × T-betfl/fl × CD19WT/WT (G), and C57BL/6 (H) mice. Scale bars: 50 μm. (I) Survival of SLE × T-betfl/fl × CD19Cre/WT, and SLE × T-betfl/fl × CD19WT/WT littermate control mice was followed over the same 12 months (n = 10 mice per group). Comparison of the survival curves and statistical analysis were performed using Prism software. *P < 0.05. Significance determined by Student’s t test (A and E) or Gehan-Berslow-Wilcoxon test (I).