B cells expressing the transcription factor T-bet drive lupus-like autoimmunity
Kira Rubtsova, Anatoly V. Rubtsov, Joshua M. Thurman, Johanna M. Mennona, John W. Kappler, Philippa Marrack
Kira Rubtsova, Anatoly V. Rubtsov, Joshua M. Thurman, Johanna M. Mennona, John W. Kappler, Philippa Marrack
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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).