Context-dependent induction of autoimmunity by TNF signaling deficiency
Tam D. Quach, Weiqing Huang, Ranjit Sahu, Catherine M.M. Diadhiou, Chirag Raparia, Roshawn Johnson, Tung Ming Leung, Susan Malkiel, Peta Gay Ricketts, Stefania Gallucci, Çagla Tükel, Chaim O. Jacob, Martin L. Lesser, Yong-Rui Zou, Anne Davidson
Tam D. Quach, Weiqing Huang, Ranjit Sahu, Catherine M.M. Diadhiou, Chirag Raparia, Roshawn Johnson, Tung Ming Leung, Susan Malkiel, Peta Gay Ricketts, Stefania Gallucci, Çagla Tükel, Chaim O. Jacob, Martin L. Lesser, Yong-Rui Zou, Anne Davidson
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Research Article Immunology

Context-dependent induction of autoimmunity by TNF signaling deficiency

Abstract

TNF inhibitors are widely used to treat inflammatory diseases; however, 30%–50% of treated patients develop new autoantibodies, and 0.5%–1% develop secondary autoimmune diseases, including lupus. TNF is required for formation of germinal centers (GCs), the site where high-affinity autoantibodies are often made. We found that TNF deficiency in Sle1 mice induced TH17 T cells and enhanced the production of germline encoded, T-dependent IgG anti-cardiolipin antibodies but did not induce GC formation or precipitate clinical disease. We then asked whether a second hit could restore GC formation or induce pathogenic autoimmunity in TNF-deficient mice. By using a range of immune stimuli, we found that somatically mutated autoantibodies and clinical disease can arise in the setting of TNF deficiency via extrafollicular pathways or via atypical GC-like pathways. This breach of tolerance may be due to defects in regulatory signals that modulate the negative selection of pathogenic autoreactive B cells.

Authors

Tam D. Quach, Weiqing Huang, Ranjit Sahu, Catherine M.M. Diadhiou, Chirag Raparia, Roshawn Johnson, Tung Ming Leung, Susan Malkiel, Peta Gay Ricketts, Stefania Gallucci, Çagla Tükel, Chaim O. Jacob, Martin L. Lesser, Yong-Rui Zou, Anne Davidson

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Figure 6

TLR7 overexpression induces pathogenic autoantibodies in Sle1 TNF–/– mice.

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TLR7 overexpression induces pathogenic autoantibodies in Sle1 TNF–/– mic...
(A) Survival plots of male Sle1 mice of the indicated genotypes. Log-rank test **P < 0.01. (B–D) Plots show relative units of IgG antibodies against cardiolipin (B), DNA (C), and Sm/RNP (D) from sera of male Sle1 mice of the indicated genotype at 3, 6, and 9 months of age. (E–H) Summary bar graphs of flow cytometry analysis. (E and F) Percentage and count of CD95+GL7+ cells in CD19+ B cells from male Sle1, Sle1 Yaa, Sle1 TNF–/–, and Sle1 Yaa TNF–/– mice. (G and H) Percentage of PNA+CD38– (G) and Ki67+Bcl6+ (H) cells in splenic CD95+GL7+ B cells. (I) Immunohistochemistry images (original magnification, 20×) show Ki67+Bcl6+ B cells in GCs of male Sle1 (top left) and Sle1 Yaa (bottom left) mice. Ki67+Bcl6+ B cells are located at the T-B border in the T cell zone of male Sle1 TNF–/– (top right) and Sle1 Yaa TNF–/– (bottom right) mice (representative of 3–4 mice per group). (J) Ki67+ cells are located in GCs in Sle1 Yaa mice and at the T-B border and in the bridging zones adjacent to extrafollicular foci in Sle1 Yaa TNF–/– mice. (K) Pie charts show mutation frequencies in VH sequences from CD138+ PCs from Sle1 Yaa (left) and Sle1 Yaa TNF–/– (right) mice. χ2, ****P < 0.0001. (L and M) Percentage and count of CD19+CD11c+ age-associated B cells (ABC) in male Sle1, Sle1 Yaa, Sle1 TNF–/–, and Sle1 Yaa TNF–/– mice. (N and O) Percentage and number of CCR6+CD38+ memory B cells in Sle1 Yaa and Sle1 Yaa TNF–/– mice. Dots on bar graphs represent individual mice. Immunohistochemistry representative of 3–5 mice per group. (B–H, L, and M) ANOVA Kruskal-Wallis with Dunn’s multiple comparisons test, *P < 0.05: **P < 0.01, ***P < 0.001. (N and O) Mann-Whitney nonparametric test.