4.5 Article

Targeting Bcl6 in the TREX1 D18N murine model ameliorates autoimmunity by modulating T-follicular helper cells and germinal center B cells

Journal

EUROPEAN JOURNAL OF IMMUNOLOGY
Volume 52, Issue 5, Pages 825-834

Publisher

WILEY
DOI: 10.1002/eji.202149324

Keywords

autoimmunity; Bcl6; inflammation; Tfh; Th1; TREX1

Categories

Funding

  1. National Institute of Allergy and Infectious Diseases [R01AI116725]
  2. National Institute of Diabetes and Kidney Diseases [R01DK105833, R01DK104963, R21DK112105]
  3. UVA School of Medicine LaunchPad Diabetes Fund [T32AI007401]
  4. Alliance for Lupus Research
  5. Cowgill and Artom Memorial Fellowship
  6. Comprehensive Cancer Center of Wake Forest University National Cancer Institute (Cancer Center Support Grant) [P30CA012197]

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The study reveals a Th1 bias and elevated Tfh cells and germinal center B cells in TREX1 D18N mice. Inhibiting Bcl6 can attenuate Tfh, germinal center, and Th1 responses and rescue TREX1 D18N mice from autoimmunity. These findings suggest that Tfh cells and germinal center B cells may serve as potential therapeutic targets for autoimmune diseases.
The Three Prime Repair EXonuclease I (TREX1) is critical for degrading post-apoptosis DNA. Mice expressing catalytically inactive TREX1 (TREX1 D18N) develop lupus-like autoimmunity due to chronic sensing of undegraded TREX1 DNA substrates, production of the inflammatory cytokines, and the inappropriate activation of innate and adaptive immunity. This study aimed to investigate Thelper (Th) dysregulation in the TREX1 D18N model system as a potential mechanism for lupus-like autoimmunity. Comparison of immune cells in secondary lymphoid organs, spleen and peripheral lymph nodes (LNs) between TREX1 D18N mice and the TREX1 null mice revealed that the TREX1 D18N mice exhibit a Th1 bias. Additionally, the T-follicular helper cells (Tfh) and the germinal celter (GC) B cells were also elevated in the TREX1 D18N mice. Targeting Bcl6, a lineage-defining transcription factor for Tfh and GC B cells, with a commercially available Bcl6 inhibitor, FX1, attenuated Tfh, GC, and Th1 responses, and rescued TREX1 D18N mice from autoimmunity. The study presents Tfh and GC B-cell responses as potential targets in autoimmunity and that Bcl6 inhibitors may offer therapeutic approach in TREX1-associated or other lupus-like diseases.

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