Translocating gut pathobiont <i>Enterococcus gallinarum</i> induces T <sub>H</sub> 17 and IgG3 anti-RNA–directed autoimmunity in mouse and human
Chronic autoimmune diseases often lead to long-term sequelae and require lifelong immunosuppression because of an incomplete understanding of the triggers and drivers in genetically predisposed patients. Gut bacteria that escape the gut barrier, known as translocating gut pathobionts, have been implicated as instigators and perpetuators of extraintestinal autoimmune diseases in mice. The gut microbial contributions to autoimmunity in humans remain largely unclear, including whether specific pathological human adaptive immune responses are triggered by such pathobionts. Here, we show that the translocating pathobiont <i>Enterococcus gallinarum</i> can induce both human and mouse interferon-γ<sup>+</sup> T helper 17 (T<sub>H</sub>17) differentiation and immunoglobulin G3 (IgG3) subclass switch of anti-<i>E. gallinarum</i> RNA antibodies, which correlated with anti-human RNA autoantibody responses in patients with systemic lupus erythematosus (SLE) and autoimmune hepatitis, two extraintestinal autoimmune diseases. <i>E. gallinarum</i> RNA, but not human RNA, triggered Toll-like receptor 8 (TLR8), and TLR8-mediated human monocyte activation promoted human T<sub>H</sub>17 induction by <i>E. gallinarum</i>. Translocation of the pathobiont triggered increased anti-RNA autoantibody titers that correlated with renal autoimmune pathophysiology in murine gnotobiotic lupus models and with disease activity in patients with SLE. These studies elucidate cellular mechanisms of how a translocating gut pathobiont induces systemic human T cell- and B cell-dependent autoimmune responses and provide a framework for developing host- and microbiota-derived biomarkers and targeted therapies in autoimmune diseases.
Authors
- Dilay Cansever (ORCID: https://orcid.org/0000-0001-7673-616X)
- Martin Kriegel (ORCID: https://orcid.org/0000-0002-7371-0391)
- Cecília Pessoa Rodrigues (ORCID: https://orcid.org/0000-0001-8617-6565)
- David Dylus (ORCID: https://orcid.org/0000-0002-0327-0781)
- Shana R. Leopold (ORCID: https://orcid.org/0000-0001-5830-1955)
- Noah W. Palm (ORCID: https://orcid.org/0000-0001-7262-9455)
- Kirsten Richter
- Noemi Santamaria de Souza (ORCID: https://orcid.org/0000-0001-7134-7480)
- Christoph Schramm (ORCID: https://orcid.org/0000-0002-4264-1928)
- Kara G. Lassen (ORCID: https://orcid.org/0000-0001-7023-461X)
- Anjelica Martin (ORCID: https://orcid.org/0000-0001-9669-8842)
- Dorothee Schwinge (ORCID: https://orcid.org/0000-0002-0679-4476)
- Konrad Gronke
- Lilly von Muenchow (ORCID: https://orcid.org/0000-0001-5394-5727)
- Sylvio Redanz (ORCID: https://orcid.org/0000-0003-1541-2545)
- Mytien Nguyen (ORCID: https://orcid.org/0000-0001-7343-6882)
- Márcia S. Pereira (ORCID: https://orcid.org/0000-0002-8708-8388)
- Nicole Sonnert (ORCID: https://orcid.org/0000-0002-2781-4675)
- Rémy Hallet
- Sílvio M. Vieira (ORCID: https://orcid.org/0000-0001-8036-4223)
- H. Fuhrmann
- Marianne Forkel (ORCID: https://orcid.org/0009-0009-3402-9710)
- Luca Piali
- Christoph Bieniossek (ORCID: https://orcid.org/0000-0002-9057-2613)
- Ulrike Löschberger
- Yi Yang (ORCID: https://orcid.org/0000-0002-5200-0614)
- David Schubert (ORCID: https://orcid.org/0000-0002-1190-7623)
- Julia Schumacher
- Nikolaus Becker (ORCID: https://orcid.org/0000-0003-3775-8512)
- Guillaume M. Daniel
- Anna Brinkhege
Institutions
- Roche (Switzerland) (CH)
- Universität Hamburg (DE)
- University of Münster (DE)
- Yale University (US)
- University Hospital Münster (DE)
- University Medical Center Hamburg-Eppendorf (DE)
- University of Pennsylvania (US)
Publication Details
- Journal
- Science Translational Medicine
- Published
- 2025-02-05
- DOI
- https://doi.org/10.1126/scitranslmed.adj6294
- Citations
- 24
- Primary Topic
- Immune Cell Function and Interaction
- Type
- article
- Field-Weighted Citation Impact
- 19.14