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Translocating gut pathobiont Enterococcus gallinarum induces TH17 and IgG3 anti-RNA–directed autoimmunity in mouse and human.

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Title: Translocating gut pathobiont Enterococcus gallinarum induces TH17 and IgG3 anti-RNA–directed autoimmunity in mouse and human.
Authors: Gronke, Konrad, Nguyen, Mytien, Fuhrmann, Helen, Santamaria de Souza, Noemi, Schumacher, Julia, Pereira, Márcia S., Löschberger, Ulrike, Brinkhege, Anna, Becker, Nathalie J., Yang, Yi, Sonnert, Nicole, Leopold, Shana, Martin, Anjelica L., von Münchow-Klein, Lilly, Pessoa Rodrigues, Cecilia, Cansever, Dilay, Hallet, Remy, Richter, Kirsten, Schubert, David A., Daniel, Guillaume M.
Source: Science Translational Medicine; 2/5/2025, Vol. 17 Issue 784, p1-17, 17p
Subject Terms: MONONUCLEAR leukocytes, T cell receptors, AUTOIMMUNE hepatitis, BACTERIAL RNA, SYSTEMIC lupus erythematosus
Abstract: 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 Enterococcus gallinarum can induce both human and mouse interferon-γ+ T helper 17 (TH17) differentiation and immunoglobulin G3 (IgG3) subclass switch of anti–E. gallinarum RNA antibodies, which correlated with anti-human RNA autoantibody responses in patients with systemic lupus erythematosus (SLE) and autoimmune hepatitis, two extraintestinal autoimmune diseases. E. gallinarum RNA, but not human RNA, triggered Toll-like receptor 8 (TLR8), and TLR8-mediated human monocyte activation promoted human TH17 induction by E. gallinarum. 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. Editor's summary: Enterococcus gallinarum is a translocating gut microbe that can escape the intestine and stimulate systemic autoimmune responses in mice; however, the role of this pathobiont in driving autoimmunity in humans remains poorly understood. Here, Gronke et al. found that E. gallinarum induced a TH17 immune response in human peripheral blood mononuclear cells characterized by increased interferon-γ and IL-17 expression in CD4+ T cells and Toll-like receptor 8–mediated activation of monocytes. In addition, E. gallinarum stimulated the production of IgG3 antibodies directed against bacterial RNA in vivo. The authors further showed that patients with systemic lupus erythematosus and autoimmune hepatitis had a high correlation between plasma concentrations of IgG3 anti–E. gallinarum RNA antibodies and anti-human RNA IgG3 antibodies. Together, these findings provide evidence of a human immune response to a gut pathobiont that may be associated with autoimmune pathology. —Molly Ogle [ABSTRACT FROM AUTHOR]
Copyright of Science Translational Medicine is the property of American Association for the Advancement of Science and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
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  Data: Translocating gut pathobiont Enterococcus gallinarum induces T<subscript>H</subscript>17 and IgG3 anti-RNA–directed autoimmunity in mouse and human.
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  Data: Science Translational Medicine; 2/5/2025, Vol. 17 Issue 784, p1-17, 17p
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  Data: <searchLink fieldCode="DE" term="%22MONONUCLEAR+leukocytes%22">MONONUCLEAR leukocytes</searchLink><br /><searchLink fieldCode="DE" term="%22T+cell+receptors%22">T cell receptors</searchLink><br /><searchLink fieldCode="DE" term="%22AUTOIMMUNE+hepatitis%22">AUTOIMMUNE hepatitis</searchLink><br /><searchLink fieldCode="DE" term="%22BACTERIAL+RNA%22">BACTERIAL RNA</searchLink><br /><searchLink fieldCode="DE" term="%22SYSTEMIC+lupus+erythematosus%22">SYSTEMIC lupus erythematosus</searchLink>
– Name: Abstract
  Label: Abstract
  Group: Ab
  Data: 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 Enterococcus gallinarum can induce both human and mouse interferon-γ<superscript>+</superscript> T helper 17 (T<subscript>H</subscript>17) differentiation and immunoglobulin G3 (IgG3) subclass switch of anti–E. gallinarum RNA antibodies, which correlated with anti-human RNA autoantibody responses in patients with systemic lupus erythematosus (SLE) and autoimmune hepatitis, two extraintestinal autoimmune diseases. E. gallinarum RNA, but not human RNA, triggered Toll-like receptor 8 (TLR8), and TLR8-mediated human monocyte activation promoted human T<subscript>H</subscript>17 induction by E. gallinarum. 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. Editor's summary: Enterococcus gallinarum is a translocating gut microbe that can escape the intestine and stimulate systemic autoimmune responses in mice; however, the role of this pathobiont in driving autoimmunity in humans remains poorly understood. Here, Gronke et al. found that E. gallinarum induced a T<subscript>H</subscript>17 immune response in human peripheral blood mononuclear cells characterized by increased interferon-γ and IL-17 expression in CD4<superscript>+</superscript> T cells and Toll-like receptor 8–mediated activation of monocytes. In addition, E. gallinarum stimulated the production of IgG3 antibodies directed against bacterial RNA in vivo. The authors further showed that patients with systemic lupus erythematosus and autoimmune hepatitis had a high correlation between plasma concentrations of IgG3 anti–E. gallinarum RNA antibodies and anti-human RNA IgG3 antibodies. Together, these findings provide evidence of a human immune response to a gut pathobiont that may be associated with autoimmune pathology. —Molly Ogle [ABSTRACT FROM AUTHOR]
– Name: Abstract
  Label:
  Group: Ab
  Data: <i>Copyright of Science Translational Medicine is the property of American Association for the Advancement of Science and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.</i> (Copyright applies to all Abstracts.)
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        Value: 10.1126/scitranslmed.adj6294
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        Text: English
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      – TitleFull: Translocating gut pathobiont Enterococcus gallinarum induces TH17 and IgG3 anti-RNA–directed autoimmunity in mouse and human.
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