Translocating Gut Pathobiont Enterococcus Gallinarum Induces Th17 and IgG3 Anti-RNA Directed Autoimmunity in Mouse and Human

Rheumatology and Immunology Life Sciences Nephrology Medicine Immunology
autoimmunity gut microbiota Th17 cells IgG3 antibodies systemic lupus erythematosus

Academic Background

Chronic autoimmune diseases are typically triggered by a combination of genetic predisposition and environmental factors, with complex and incompletely understood mechanisms. In many cases, these diseases require lifelong immunosuppressive treatments, imposing a heavy burden on patients. Recent research has found that gut microbiota plays a significant role in autoimmune diseases, particularly “pathobionts” that can cross the gut barrier and enter systemic circulation. These bacteria may trigger or exacerbate autoimmune responses outside the gut. However, how gut microbiota specifically affects human autoimmune responses, especially how it induces specific adaptive immune responses, remains a mystery. This study focuses on a gut pathobiont called Enterococcus gallinarum (E. gallinarum), aiming to reveal how it induces Th17 cell differentiation and IgG3 antibody production, thereby triggering systemic autoimmune responses in humans and mice, particularly in systemic lupus erythematosus (SLE) and autoimmune hepatitis (AIH).

Source of the Paper

This paper was collaboratively completed by a research team including Konrad Gronke, Mytien Nguyen, and others from the Roche Innovation Center Basel, Yale University School of Medicine, the University of Münster, and several other institutions. It was published in the journal Science Translational Medicine on February 5, 2025.

Research Process and Results

1. E. gallinarum Induces Human Th17 Cell Differentiation

The research team first used peripheral blood mononuclear cells (PBMCs) from healthy human donors to test the effects of E. gallinarum and several other gut commensals on Th17 cell differentiation. The study found that E. gallinarum significantly increased the secretion of IL-17 and IFN-γ, thereby inducing Th17 cell differentiation. This effect was confirmed in almost all donors, and compared to other enterococci (such as E. faecalis and E. casseliflavus), E. gallinarum showed a more pronounced effect. Additionally, the study discovered that E. gallinarum could activate monocytes through Toll-like receptor 8 (TLR8), further promoting Th17 cell differentiation.

2. Migration and Systemic Dissemination of E. gallinarum In Vivo

To investigate the migration mechanism of E. gallinarum in vivo, the research team used a gnotobiotic mouse model monocolonized with E. gallinarum. Through immunohistochemistry and bacterial culture techniques, researchers found that E. gallinarum could rapidly cross the gut epithelial barrier and reach the mesenteric lymph nodes (MLNs), liver, and spleen. This migration was time-dependent, with E. gallinarum gradually spreading from the gut to more distal organs, eventually entering systemic circulation. This systemic dissemination was closely related to the pathological features of lupus-like disease in mice.

3. E. gallinarum Triggers IgG3 Antibody Production and Autoantibody Responses

The study further demonstrated that E. gallinarum not only induces Th17 cell differentiation but also promotes B cell maturation and leads to the production of IgG3 subclass antibodies. In a lupus-like mouse model, monocolonization with E. gallinarum significantly increased the number of mature plasma cells in the spleen and elevated serum levels of autoantibodies targeting RNA and double-stranded DNA (dsDNA). Moreover, in human SLE and AIH patients, the antibody levels against E. gallinarum RNA were significantly correlated with autoantibodies against human RNA, particularly in the IgG3 subclass.

4. The Key Role of TLR8 in E. gallinarum-Induced Immune Responses

Through gene knockout and drug inhibition experiments, the research team revealed that TLR8 is the key receptor for E. gallinarum-induced Th17 cell differentiation. E. gallinarum RNA could activate TLR8, whereas human RNA could not trigger this response. This finding indicates that E. gallinarum RNA, as a pathogen-associated molecular pattern (PAMP), plays a critical role in autoimmune responses. Additionally, the study found that hydroxychloroquine (HCQ)—a drug commonly used to treat SLE—could significantly reduce Th17 cell differentiation by inhibiting the TLR8 signaling pathway.

5. The Pathological Role of E. gallinarum in Lupus-Like Disease

In a lupus-like mouse model, the introduction of E. gallinarum resulted in severe proteinuria and kidney damage, which are typical pathological features of lupus nephritis. The study also found that the deposition of IgG3 antibodies in the kidneys was significantly correlated with the severity of proteinuria, indicating that IgG3 plays a critical role in autoimmune kidney disease.

Conclusion and Significance

This study is the first to reveal how E. gallinarum induces human Th17 cell differentiation and IgG3 antibody production through the TLR8 signaling pathway, thereby triggering autoimmune responses in systemic lupus erythematosus and autoimmune hepatitis. This not only provides new mechanistic insights into the role of gut microbiota in autoimmune diseases but also lays the foundation for developing precision treatment strategies based on host and microbial biomarkers. Furthermore, the findings suggest that targeting the TLR8 pathway may offer new directions for the treatment of autoimmune diseases.

Research Highlights

  1. E. gallinarum is the first gut pathobiont proven to induce human Th17 cell differentiation and IgG3 antibody production.
  2. The TLR8 signaling pathway plays a central role in E. gallinarum-triggered autoimmune responses.
  3. The study reveals the pathological role of IgG3 antibodies in autoimmune kidney disease, providing new therapeutic targets for SLE.
  4. A combination of human and mouse models comprehensively validates the mechanism of E. gallinarum in systemic autoimmune diseases.

Additional Valuable Information

This study also provides potential biomarkers for the early diagnosis of autoimmune diseases, such as antibody levels against E. gallinarum RNA, which may serve as auxiliary diagnostic indicators for SLE and AIH. Additionally, the findings emphasize the importance of gut microbiota in autoimmune diseases, offering theoretical support for future microbiome-based therapeutic approaches.