Intestinal microbiota sustains inflammation and autoimmunity induced by hypomorphic RAG defects.

Area of Science:

• Immunology
• Gastroenterology
• Microbiology

Background:

• Omenn syndrome (OS) results from hypomorphic Rag mutations, causing severe immunodeficiency and autoimmune-like symptoms.
• OS pathogenesis involves oligoclonal T and B cells, but the role of microbial signals remains unclear.

Purpose of the Study:

• To investigate the role of microbial signals in Omenn syndrome pathogenesis using a Rag2(R229Q) mouse model.
• To explore the therapeutic potential of antibiotics in ameliorating OS-associated inflammation and autoimmunity.

Main Methods:

• Rag2(R229Q) knock-in mice were used to model OS, exhibiting inflammatory bowel disease.
• T cell transfer experiments and microbiota transplantation were performed.
• The effects of broad-spectrum antibiotics (ABXs) on disease manifestations were assessed.

Main Results:

• Rag2(R229Q) mice developed inflammatory bowel disease, with Th1/Th17 CD4 T cells driving pathology.
• Impaired oral tolerance and altered gut microbiota contributed to disease severity.
• Antibiotic treatment significantly reduced intestinal and systemic inflammation, decreased gut-tropic T cells, and normalized hyper-IgE levels.

Conclusions:

• Intestinal microbes play a critical role in the immune dysregulation characteristic of Omenn syndrome.
• Targeting the gut microbiota with antibiotics shows therapeutic promise for OS.