Abstract: TH-OR080
Breakdown of Oral Tolerance to Gut Bacteria-Derived Galactose-Deficient IgA1 Drives IgAN
Session Information
- Glomerular Diseases: Novel Mechanisms of Injury
October 22, 2026 | Location: Room 401, Convention Center
Abstract Time: 05:40 PM - 05:50 PM
Category: Glomerular Diseases
- 1401 Glomerular Diseases: Mechanisms, including Podocyte Biology
Authors
- Lam, Derek Kong, The University of Hong Kong, Hong Kong, Hong Kong
- Cheung, Pui Ting, The University of Hong Kong, Hong Kong, Hong Kong
- Ng, Yuen Yee, The University of Hong Kong, Hong Kong, Hong Kong
- Leung, Hoi Ching, The University of Hong Kong, Hong Kong, Hong Kong
- Zheng, Siqi, The University of Hong Kong, Hong Kong, Hong Kong
- Du, Yujun, The University of Hong Kong, Hong Kong, Hong Kong
- Ruan, Yuyi, The University of Hong Kong, Hong Kong, Hong Kong
- Liu, Dan, The University of Hong Kong, Hong Kong, Hong Kong
- Ma, Jingyuan, The University of Hong Kong, Hong Kong, Hong Kong
- Yiu, Wai Han, The University of Hong Kong, Hong Kong, Hong Kong
- Mak, Lung Yi, The University of Hong Kong, Hong Kong, Hong Kong
- Tang, Sydney, The University of Hong Kong, Hong Kong, Hong Kong
Background
Galactose-deficient IgA1 (Gd-IgA1) is the key putative autoantigen in IgA nephropathy (IgAN). Serum Gd-IgA1 levels are elevated in IgAN patients, yet healthy individuals also have background levels, and unaffected relatives often have high levels without developing disease. Why tolerance to this "self-antigen" is lost in some individuals remains unknown.
Methods
We collected serum, urine, stool, colonic biopsy samples from IgAN, non-IgAN CKD patients, and healthy controls. Bacteria-derived Gd-IgA1 was administered orally to C57BL/6 mice (3x/week for 4 weeks) with low-dose LPS stimulation (0.05 mg, 1x/week for 3 weeks; I.P.).
Results
We identified the gut microbiome as a significant exogenous source of Gd-IgA1. Anaerobic culture of IgAN stool with human IgA produced more Gd-IgA1 than healthy controls. The stool Gd-IgA1/IgA ratio was at least 100-fold higher than in serum for both groups. To further identify specific bacterial strains capable of producing Gd-IgA1, we created a diverse culture collection of gut bacteria isolated from IgAN patient stools, which revealed multiple gut commensals that can enzymatically deglycosylate human IgA1 into Gd-IgA1 in vitro. In wild-type C57BL/6 mice, oral administration of the purified Gd-IgA1, generated from these Gd-IgA1-producing strains isolated from IgAN patients, alone did not induce anti-Gd-IgA1 IgG production or kidney injury at 4 weeks, demonstrating oral tolerance to bacterial-derived Gd-IgA1. However, a low-dose LPS stimulation abrogated this tolerance, resulting in increased serum anti-Gd-IgA1 IgG, glomerular deposition of human IgA/mouse IgG complex, and kidney injury and inflammation (e.g. elevated NGAL, CCL2, CCL5). Bulk RNA-seq of the small intestine from oral intolerance mice revealed a strong Th17 signature and B cell activation compared to vehicle-treated mice. Consistent with our animal model, scRNA-seq analysis identified clusters of disease-specific BAFF+ myeloid cells with high expression of S100A9 from colonic biopsies from IgAN patients. These cells may serve as the potential antigen presenting cells (APCs) that drive autoantibody production in IgAN patients.
Conclusion
Loss of oral tolerance to the bacterial-derived antigen (i.e. Gd-IgA1) via innate immune activation represents a previously unrecognized mechanism in IgAN. Restoring tolerance and modulating the gut microbiome may offer a new therapeutic paradigm.
Acknowledgment
This study is supported by Health and Medical Research Fund (12232706)
Funding
- Government Support – Non-U.S.