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Abstract: SA-OR97

Humanized IGHA1 Mouse Induced by Lactobacillus casei Cell Wall Extract: A Novel Galactose-Deficient Immunoglobulin A1 (IgA1) Elevated Mouse Model of IgA Nephropathy

Session Information

Category: Glomerular Diseases

  • 1401 Glomerular Diseases: From Inflammation to Fibrosis

Authors

  • Li, Run, Peking University First Hospital; Key Laboratory of Renal Disease, Ministry of Health of China; Key Laboratory of CKD Prevention and Treatment (Peking University), Ministry of Education, Beijing, China
  • Wang, Manliu, Peking University First Hospital; Key Laboratory of Renal Disease, Ministry of Health of China; Key Laboratory of CKD Prevention and Treatment (Peking University), Ministry of Education, Beijing, China
  • Xie, Xinfang, Department of Nephrology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
  • Tian, Wenmin, Department of Biochemistry and Biophysics, Center for Precision Medicine Multi-Omics Research, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
  • Zhang, Yong, Institutes for Systems Genetics, West China Hospital, Sichuan University, Chengdu, China
  • Li, Jingyi, Peking University First Hospital; Key Laboratory of Renal Disease, Ministry of Health of China; Key Laboratory of CKD Prevention and Treatment (Peking University), Ministry of Education, Beijing, China
  • Dong, Yaping, Peking University First Hospital; Key Laboratory of Renal Disease, Ministry of Health of China; Key Laboratory of CKD Prevention and Treatment (Peking University), Ministry of Education, Beijing, China
  • Zan, Jincan, Peking University First Hospital; Key Laboratory of Renal Disease, Ministry of Health of China; Key Laboratory of CKD Prevention and Treatment (Peking University), Ministry of Education, Beijing, China
  • Jin, Jing, Department of Medicine, Division of Nephrology and Hypertension, Feinberg Cardiovascular and Renal Research Institute, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
  • Lv, Jicheng, Peking University First Hospital; Key Laboratory of Renal Disease, Ministry of Health of China; Key Laboratory of CKD Prevention and Treatment (Peking University), Ministry of Education, Beijing, China
  • Zhang, Hong, Peking University First Hospital; Key Laboratory of Renal Disease, Ministry of Health of China; Key Laboratory of CKD Prevention and Treatment (Peking University), Ministry of Education, Beijing, China
Background

IgA nephropathy (IgAN) is the most common primary glomerulonephritis in the world. A ‘multi-hit’ hypothesis has been proposed to explain the pathogenesis of IgAN and galactose-deficient IgA1 (Gd-IgA1) was defined as the first hit. In this study, we constructed a novel Gd-IgA1 elevated mouse model with typical histopathology features of IgAN, by immunizing the immunoglobulin heavy constant alpha 1 knock-in (IGHA1+/+) mice with Lactobacillus casei Cell Wall Extract (LCWE).

Methods

IGHA1+/+ mice were generated by replacing the endogenous mouse Igha gene with the human IGHA1 gene via a CRISPR/Cas9 system. 2-month-old male IGHA1+/+ mice were injected i.p. with either 0.5mg/g LCWE plus complete Freund's adjuvant (CFA) or PBS eight times. 8-month-old mice were euthanized for further examination.

Results

IGHA1+/+ mice expressed human IgA1 heavy chain instead of mouse IgA. Human IgA, human IgA-mouse IgG complex, and CD89-binding pIgA1 complex levels were significantly increased from 4 months old in the serum of IGHA1+/+ mice induced by LCWE plus CFA compared with PBS. Meanwhile, as observations continued, the serum Gd-IgA1 absolute value and relative proportion to hIgA1 increased 4 times in IGHA1+/+-LCWE mice. We quantitatively analyzed the O-glycopeptides of human IgA1 hinge region (HR) using LC-MS analysis and found HR from IGHA1+/+-LCWE mice showed hypo-galactosylation than IGHA1+/+-PBS mice.
IGHA1+/+-LCWE mice showed a continuous and stable human IgA1 (positive rate: 100%) kidney mesangial deposition with C3 co-deposits (positive rate: 81.25%) until 8 months old. Histology demonstrated a significant rise in mesangial expansion and hypercellularity. Electron microscopy showed typical mesangial electron-dense deposits in IGHA1+/+-LCWE mice.

Conclusion

We established a novel serum Gd-IgA1 elevated mouse model presenting typical pathological characteristics of IgAN, which will be used to further explore the mechanisms and new therapeutic strategies.

Funding

  • Government Support – Non-U.S.