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Abstract: TH-OR116

Immunological and Genomic Analysis of Phenotype Discordant Monozygotic Twins Reveals a Novel Role of T-Follicular Helper Cells in IgA Nephropathy

Session Information

  • Mostly IgA Nephropathy
    November 07, 2019 | Location: Ballroom C, Walter E. Washington Convention Center
    Abstract Time: 06:06 PM - 06:18 PM

Category: Glomerular Diseases

  • 1202 Glomerular Diseases: Immunology and Inflammation

Authors

  • Steers, Nicholas J., Columbia University , New York, New York, United States
  • Sheng, Zizhang, Columbia University , New York, New York, United States
  • Wold, Jaclyn L., Columbia University , New York, New York, United States
  • Kodali, Swetha, Columbia University , New York, New York, United States
  • Chatterjee, Debanjana, Columbia University , New York, New York, United States
  • Kil, Byum hee, Columbia University , New York, New York, United States
  • Marasa, Maddalena, Columbia University , New York, New York, United States
  • Appel, Gerald B., Columbia University , New York, New York, United States
  • Bomback, Andrew S., Columbia University , New York, New York, United States
  • Canetta, Pietro A., Columbia University , New York, New York, United States
  • Radhakrishnan, Jai, Columbia University , New York, New York, United States
  • Ahn, Wooin, Columbia University , New York, New York, United States
  • Rao, Maya K., Columbia University , New York, New York, United States
  • Kiryluk, Krzysztof, Columbia University , New York, New York, United States
  • Shapiro, Lawrence, Columbia University , New York, New York, United States
  • Gharavi, Ali G., Columbia University , New York, New York, United States
Background

IgA nephropathy (IgAN) is the most common glomerulonephritis caused by deposition of IgA dominant immune complexes in the glomerulus. The cause of the excess IgA1 production is unclear, and has been attributed to self-proliferation of IgA antibody secreting cells (ASC) or an imbalance in the B-cell-T-cell interactions. T-follicular helper cells (TFH) have been shown to play an essential role in antibody responses.

Methods

We studied 15 IgAN, 10 Lupus Nephritis (LN), 10 Polycystic Kidney Disease (PKD) patients, 20 healthy controls (HC), and 3 pairs of discordant monozygotic twins for IgAN, using flow cytometry and antibody repertoire sequencing.

Results

IgAN patients had a 3.6-fold increase in the IgA ASC, and 1.6-fold increase in the TFH-like cells compared to HC and PKD patients, that correlated with the elevated plasma concentrations of IgA and IgA1. Immunoglobulin sequencing revealed no differences in the usage of heavy chain V, J and kappa genes. However, there was an enhanced usage of the lambda light chain IGLV2-8 gene in IgAN patients (12.9%) compared to HC (7.9%, p<0.01). Autologous co-culture experiments of the TFH-like cells with naïve B-cells demonstrated an elevated IgA production for cells derived from IgAN patients (17.2+6.1 ng/ml) compared to HC, LN and PKD patients (5.8+1.3, 7.7+ 2.9, and 7.0+1.7 ng/ml, respectively). We performed co-culture experiments in cells from IgAN discordant monozygotic twins. Co-culture of cells derived from the IgAN twins yielded significantly higher IgA production compared to the cells from the healthy twins. In addition, TFH-like cells from the IgAN twins significantly increased IgA production in the naïve B-cells from their corresponding healthy twins (14.2+4.3 ng/ml). Whereas, TFH-like cells from the healthy twins only elicited a baseline IgA production from naïve B-cells from their corresponding IgAN twins (6.7+1.1 ng/ml).

Conclusion

Our data demonstrates an essential interaction of naïve B-cells and TFH-like cells in the augmented generation of IgA in IgAN patients, identifying a new pathway for intervention to reduce IgA production.

Funding

  • NIDDK Support