Abstract: FR-PO820
Loss of GalNAc-T14 Links O-glycosylation Defects to Alterations in B Cell Homing in IgA Nephropathy
Session Information
- Glomerular Diseases: Inflammation and Immunology
October 25, 2024 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Glomerular Diseases
- 1401 Glomerular Diseases: Mechanisms, including Podocyte Biology
Authors
- Steers, Nicholas J., Columbia University Irving Medical Center, New York, New York, United States
- Prakash-Polet, Sindhuri, Columbia University Irving Medical Center, New York, New York, United States
- Robbins, Isabel, Columbia University Irving Medical Center, New York, New York, United States
- Simpson, Jenna, Columbia University Irving Medical Center, New York, New York, United States
- Pathak, Sharvari, Columbia University Irving Medical Center, New York, New York, United States
- Stevens, Kelsey O., Columbia University Irving Medical Center, New York, New York, United States
- Sanna-Cherchi, Simone, Columbia University Irving Medical Center, New York, New York, United States
- D'Agati, Vivette D., Columbia University Irving Medical Center, New York, New York, United States
- Novak, Jan, University of Alabama at Birmingham, Birmingham, Alabama, United States
- Gharavi, Ali G., Columbia University Irving Medical Center, New York, New York, United States
Background
Defects in O-glycosylation of IgA1 are a characteristic finding in IgA nephropathy (IgAN). It is not known if aberrant O-glycosylation can impact IgA homeostasis, such as B-cell residence, homing, and migration. Up to 20 different N-acetylgalactosaminyltransferases (GalNAc-Ts) can initiate O-glycosylation of proteins in humans.
Methods
We studied the circulating IgA, and the mucosal and non-mucosal tissue resident B-cells in Galnt14-/- and WT mice using ELISA and flow cytometry.
Results
GALNT14 is expressed in human and murine lymphoid tissues, specifically within germinal centers, the major site for B-cell maturation, antibody class switching, and proliferation. We have identified a heterozygous predicted loss-of-function (LOF) variant in GALNT14 in a family with IgAN. Galnt14-null mice had elevated serum IgA levels compared to WT mice (0.88+0.2 mg/ml and 0.37+0.1 mg/ml, respectively, P<0.01), and the Galnt14-null mice developed glomerular IgA deposition with aging and after induction of sterile colitis. Galnt14-null mice also displayed an attenuated mucin layer in the colon and redistribution of IgA-producing cells from mucosal to systemic sites. A significant decrease in the percentage of IgA+ B-cells was observed in the Peyer’s patches of Galnt14-/- mice compared to WT mice (20.2+3.7% and 24.4+3.8%, respectively, P<0.01), and an increase in the percentage of IgA+ B-cells was observed in non-mucosal tissues of Galnt14-/- mice compared to WT mice (spleen: 4.2+0.9% and 3.0+0.7%, respectively, P<0.01; PMBC: 3.9+0.7% and 2.6+0.4%, respectively, P < 0.01). The increased IgA in the circulation in Galnt14-/- mice correlated with the increased IgA+ B-cells in the circulation (P<0.01) and the reduced IgA+ B-cells in the Peyer’s patches (P<0.01). Analysis of the germinal center B-cells in Galnt14-/- mice demonstrated a reduction on the O-glycosylation of cell-surface molecules. Finally, adoptive-transfer experiments indicated impaired homing of spleen-derived Galnt14-deficient B-cells, resulting in increased retention in peripheral blood.
Conclusion
These findings suggest that abnormalities in O-glycosylation alter mucosal immunity and B-cell homing, pointing to an expanded role of aberrant O-glycosylation in the pathogenesis of IgAN.
Funding
- NIDDK Support