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Abstract: SA-PO825

Analysis of Galnt14-Null Mice Links O-Glycosylation Defects to Elevated Circulating IgA Levels and Altered IgA+ B Cell Tissue Distribution

Session Information

Category: Glomerular Diseases

  • 1401 Glomerular Diseases: From Inflammation to Fibrosis

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
  • 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. It is not known if aberrant O-glycosylation can impact IgA homeostasis, such as B-cell residence, homing, and migration. At least 17 distinct N-acetylgalactosaminyltransferases (GalNAc-T1-17) can initiate O-glycosylation of proteins.

Methods

We studied the circulating IgA, and the mucosal and non-mucosal tissue resident IgA+ B-cells in Galnt14-/- and WT mice using ELISA and flow cytometry.

Results

GALNT14 is expressed in human and murine lymphoid tissue, specifically within germinal centers which is the major site for B-cell maturation, antibody class switching and proliferation. Serum IgA levels were significantly elevated in the Galnt14-/- mice compared to the WT mice (1.31+0.4 mg/ml and 0.75+0.1 mg/ml, respectively, P < 0.01). IgA+ B-cells in mucosal and non-mucosal tissues were examined to determine if there was an abnormal distribution of IgA+ B-cells. An increase in the percentage of IgA+ B-cells was observed in non-mucosal tissues of Galnt14-/- mice compared to WT mice (PMBC: 3.9+0.7% and 2.6+0.4%, respectively, P < 0.01; spleen: 4.2+0.9% and 3.0+0.7%, respectively, P < 0.01; and peritoneal cavity: 6.1+2.3% and 3.8+0.9%, respectively, P < 0.01). In addition, 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). No differences in the percentage of IgA+ B-cells was observed in non-mucosal lymph nodes. 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). Finally, reciprocal adoptive transfer experiments demonstrated that splenic derived B-cells isolated from Galnt14-/- mice have a reduced ability to home to the spleen, regardless of the recipient genotype.

Conclusion

Galnt14-/- mice have an altered distribution of IgA+ B-cells in mucosal and non-mucosal tissues, partially explaining the elevated levels of circulating IgA. We are currently exploring the mechanisms of the alterations observed in IgA+ B-cell recruitment and residence in mucosal and lymphoid tissues of Galnt14-/- mice.

Funding

  • NIDDK Support