Loss of GalNAc-T14 links O-glycosylation defects to alterations in B cell homing in IgA nephropathy
Sindhuri Prakash, … , Jan Novak, Ali G. Gharavi
Sindhuri Prakash, … , Jan Novak, Ali G. Gharavi
Published March 28, 2025
Citation Information: J Clin Invest. 2025;135(10):e181164. https://doi.org/10.1172/JCI181164.
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Research Article Genetics Nephrology

Loss of GalNAc-T14 links O-glycosylation defects to alterations in B cell homing in IgA nephropathy

Abstract

Aberrant O-glycosylation of the IgA1 hinge region is a characteristic finding in patients with IgA nephropathy (IgAN) and is thought to contribute to immune-complex formation and kidney injury. Other studies have suggested that abnormalities in mucosal immunity and lymphocyte homing are major contributors to disease. We identified a family with IgAN segregating a heterozygous predicted loss-of-function (LOF) variant in GALNT14, the gene encoding N-acetylgalactosaminyltransferase 14, one of the enzymes involved in mucin-type protein O-glycosylation. While GALNT14 is expressed in IgA1-producing cells, carriers of the LOF variant did not have altered levels of poorly glycosylated IgA1, suggesting other disease mechanisms. Investigation of Galnt14-null mice revealed elevated serum IgA levels and ex vivo IgA production by B cells. These 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. Adoptive-transfer experiments indicated impaired homing of spleen-derived Galnt14-deficient B lymphocytes, resulting in increased retention in peripheral blood. These findings suggest that abnormalities in O-glycosylation alter mucosal immunity and B lymphocyte homing, pointing to an expanded role of aberrant O-glycosylation in the pathogenesis of IgAN.

Authors

Sindhuri Prakash, Nicholas J. Steers, Yifu Li, Elena Sanchez-Rodriguez, Miguel Verbitsky, Isabel Robbins, Jenna Simpson, Sharvari Pathak, Milan Raska, Colin Reily, Anna Ng, Judy Liang, Natalia DeMaria, Amanda Katiraei, Kelsey O. Stevens, Clara Fischman, Samantha Shapiro, Swetha Kodali, Jason McCutchan, Heekuk Park, Djamila Eliby, Marco Delsante, Landino Allegri, Enrico Fiaccadori, Monica Bodria, Maddalena Marasa, Elizabeth Raveche, Bruce A. Julian, Anne-Catrin Uhlemann, Krzysztof Kiryluk, Hong Zhang, Vivette D. D’Agati, Simone Sanna-Cherchi, Jan Novak, Ali G. Gharavi

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Figure 3

Elevated IgA concentrations in the mucosal compartments of Galnt14–/– mice.

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Elevated IgA concentrations in the mucosal compartments of Galnt14–/– mi...
(A) Increased IgA in the peritoneal cavity in Galnt14–/– mice (n = 11, 6 male and 5 female) compared to Galnt14+/+ mice (n = 17, 10 male and 7 female) (B) Increased (of IgA bound to bacteria in the small intestine of the Galnt14–/– mice (n = 8, 4 male and 4 female) compared to the Galnt14+/+ mice (n = 15, 9 male and 6 female). (C) no difference in the ‘free’ IgA in the small intestine, (D), increased IgA bound to fecal bacteria in the colons, (E) increased free IgA in the colons the Galnt14–/– mice (n = 11, 6 male and 5 female) compared to the Galnt14+/+ mice (n = 17, 10 male and 7 female). (F) Flow cytometric analysis identifying the fecal bacteria in Galnt14+/+ mice and (G) Galnt14–/– mice, (H) IgA bound to fecal bacteria in Galnt14+/+ mice, and (I) Galnt14–/– mice. (J) Increased percentage of fecal bacteria identified as IgA high/positive in Galnt14–/– mice and (K) in Galnt14–/– mice. Mouse numbers: Galnt14+/+ mice (n = 7, 4 male and 3 female) and Galnt14–/– mice (n = 6, 3 male and 3 female). (L) In ex vivo cultures, splenic lymphocytes from Galnt14–/– mice (n = 8, 4 male and 4 female) secreted significantly more IgA into the supernatant compared with splenic lymphocytes from Galnt14+/+ mice (n = 15, 9 male and 6 female). (M) In ex vivo cultures of peritoneal lymphocytes, no genotype differences in the amounts of IgA secreted into the supernatant; Galnt14–/– mice (n = 8, 4 male and 4 female) and Galnt14+/+ mice (n = 14, 8 male and 6 female). All comparisons are based on unpaired t test. *P < 0.05, **P < 0.01, ***P < 0.005, and ****P < 0.001.