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.
Loss of GalNAc-T14 links O-glycosylation defects to alterations in B cell homing in IgA nephropathy / Prakash, S.; Steers, N. J.; Li, Y.; Sanchez-Rodriguez, E.; Verbitsky, M.; Robbins, I.; Simpson, J.; Pathak, S.; Raska, M.; Reily, C.; Ng, A.; Liang, J.; Demaria, N.; Katiraei, A.; Stevens, K. O.; Fischman, C.; Shapiro, S.; Kodali, S.; Mccutchan, J.; Park, H.; Eliby, D.; Delsante, M.; Allegri, L.; Fiaccadori, E.; Bodria, M.; Marasa, M.; Raveche, E.; Julian, B. A.; Uhlemann, A. -C.; Kiryluk, K.; Zhang, H.; D'Agati, V. D.; Sanna-Cherchi, S.; Novak, J.; Gharavi, A. G.. - In: THE JOURNAL OF CLINICAL INVESTIGATION. - ISSN 0021-9738. - 135:10(2025), pp. e181164.1-e181164.15. [10.1172/JCI181164]
Loss of GalNAc-T14 links O-glycosylation defects to alterations in B cell homing in IgA nephropathy
Delsante M.;Allegri L.;Fiaccadori E.;Bodria M.;
2025-01-01
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.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
