Loss of GalNAc-T14 links O-glycosylation defects to alterations in B cell homing in IgA nephropathy
Status Publisher Jazyk angličtina Země Spojené státy americké Médium print-electronic
Typ dokumentu časopisecké články
PubMed
40153534
DOI
10.1172/jci181164
PII: 181164
Knihovny.cz E-zdroje
- Klíčová slova
- Genetic diseases, Genetics, Glycobiology, Immunoglobulins, Nephrology,
- Publikační typ
- časopisecké články MeSH
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.
Department of Immunology University of Alabama at Birmingham Birmingham Czech Republic
Department of Microbiology University of Alabama at Birmingham Birmingham United States of America
Departments of Medicine and Surgery University of Parma Parma Italy
Division of Infectious Diseases Columbia University New York United States of America
Division of Nephrology Columbia University New York United States of America
Division of Nephrology University of Alabama at Birmingham Birmingham United States of America
Division of Renal Pathology Columbia University New York United States of America
The Renal Division Peking University 1st Hospital Beijing China
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