{"doi":"10.1111/nep.14350","title":"Pathogenesis of <scp>IgA</scp> nephropathy: Omics data inform glycomedicine","abstract":"IgA nephropathy (IgAN) was initially described in 1968 based on evaluation of kidney-biopsy specimens from patients with mild proteinuria and microscopic hematuria, most of whom had experienced recurrent macroscopic hematuria, stained with fluorochrome-conjugated antibodies specific for several human proteins.1 The description “Intercapillary deposits of IgA-IgG” was based on the detection of IgA and IgG in the mesangium. Moreover, complement C3 was also detected, although at that time it was called β1C. This observation thus defined a new entity, IgAN, based on the characteristic glomerular immunodeposits containing IgA, IgG, and C3.2, 3 Follow-up studies revealed that of the two human IgA subclasses, only IgA1 was present in the glomerular immunodeposits.4 IgA1, unlike IgA2, has clustered O-glycans in the heavy-chain hinge region (for review, see References5, 6). Initial studies of circulatory IgA1 from patients with IgAN and healthy controls indicated possible differences of IgA1 O-glycosylation. The analyses evolved from lectin-based techniques to glycomics approaches using chromatographic and spectrometric methods. O-glycans of circulatory IgA1 are core 1 O-glycans, that is, serine/threonine-linked disaccharides consisting of N-acetylgalactosamine (GalNAc) with β1,3-linked galactose (Gal); one or both sugars may be sialylated. Based on lectin assays, gas–liquid chromatography, and mass spectrometry analyses, most patients with IgAN have more circulatory IgA1 with some O-glycans deficient in galactose; that is, galactose-deficient IgA1 (Gd-IgA1).5, 7-11 In 2001, two groups determined that glomerular immunodeposits in IgAN are enriched for Gd-IgA1 glycoforms.12, 13 These and other findings established IgAN as a disease associated with abnormal O-glycosylation, adding another entity to the emerging field of glycomedicine.6 Additional information about the pathogenesis of IgAN came from genomics, namely from genome-wide association studies (GWAS).14, 15 Currently, 30 genetic loci have been associated with the disease.16 The main pathways include biosynthesis of IgA1, cytokine-cytokine receptor signalling, complement, and several other factors in innate and acquired immunity. Other studies established that serum levels of Gd-IgA1 are genetically co-determined17 and that the loci controlling O-glycosylation of IgA1 encode β1,3-galactosyltransferase (C1GalT1)18, 19 and its molecular chaperone (C1GalT1C1).19 Notably, the levels of serum IgA1 are also genetically controlled, as revealed by a recent GWAS that identified 20 genome-wide significant loci.20 Furthermore, Mendelian randomization determined that an elevated serum level of IgA is a causal factor in IgAN.20 Glycomics can contribute to detailed characterization of glycoforms of IgA1 in the circulation and in the glomerular immunodeposits.10, 11, 13, 21-26 Using IgA1-secreting cell lines derived from the peripheral-blood B cells of patients with IgAN and healthy controls as a model system, the production of Gd-IgA1 was associated with dysregulated expression and activity of several specific enzymes, including C1GalT1 and ST6GalNAc2 sialyltransferase, an enzyme that adds sialic acid in a α2,6 linkage to GalNAc.27 Additional effects can be exerted by the O-glycan-initiating enzymes, GalNAc-transferases (GalNAc-Ts). The main presumed GalNAc-T is GalNAc-T2,28 although other GalNAc-Ts can add GalNAc to the IgA1 hinge-region peptides in vitro.29, 30 More recently, GalNAc-T14 was identified as an additional GalNAc-T that may be involved in the production of Gd-IgA1.31 In addition to the regulation of expression of GalNAc-T isoforms in IgA1-producing cells, other factors may affect the glycosylation of clustered O-glycans of IgA1 and impact the follow-up glycosylation and galactose deficiency. Most GalNAc-Ts have, in addition to the catalytic domain, a lectin domain that can bind to the already attached GalNAc residues and affect overall activity and specificity of these enzymes; mo","journal":"Nephrology","year":2024,"id":472017,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":2,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9598,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":42064,"name":"Jan Novák","orcid":"0000-0002-9211-6670","position":0,"is_corresponding":true}],"reference_count":63,"raw_metadata":null,"created_at":"2026-07-19T02:05:53.032464Z","pmid":"39327757","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}