{
  "abstract": "Rationale & Objective: Immunoglobulin A nephropathy (IgAN) is characterized by mesangial deposition of immune complexes containing galactose-deficient IgA1 (Gd-IgA1), predominantly with {lambda} light chains and Gd-IgA1 glycans-recognizing antibodies. Disease exacerbations are frequently linked to mucosal infections, underscoring the role of dysregulated mucosal immunity. Whereas current therapeutic strategies targeting Gd-IgA1-producing cells are largely evaluated based on clinical endpoints, a critical gap remains in understanding how these therapies influence Gd-IgA production and whether targeting mucosal immunity represents an effective therapeutic strategy. Here, we provide a mechanistic insight into Gd-IgA1+ B cell behavior within inflammatory mucosal-like microenvironment. Study Design: Case-control study with ex vivo functional analysis. Setting & Participants: Peripheral blood mononuclear cells from patients with biopsy-proven IgAN and healthy controls. Exposure(s): Stimulation with a cytokine combination mimicking mucosal immune activation (IL-6, IL-21, BAFF, APRIL). Outcome(s): Differentiation of B cell subsets involved in IgAN and production of IgA, Gd-IgA1, and IgG. Analytical Approach: Flow cytometry, ELISA, cytometric bead array, and Western blotting. Results: Mucosal cytokine stimulation induced robust differentiation of B cells into CD38high plasmablasts and CD138high plasma cells, with a disproportionate expansion of Gd-IgA1 populations in IgAN. Compared with controls, PBMCs from IgAN patients demonstrated markedly increased production of Gd-IgA1, predominantly in polymeric form and strongly enriched for {lambda} light chains (~90% vs ~51%). This response was accompanied by selective expansion of Gd-IgA1{lambda} plasma cells, identifying a disease-specific, highly responsive B cell compartment. Limitations: The cytokine combination was selected to reflect key signals present in mucosal immune environments, although in vivo conditions are more complex. Conclusions: Mucosal cytokine signals directly amplify pathogenic B cell responses in IgAN, driving production of polymeric, {lambda}-enriched Gd-IgA1. These findings provide mechanistic validation for therapies targeting the mucosal-systemic axis and offer a biologic explanation for the clinical efficacy of gut-directed corticosteroids and BAFF/APRIL inhibition.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Immunology, Faculty of Medicine and Dentistry, Palacky University Olomouc, Olomouc, Czech Republic"
  ],
  "article_type": "New results",
  "arxiv": null,
  "author_total": 11,
  "authors": [
    {
      "name": "K. Zachova"
    },
    {
      "name": "A. Cutkova"
    },
    {
      "name": "P. Kosztyu"
    },
    {
      "name": "Y. Ohyama"
    },
    {
      "name": "K. Takahashi"
    },
    {
      "name": "J. Zadrazil"
    },
    {
      "name": "J. Orsag"
    },
    {
      "name": "N. Petejova"
    },
    {
      "name": "D. Galuszkova"
    },
    {
      "name": "J. Mestecky"
    },
    {
      "affs": [
        0
      ],
      "name": "M. Raska"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/783e2q0ntw7v0.bib",
  "cited_by": 0,
  "doi": "10.64898/2026.10.19.759132",
  "fulltext_url": "https://www.biorxiv.org/content/10.64898/2026.10.19.759132v1.full",
  "id": "783e2q0ntw7v0",
  "issns": [],
  "landing_url": "https://www.biorxiv.org/content/10.64898/2026.10.19.759132v1",
  "language": null,
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "biorxiv",
      "immunology"
    ],
    [
      "openalex",
      "2727|Renal Diseases and Glomerulopathies"
    ]
  ],
  "openalex": "W7221121220",
  "pdf_url": "https://www.biorxiv.org/content/10.64898/2026.10.19.759132v1.full.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-10-19",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/783e2q0ntw7v0.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:29:28Z",
      "native_id": "10.64898/2026.10.19.759132",
      "source": "biorxiv",
      "url": "https://www.biorxiv.org/content/10.64898/2026.10.19.759132v1"
    }
  ],
  "subjects": [
    {
      "field": "biology",
      "origin": "biorxiv:immunology",
      "subfield": "immunology"
    }
  ],
  "title": "Mucosal Inflammation as a Driver of Gd-IgA1 Production in IgA Nephropathy: Mechanistic Support for Targeted Therapies",
  "title_text": "Mucosal Inflammation as a Driver of Gd-IgA1 Production in IgA Nephropathy: Mechanistic Support for Targeted Therapies",
  "type": "preprint",
  "updated_at": "2026-10-30T12:29:28Z",
  "url": "https://research.draconitic.com/paper/783e2q0ntw7v0",
  "venue": "bioRxiv",
  "versions": []
}