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Abstract: SA-PO638

LIF/JAK2/STAT1 Signaling Enhances Production of Galactose-Deficient IgA1 by IgA1-Producing Cell Lines Derived From Tonsils of Patients With IgA Nephropathy

Session Information

Category: Glomerular Diseases

  • 1302 Glomerular Diseases: Immunology and Inflammation

Authors

  • Yamada, Koshi, Juntendo University Faculty of Medicine, Tokyo, Japan
  • Huang, Zhi qiang, University of Alabama at Birmingham, Birmingham, Alabama, United States
  • Reily, Colin, University of Alabama at Birmingham, Birmingham, Alabama, United States
  • Suzuki, Hitoshi, Juntendo University Faculty of Medicine, Tokyo, Japan
  • Novak, Jan, University of Alabama at Birmingham, Birmingham, Alabama, United States
  • Suzuki, Yusuke, Juntendo University Faculty of Medicine, Tokyo, Japan
Background

Galactose-deficient IgA1 (Gd-IgA1) have a key role in the pathogenesis of IgA nephropathy (IgAN). Tonsillectomy is one of the effective treatments and is prospective to reduce serum levels of Gd-IgA1. Thus, abnormal responses of the tonsil-residing B cells in pro-inflammatory condition may be involved in synthesis of Gd-IgA1. However, the mechanisms of production of Gd-IgA1 in tonsils remain unknown. In this study, we used IgA1-producing cell lines derived from tonsils of patients with IgAN and assessed the effects of cytokines, Leukemia inhibitory factor (LIF) and Oncostatin M (OSM), encoded in the Chr.22q12 IgAN-risk locus, on cellular signaling and production of Gd-IgA1.

Methods

IgA1-producing cell lines were derived from palatine tonsils of patients with IgAN and patients with chronic tonsillitis (CT) after EBV immortalization. Tonsillar-tissue sections were stained with antibodies specific for components of JAK-STAT pathway. Gd-IgA1 production was measured by lectin ELISA, JAK-STAT signaling in cultured cells was assessed by immunoblotting of cell lysates and validated by using siRNA gene-specific knock-down and small-molecule inhibitors.

Results

Staining for JAK2 was observed in the crypt epithelium and germinal center (GC) of palatine tonsils from both IgAN and CT groups. Staining for phospho-STAT1 was enhanced in GC regions of palatine tonsils from IgAN patients compared to CT groups. IgA1-producing cells derived from tonsils of patients with IgAN, compared to those of CT, exhibited enhanced STAT1 phosphorylation and elevated Gd-IgA1 production in response to LIF, but not OSM. JAK2 inhibitor and STAT1 siRNA knock-down blocked these LIF-induced effects.

Conclusion

In summary, palatine-tonsil-derived IgA1-producing cells exhibit dysregulation of LIF-mediated signaling resulted in Gd-IgA1 overproduction. These findings indicate that LIF-mediated abnormal mucosal immune responses may be involved in the overproduction of the main autoantigen in IgAN, Gd-IgA1.

Funding

  • NIDDK Support