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OP0072 Plasmacytoid Dendritic Cells Activated by Neutrophil Extracellular Traps Contribute to the Pathogenesis of IGG4-Related Disease
  1. Y. Arai1,
  2. K. Yamashita1,
  3. K. Mizugishi1,
  4. A. Takaori-Kondo1
  1. 1Department of Hematology and Oncology, Kyoto University, Kyoto, Japan


Background Plasmacytoid dendritic cells (pDCs) produce type I interferons (IFNs) in response to the presence of viral or bacterial DNA. pDCs play a pivotal role in regulating immune responses by linking the innate and adaptive arms of the immune system. Recent studies on systemic lupus erythematosus have shown that pDCs incorporate neutrophil extracellular traps (NETs) and produce type I IFNs, resulting in B cell proliferation and auto-antibody production. Among the various autoimmune disorders, IgG4-related disease (IgG4-RD) is a newly recognized fibroinflammatory condition characterized by infiltration of IgG4-positive plasma cells into the pancreas, biliary tracts, or salivary glands.

Objectives The pathogenesis of IgG4-RD remains largely unclear, and the innate immune responses leading to adaptive IgG4 antibody responses are poorly understood. We aimed to analyze the contribution of NET-activated pDCs to the pathogenesis of IgG4-RD.

Methods We enrolled patients who had newly diagnosed IgG4-RD complicated with autoimmune pancreatitis. Resected pancreas specimens were obtained and observed using confocal laser microscopy after immunofluorescence staining of CD303 (pDCs), CD138 (plasma cells), IgG4, IFN-α and B cell activating factor (BAFF). Neutrophils, B cells, and pDCs were isolated from the peripheral blood of healthy controls and IgG4-RD patients. Neutrophils were incubated with monosodium urate crystals to induce NET production, and B cells and pDCs were co-cultured in vitro with NETs. After 7-days of incubation, the IgG4, IFN-α, and BAFF levels in the suspension were analyzed using enzyme-linked immunosorbent assays (ELISAs). pDCs were collected during the incubation period and immunofluorescence staining of interferon regulatory factor 7 (IRF7) was performed to examine nuclear translocation.

Results Immunofluorescence staining of the pancreas of IgG4-RD patients confirmed the infiltration of pDCs as well as of IgG4-producing plasma cells into the pancreas. These pDCs were positive for IFN-α and BAFF. The ELISA result for the controls showed secretion of IgG4 (2.31 ± 0.24 ng/mL, mean ± standard error), as well as that of IFN-α and BAFF, and the values significantly decreased in other incubation settings such as absence of NETs or pDCs, or addition of DNase or anti IFN-α antibody (p < 0.01). Immunofluorescence staining of pDCs in vitro showed that nuclear translocation of IRF7 was higher after incubation with NETs than in pDCs incubated without NETs. On substitution of control pDCs with those derived from IgG4-RD patients in the in vitro co-culture assays, significantly higher secretion of IgG4 (41.2 ± 13.1 ng/mL, p = 0.01) as well as of IFN-α and BAFF, along with increased nuclear translocation of IRF7, was seen. No significant differences were seen on substitution of control NETs with those from IgG4-RD patients.

Conclusions pDCs were activated by NETs and produced large amounts of IFN-α and BAFF through IRF7 nuclear translocation, resulting in B cell maturation and IgG4-positive plasma cell induction in healthy controls. This signaling pathway was significantly enhanced in IgG4-RD patients. Abnormal responses of pDCs to NETs may underlie IgG4-RD immunopathogenesis and represent a potential therapeutic target in the near future.

Disclosure of Interest None Declared

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