Regulation of selective class switching provides long-term therapeutic benefits for hay fever
Naoki Morita, Kohta Yamamoto, Ryutaro Tamano, Peng Gao, Takahiro Nagatake, Takenori Inomata, Tianxiang Huang, Yasuhiro Yamada, Takahiro Adachi, Manabu Sugai, Keiichi I. Nakayama, Hirotatsu Kojima, Reiko Shinkura
Naoki Morita, Kohta Yamamoto, Ryutaro Tamano, Peng Gao, Takahiro Nagatake, Takenori Inomata, Tianxiang Huang, Yasuhiro Yamada, Takahiro Adachi, Manabu Sugai, Keiichi I. Nakayama, Hirotatsu Kojima, Reiko Shinkura
View: Text | PDF
Research Article Immunology Inflammation

Regulation of selective class switching provides long-term therapeutic benefits for hay fever

Abstract

IgA protects the body from invaders in the mucosal sites, but its role in allergic diseases, such as hay fever, is poorly understood. We demonstrate an increased susceptibility to cedar-pollen-induced hay fever associated with increasing pollen penetration into the body in IgA-deficient mice, indicating that IgA prevents pollen invasion in the mucosa. We identified bryostatin 1, an anticarcinogenic protein kinase Cδ (PKCδ) activator, as an IgA/IgE class-switching regulator in B cells. Bryostatin 1 enhanced IgA production through induction of germline transcript α (GLTα) via the PKCδ/MEK/ERK/RUNX1 pathway and suppressed IgE by reducing GLTε through the PKCδ/STAT5/ID2 pathway. Production of Th2 cytokines and eosinophil infiltration in the lungs was also reduced. Furthermore, hay fever alleviation by bryostatin 1 demonstrated diminished symptoms in mice in vivo 3 months subsequent to intranasal administration.

Authors

Naoki Morita, Kohta Yamamoto, Ryutaro Tamano, Peng Gao, Takahiro Nagatake, Takenori Inomata, Tianxiang Huang, Yasuhiro Yamada, Takahiro Adachi, Manabu Sugai, Keiichi I. Nakayama, Hirotatsu Kojima, Reiko Shinkura

×

Figure 2

Bryostatin 1 enhances IgA class switching and suppresses IgE class switching through PKCδ activation.

Options: View larger image (or click on image) Download as PowerPoint
Bryostatin 1 enhances IgA class switching and suppresses IgE class switc...
(A) Production of IgA and IgE in the supernatant of cultured WT B cells with indicated stimulation (left: structure of bryostatin 1). (B and C) Flow cytometry of IgA+ B cells. (B) Representative plots of cultured naive B cells with or without bryostatin 1 under stimulation with LPS and cytokines. (C) Frequency of IgA+B220+ cells (n = 4). (D) Expression of GLTα in cultured mouse B cells (n = 4). (E) Expression of GLTα1 and GLTα2 in cultured human B cells (n = 5). (F) Expression of GLTε in cultured mouse B cells measured (n = 4). (G) Expression of GLTε in cultured human B cells determined (n = 5). (H and I) Flow cytometry of IgA+ B cells. (H) Representative plots of cultured naive B cells with or without bryostatin 1 in WT and Prckd–/– B cells under IgA class-switching-inducible condition. (I) Frequency of IgA+B220+ cells (n = 6). (J) Expression of GLTα in cultured mouse WT and Prckd–/– B cells (n = 6). (K) Expression of GLTε in cultured mouse WT (n = 7) and Prckd–/– (n = 6) B cells. Statistical analysis was performed by unpaired, 2-tailed Student’s t test (A, C–G, and I–K). Data are expressed as mean ± SD in A, C–G, and I–K.