Session Information
Title: B cell Biology and Targets in Autoimmune Disease: Systemic Lupus Erythematosus and Related Diseases
Session Type: Abstract Submissions (ACR)
Background/Purpose The advent of B-cell depletion therapy in autoimmune diseases identifies a novel B cell population, referred to as regulatory B cells (Bregs), that exerts regulatory functions via IL-10 production. We previously showed that human Bregs are strongly induced in IgM-memory B cell subsets following TLR9 stimulation and Breg induction is significantly impaired in systemic lupus erythematosus (SLE). The underlying mechanisms of these findings, however, remain largely elusive. In the present study we have sought to elucidate how Bregs are induced and their function is crippled in SLE patients.
Methods Gene expression and protein production in B cells were assessed by quantitative PCR, ELISA and flow cytometry analysis. Bregs were co-cultured with T cells, and proliferation and IFNγ production of T cells were assessed. The knock-down vector of Blimp-1 was generated and transfected into B cells.
Results We first tested the function of Bregs in healthy controls and SLE patients. TLR9-induced Bregs from healthy controls inhibited proliferation and IFN γ production of T cells, while such Bregs from SLE patients exerted less regulatory effects on the function of T cells. A previous study in the mouse system suggested that Breg induction is associated with plasma cell differentiation of B cells. In light of a critical role of Blimp-1 in plasma cell differentiation, we generated Blimp-1 knocked down B cells and found that Breg induction is impaired by Blimp-1 silencing. Intriguingly, fleshly-isolated B cells from SLE patients exhibited higher basal levels of Blimp-1 and IL-10 expression, while further induction of Blimp-1 by TLR9 stimulation was significantly abrogated along with less IL-10 production, highlighting the induction of Blimp-1, but not its levels, in Breg induction.
Conclusion Together, these findings provide not only a better understanding of molecular mechanisms of Breg induction in humans, but also a novel clue to revitalizing Bregs for the treatment of SLE.
Disclosure:
S. I. Ota,
None;
H. Niiro,
None;
N. Ueki,
None;
Y. Hirosaki,
None;
H. Tsuzuki,
None;
K. Noda,
None;
S. Jabbarzadeh-Tabrizi,
None;
A. Tanaka,
None;
H. Mitoma,
None;
M. Akahoshi,
None;
Y. Arinobu,
None;
H. Tsukamoto,
None;
K. Akashi,
None.
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