| Co-Investigator(Kenkyū-buntansha) |
KOJIMA Hidefumi Dokkyo Med U, Sch Med, Dept Immunol, Asst Prof, 医学部, 講師 (40322408)
SAKURAI Daisuke Dokkyo Med U, Sch Med, Dept Immunol, Res Assoc, 医学部, 助手 (30382964)
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| Budget Amount *help |
¥3,100,000 (Direct Cost: ¥3,100,000)
Fiscal Year 2005: ¥1,200,000 (Direct Cost: ¥1,200,000)
Fiscal Year 2004: ¥1,900,000 (Direct Cost: ¥1,900,000)
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| Research Abstract |
BAFF, a member of the TNF superfamily, plays critical roles in B-cell survival, differentiation, and activation. BAFF binds to three receptors : BAFF-R, TACI, and BCMA. While BAFF-R is the primary receptor for B-cell costimulation by BAFF, TACI is thought to serve as a negative regulator of B-cell responses. To determine the role of BAFF in germinal centers and its positive and negative ability for B-cell responses, we developed anti-human BAFF mAb, anti-human BAFF-R mAb, and anti-human TACI mAb.
We found that follicular dendritic cells (FDCs) in human lymph nodes expressed BAFF abundantly. BAFF up-regulated a B-cell specific transcription factor Pax5/BSAP activity and its target CD19, a major component of the B-cell coreceptor complex, and synergistically enhanced CD19 phosphorylation by B-cell antigen receptor (BCR). BAFF further enhanced B-cell proliferation, IgG production and reactivity to CD40 ligand by BCR/CD19 co-ligation and IL-15.
Moreover, BAFF-R and CD40 enhanced B-cell proliferation, IgG class switching, AID expression, their binding to TRAF3, TRAF3/NIK dissociation, NIK phosphorylation, and NF-κB2 activation inside B cells, all of which were cancelled by TACI although TACI enhanced TRAF2/TRAF3 dissociation, TRAF3/NIK and TRAF3/Act1 association, TANK expression, and NF-κB1 activation. Importantly, BAFF-R and CD40 enhanced B-cell responsiveness to TACI-mediated suppression.
Our results suggest that BAFF may play an important role in FDC-B-cell interactions through the B-cell co-receptor complex and a possibly sequential link between the T-cell-independent and -dependent B-cell responses in the germinal centers, and that BAFF may attenuate T-cell-independent and -dependent B-cell responses by TACI by regulating TRAF3 sequestration and NF-κB2 activation.
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