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Article: Local BAFF gene silencing suppresses Th17-cell generation and ameliorates autoimmune arthritis

TitleLocal BAFF gene silencing suppresses Th17-cell generation and ameliorates autoimmune arthritis
Authors
Issue Date2008
PublisherNational Academy of Sciences. The Journal's web site is located at http://www.pnas.org
Citation
Proceedings Of The National Academy Of Sciences Of The United States Of America, 2008, v. 105 n. 39, p. 14993-14998 How to Cite?
AbstractRheumatoid arthritis (RA) is a chronic disease characterized by synovial inflammation and joint damage. Although both T cells and B cells mediate the disease pathogenesis, proinflammatory cytokines are critically involved. The TNF superfamily member B cell-activating factor (BAFF) plays an important role in humoral immunity and in autoimmune diseases, including RA. Here, we show that intra-articular injection of lentivirus expressing shRNA for BAFF gene silencing provides long-term suppression of arthritic development in a collagen-induced arthritis model. Local BAFF gene targeting inhibited proinflammatory cytokine expression, suppressed generation of plasma cells and Th17 cells, and markedly ameliorated joint pathology. Lentivirus targets dendritic cells in the joint tissue and BAFF gene silencing inhibits dendritic cell maturation and their function in driving Th17-cell differentiation in vitro. Moreover, we revealed a previously unrecognized role for BAFF in promoting the expansion of Th17 cells and demonstrated IL-17 as a crucial effector cytokine for BAFF-mediated proinflammatory effects during collagen-induced arthritis development. Taken together, these findings identify BAFF as a valuable gene-silencing target potentially for the effective treatment of RA. © 2008 by The National Academy of Sciences of the USA.
Persistent Identifierhttp://hdl.handle.net/10722/59380
ISSN
2015 Impact Factor: 9.423
2015 SCImago Journal Rankings: 6.883
ISI Accession Number ID
Funding AgencyGrant Number
Iwakura (University of Tokyo)
Hong Kong Innovation and Technology CommissionITS/073/06
Research Grant Council of Hong KongHKU7608/06M
Funding Information:

We thank Sarah Chan, Cherry Lo, and Eric Poon for technical assistance and Dr. Keung Leung for CT scan analysis. We are grateful to Dr. Yoichiro Iwakura (University of Tokyo) for providing IL-17-/- mice. This work was supported by grants from Hong Kong Innovation and Technology Commission Grant ITS/073/06 (to L. L.) and the Research Grant Council of Hong Kong Grant HKU7608/06M (to L.).

References
Grants

 

DC FieldValueLanguage
dc.contributor.authorLam, QLKen_HK
dc.contributor.authorKo, OKHen_HK
dc.contributor.authorZheng, BJen_HK
dc.contributor.authorLu, Len_HK
dc.date.accessioned2010-05-31T03:48:54Z-
dc.date.available2010-05-31T03:48:54Z-
dc.date.issued2008en_HK
dc.identifier.citationProceedings Of The National Academy Of Sciences Of The United States Of America, 2008, v. 105 n. 39, p. 14993-14998en_HK
dc.identifier.issn0027-8424en_HK
dc.identifier.urihttp://hdl.handle.net/10722/59380-
dc.description.abstractRheumatoid arthritis (RA) is a chronic disease characterized by synovial inflammation and joint damage. Although both T cells and B cells mediate the disease pathogenesis, proinflammatory cytokines are critically involved. The TNF superfamily member B cell-activating factor (BAFF) plays an important role in humoral immunity and in autoimmune diseases, including RA. Here, we show that intra-articular injection of lentivirus expressing shRNA for BAFF gene silencing provides long-term suppression of arthritic development in a collagen-induced arthritis model. Local BAFF gene targeting inhibited proinflammatory cytokine expression, suppressed generation of plasma cells and Th17 cells, and markedly ameliorated joint pathology. Lentivirus targets dendritic cells in the joint tissue and BAFF gene silencing inhibits dendritic cell maturation and their function in driving Th17-cell differentiation in vitro. Moreover, we revealed a previously unrecognized role for BAFF in promoting the expansion of Th17 cells and demonstrated IL-17 as a crucial effector cytokine for BAFF-mediated proinflammatory effects during collagen-induced arthritis development. Taken together, these findings identify BAFF as a valuable gene-silencing target potentially for the effective treatment of RA. © 2008 by The National Academy of Sciences of the USA.en_HK
dc.languageengen_HK
dc.publisherNational Academy of Sciences. The Journal's web site is located at http://www.pnas.orgen_HK
dc.relation.ispartofProceedings of the National Academy of Sciences of the United States of Americaen_HK
dc.subject.meshAnimalsen_HK
dc.subject.meshArthritis, Experimental - immunology - therapyen_HK
dc.subject.meshArthritis, Rheumatoid - immunology - therapyen_HK
dc.subject.meshAutoimmune Diseases - immunology - therapyen_HK
dc.subject.meshB-Cell Activating Factor - geneticsen_HK
dc.subject.meshCell Lineen_HK
dc.subject.meshGene Silencingen_HK
dc.subject.meshGene Therapyen_HK
dc.subject.meshHumansen_HK
dc.subject.meshImmunosuppressionen_HK
dc.subject.meshInterleukin-17 - immunologyen_HK
dc.subject.meshLentivirusen_HK
dc.subject.meshMiceen_HK
dc.subject.meshMice, Inbred C57BLen_HK
dc.subject.meshRNA, Small Interfering - geneticsen_HK
dc.subject.meshT-Lymphocytes, Helper-Inducer - immunologyen_HK
dc.titleLocal BAFF gene silencing suppresses Th17-cell generation and ameliorates autoimmune arthritisen_HK
dc.typeArticleen_HK
dc.identifier.emailLam, QLK:qlam@pathology.hku.hken_HK
dc.identifier.emailZheng, BJ:bzheng@hkucc.hku.hken_HK
dc.identifier.emailLu, L:liweilu@hkucc.hku.hken_HK
dc.identifier.authorityLam, QLK=rp00312en_HK
dc.identifier.authorityZheng, BJ=rp00353en_HK
dc.identifier.authorityLu, L=rp00477en_HK
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1073/pnas.0806044105en_HK
dc.identifier.pmid18820032-
dc.identifier.scopuseid_2-s2.0-54449087291en_HK
dc.identifier.hkuros156468en_HK
dc.identifier.hkuros152671-
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-54449087291&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume105en_HK
dc.identifier.issue39en_HK
dc.identifier.spage14993en_HK
dc.identifier.epage14998en_HK
dc.identifier.eissn1091-6490-
dc.identifier.isiWOS:000261914300031-
dc.publisher.placeUnited Statesen_HK
dc.identifier.f10001123380-
dc.relation.projectInnovative development of a gene-targeted therapy for rheumatoid arthritis-
dc.identifier.scopusauthoridLam, QLK=8722491000en_HK
dc.identifier.scopusauthoridKo, OKH=8119962000en_HK
dc.identifier.scopusauthoridZheng, BJ=7201780588en_HK
dc.identifier.scopusauthoridLu, L=7403963552en_HK

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