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This Article Full Text (PDF) Data Supplement All Versions of this Article: jimmunol.0900948v1 183/2/1346    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Google Scholar Articles by Chen, Y. Articles by Silverman, G. J. PubMed PubMed Citation Articles by Chen, Y. Articles by Silverman, G. J. Pubmed/NCBI databases GEO DataSet Substance via MeSH Medline Plus Health Information Joint Disorders

Regulation of Dendritic Cells and Macrophages by an Anti-Apoptotic Cell Natural Antibody that Suppresses TLR Responses and Inhibits Inflammatory Arthritis¹

Yifang Chen^*, Sahil Khanna^*, Carl S. Goodyear^2,*, Yong Beom Park^3,*, Eyal Raz^*, Steffen Thiel, Caroline Grönwall^*, Jaya Vas^*, David L. Boyle^*, Maripat Corr^*, Dwight H. Kono and Gregg J. Silverman^4,*

*Laboratory of B Cell Immunobiology, University of California, San Diego, La Jolla, CA 92093; University of Aarhus, Aarhus, Denmark; and Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037

Although natural Abs (NAbs) are present from birth, little is known about what drives their selection and whether they have housekeeping functions. The prototypic T15-NAb, first identified because of its protective role in infection, is representative of a special type of NAb response that specifically recognizes and forms complexes with apoptotic cells and which promotes cell-corpse engulfment by phagocytes. We now show that this T15-NAb IgM-mediated clearance process is dependent on the recruitment of C1q and mannose-binding lectin, which have known immune modulatory activities that also provide "eat me" signals for enhancing phagocytosis. Further investigation revealed that the addition of T15-NAb significantly suppressed in vitro LPS-induced TNF- and IL-6 secretion by the macrophage-like cell line, RAW264.7, as well as TLR3-, TLR4-, TLR7-, and TLR9-induced maturation and secretion of a range of proinflammatory cytokines and chemokines by bone marrow-derived conventional dendritic cells. Significantly, high doses of this B-1 cell produced NAb also suppressed in vivo TLR-induced proinflammatory responses. Although infusions of apoptotic cells also suppressed such in vivo inflammatory responses and this effect was associated with the induction of high levels of IgM antiapoptotic cell Abs, apoptotic cell treatment was not effective at suppressing such TLR responses in B cell-deficient mice. Moreover, infusions of T15-NAb also efficiently inhibited both collagen-induced arthritis and anti-collagen II Ab-mediated arthritis. These studies identify and characterize a previously unknown regulatory circuit by which a NAb product of innate-like B cells aids homeostasis by control of fundamental inflammatory pathways.

⁴Address correspondence and reprint requests to Dr. Gregg J. Silverman, Laboratory of B Cell Immunobiology, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0663. E-mail address: gsilverman{at}ucsd.edu

¹ This work was supported by Grants AI40305, AR47360, AR50659, and AI46637 from the National Institutes of Health, the Alliance for Lupus Research and Within Our Reach grant from Research Education Foundation (to G.J.S.), and an Arthritis Foundation fellowship (to S.K.) and Innovative Research Grant (G.J.S.).

² Current address: Glasgow Biomedical Research Centre, University of Glasgow, Glasgow, United Kingdom.

³ Current address: Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea.