HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Martin, D. A. Articles by Elkon, K. B. Search for Related Content PubMed PubMed Citation Articles by Martin, D. A. Articles by Elkon, K. B.

Autoimmunity Stimulated by Adoptively Transferred Dendritic Cells Is Initiated by Both and T Cells but Does Not Require MyD88 Signaling¹

David A. Martin^2,*, Kang Zhang^*, Justin Kenkel^*, Grant Hughes^*, Edward Clark^,, Anne Davidson and Keith B. Elkon^3,*,

^* Division of Rheumatology, Department of Microbiology, and Department of Immunology, University of Washington School of Medicine, Seattle, WA 98195; and Feinstein Institute for Medical Research, North Shore-Long Island Jewish Health System, Manhasset, NY 11030

Vaccination of nonautoimmune prone mice with syngeneic dendritic cells (DC) readily induces anti-DNA autoantibodies but does not trigger systemic disease. We observed that anti-DNA autoantibody generation absolutely required T cells and that T cells also contributed to the response, but that regulatory T cells restrained autoantibody production. Although both NZB/W F₁ mice and DC vaccinated C57/BL6 mice produced autoantibodies against dsDNA, vaccinated mice had higher levels of Abs against H1 histone and lower levels of antinucleosome Abs than NZB/W F₁ mice. Despite a 100-fold increase in IL-12 and Th1 skewing to a foreign Ag, OVA, synergistic TLR activation of DC in vitro failed to augment anti-DNA Abs or promote class switching beyond that induced by LPS alone. TLR stimulation was not absolutely required for the initial loss of B cell tolerance because anti-DNA levels were similar when wild-type (WT) or MyD88-deficient DC were used for vaccination or WT and MyD88-deficient recipients were vaccinated with WT DC. In contrast, systemic administration of LPS, augmented anti-DNA Ab levels and promoted class switching, and this response was dependent on donor DC signaling via MyD88. LPS also augmented responses in the MyD88-deficient recipients, suggesting that LPS likely exerts its effects on both transferred DC and host B cells in vivo. These results indicate that both the and subsets are necessary for promoting autoantibody production by DC vaccination, and that although TLR/MyD88 signaling is not absolutely required for initiation, this pathway does promote augmentation, and Th1-mediated skewing, of anti-DNA autoantibodies.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work is supported by Grant K08AR052804-02 (to D.A.M.) and Grant AR48796 (to K.B.E.) from National Institute of Arthritis and Musculoskeletal and Skin Diseases. D.A.M. is also the recipient of an Howard Hughes Medical Institute Physician-Scientist Early Career Award.

² Current address: Amgen Inc., Mail Stop AW2-D 3262, 1201 Amgen Court West, Seattle, WA 98119-3105.

³ Address correspondence and reprint requests to Dr. Keith B. Elkon, Division of Rheumatology, University of Washington, 1959 NE Pacific Avenue, Box 356428, Seattle, WA 98195. E-mail address: elkon{at}u.washington.edu

⁴ Abbreviations used in this paper: DC, dendritic cell; NZB, New Zealand Black; NZW, New Zealand White; Treg, regulatory T cell; SLE, systemic lupus erythematosus; WT, wild type.