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 Request Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Okamoto, A. Articles by Yamamoto, K. Search for Related Content PubMed PubMed Citation Articles by Okamoto, A. Articles by Yamamoto, K. Pubmed/NCBI databases Medline Plus Health Information Lupus

Splenic Phagocytes Promote Responses to Nucleosomes in (NZB x NZW) F₁ Mice¹

Akiko Okamoto^*, Keishi Fujio^2,*, Nico van Rooijen, Nelson H. Tsuno, Koki Takahashi, Hiromichi Tsurui, Sachiko Hirose, Keith B. Elkon^¶ and Kazuhiko Yamamoto^*

^* Department of Allergy and Rheumatology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan; Department of Molecular Cell Biology, Faculty of Medicine, Free University, Amsterdam, The Netherlands; Department of Transfusion Medicine, Graduate School of Medicine, University of Tokyo, Tokyo, Japan; Department of Pathology, Juntendo University School of Medicine, Tokyo, Japan; and ^¶ Division of Rheumatology, University of Washington, Seattle, WA 98125

Autoantigen presentation to T cells is crucial for the development of autoimmune disease. However, the mechanisms of autoantigen presentation are poorly understood. In this study, we show that splenic phagocytes play an important role in autoantigen presentation in murine lupus. Nucleosomes are major autoantigens in systemic lupus erythematosus. We found that nucleosome-specific T cells were stimulated dominantly in the spleen, compared with lymph nodes, lung, and thymus. Among splenic APCs, F4/80⁺ macrophages and CD11b⁺CD11c⁺ dendritic cells were strong stimulators for nucleosome-specific T cells. When splenic phagocytes were depleted in (NZB x NZW) F₁ (NZB/W F₁) mice, nucleosome presentation in the spleen was dramatically suppressed. Moreover, depletion of splenic phagocytes significantly suppressed anti-nucleosome Ab and anti-dsDNA Ab production. Proteinuria progression was delayed and survival was prolonged in phagocyte-depleted mice. The numbers of autoantibody- secreting cells were decreased in the spleen from phagocyte-depleted mice. Multiple injections of splenic F4/80⁺ macrophages, not those of splenic CD11c⁺ dendritic cells, induced autoantibody production and proteinuria progression in NZB/W F₁ mice. These results indicate that autoantigen presentation by splenic phagocytes including macrophages significantly contributes to autoantibody production and disease progression in lupus-prone mice.

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 study was supported by Program and Project Grant funding from Japan Society for the Promotion of Science; Ministry of Health, Labour and Welfare; and Ministry of Education, Culture, Sports, Science and Technology. Keith B. Elkon is supported by Grant RO1 AR48796 from the National Institutes of Health (NIAMS).

² Address correspondence and reprint requests to Dr. Keishi Fujio, Department of Allergy and Rheumatology, Graduate School of Medicine, University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan. E-mail address: kfujio-tky{at}umin.ac.jp

³ Abbreviations used in this paper: SLE, systemic lupus erythematosus; DC, dendritic cell; BM, bone marrow; LN, lymph node; PC, plasma cell; Cl₂MDP, dichloromethylene diphosphonate.