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Protection of Murine Systemic Lupus by the Ea Transgene without Expression of I-E Heterodimers¹

Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland

A high-level expression of the Ea transgene encoding the MHC class II I-E -chain is very effective in the protection from systemic lupus erythematosus (SLE) in mice. However, it has not been elucidated whether this protection results from the induction or increased expression of I-E heterodimers or from the generation of I-E -chain-derived peptides displaying high affinity for I-A molecules, because previous studies were conducted in lupus-prone mice expressing I-E β-chains. To address this question, we assessed the protective effect of the Ea transgene in lupus-prone BXSB mice bearing the H2^q haplotype (i.e., unable to express I-E heterodimers because of a deficiency in I-E β-chains). We observed that the Ea transgene expression resulted in a marked suppression of the development of SLE in H2^q BXSB mice despite the absence of I-E expression. The observed protection was not associated with any detectable levels of T cell depletion and regulatory T cell expansion. Significantly, transgenic I-E -chains were substantially expressed on the surface of B lymphocytes and dendritic cells, but not of macrophages, without apparent formation of mixed-isotype heterodimers with I-A β-chains. Our results demonstrate for the first time that the Ea transgene is able to prevent the development of SLE without induction of I-E heterodimer expression, indicating a critical role of I-E -chains, but not I-E heterodimers, in the Ea transgene-mediated protection from SLE. Taken together, our data favor a model of autoimmunity prevention based on competition for Ag presentation between I-E -chain-derived peptides and autoantigens.

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 was supported by a grant from the Swiss National Foundation for Scientific Research.

² Address correspondence and reprint requests to Dr. Shozo Izui, Department of Pathology and Immunology, Centre Médicale Universitaire, 1211 Geneva 4, Switzerland. E-mail address: Shozo.Izui{at}medecine.unige.ch

³ Abbreviations used in this paper: SLE, systemic lupus erythematosus; DC, dendritic cell; gp70 IC, gp70-anti-gp70 immune complexes; NZB, New Zealand Black; NZW, New Zealand White; Treg, regulatory T; Yaa, Y-linked autoimmune acceleration.