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Klaus J. Erb^*, Beate Rüger^*, Maja von Brevern, Bernhard Ryffel, Annelise Schimpl, and Karen Rivett^*

From ^* The Malaghan Institute of Medical Research and the Department of Medicine, Wellington School of Medicine, Wellington South, New Zealand; Institut für Virologie und Immunbiologie der Universität Würzburg, D-97070 Würzburg, Germany; and Swiss Institute of Technology, Institute of Toxicology, CH-8603 Schwerzenbach, Switzerland

The transgenic (tg) expression of interleukin (IL)-4 under the control of a major histocompatibility complex (MHC) class I promoter leads to B cell hyperactivity in mice, characterized by increased B cell surface MHC class II and CD23 expression, elevated responsiveness of the B cells to polyclonal ex vivo stimulation, and increased immunoglobulin (Ig)G1 and IgE serum levels. Tg mice develop anemia, glomerulonephritis with complement and immune deposition in the glomeruli, and show increased production of autoantibodies. Treatment of IL-4 tg mice with anti-IL-4 neutralizing antibodies protected the mice from disease development, showing that IL-4 was responsible for the observed disorders. Deletion of superantigen responsive autoreactive T cells in the IL-4 tg mice was normal and treatment of mutant mice with deleting anti-CD4 antibodies failed to ablate the onset of autoimmune-like disease, suggesting that CD4⁺T cells were not the primary cause of the disorders. Furthermore, the deletion of B cells reacting against MHC class I molecules was also normal in the IL-4 tg mice. Therefore the most likely explanation for the increased production of autoantibodies and the autoimmunelike disorders is that IL-4 acts directly on autoreactive B cells by expanding them in a polyclonal manner. Taken together our results show that inappropriate multi-organ expression of IL-4 in vivo leads to autoimmune-type disease in mice.

The authors wish to thank Dr. G. LeGros, Dr. F. Ronchese, and Dr. Paige Lacy (Malaghan Institute of Medical Research, Wellington, New Zealand) for providing reagents and their critical discussions.

This work was supported by the Deutsche Forschungsgemeinschaft (SFB 165), the Bundesministerium für Forschung und Technologie (AIDS-Scholarship), Germany, and Fonds der Chemischen Industrie.

¹ Abbreviations used in this paper: AIHA, autoantibody-induced hemolytic anemia; ANA, anti-nuclear antigen; ASMA, anti-smooth muscle antigen; ENA, endonuclear antigen; MMTV, murine mammary tumor viruses; SLE, systemic lupus erythematosus; tg, transgenic.

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