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p300 Protein Acetyltransferase Activity Suppresses Systemic Lupus Erythematosus-Like Autoimmune Disease in Mice¹

Nicole Forster^*, Sven Gallinat^*, Jadwiga Jablonska, Siegfried Weiss, Hans-Peter Elsässer and Werner Lutz^2,*

^* Institute of Molecular Biology and Tumor Research, University of Marburg, Marburg, Germany; Helmholtz Centre for Infection Research, Molecular Immunology, Braunschweig, Germany; and Institute of Cytobiology and Cytopathology, University of Marburg, Marburg, Germany

Conditional knock-in mice expressing a histone acetyltransferase-deficient version of the transcriptional coregulator p300 exclusively in B lymphocytes die prematurely with full penetrance. The mice develop an autoimmune disease similar to systemic lupus erythematosus in its pathological manifestations, such as splenomegaly, glomerulonephritis, vasculitis, deposition of immune complexes, and production of autoantibodies against dsDNA. Aged mice show a severe reduction of transitional and marginal zone B cells and generate aberrant mature B cells. These B cells show diminished proliferation in response to stimulation of the BCR, but respond normally to other stimuli. Yet, the mice mount a normal primary immune response against a T-dependent Ag. In contrast, the memory response is impaired. In addition, serum Ig levels, in particular IgG2b, are increased. We conclude that p300 acetyltransferase activity is essential for maintaining self-tolerance of B lymphocytes. These findings support the concept of treating lupus with inhibitors of protein deacetylases and point to B cells as a critical target of these drugs.

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 grants from the Deutsche Forschungsgemeinschaft (Grant Lu 194/2 and International Graduate School 767).

² Address correspondence and reprint requests to Dr. Werner Lutz, Philipps-University, Marburg, Institute of Molecular Biology and Tumor Research, Marburg, Germany. E-mail address: lutz{at}imt.uni-marburg.de

³ Abbreviations used in this paper: HAT, histone acetyltransferase; HDAC, histone deacetylase; AT, acetyltransferase; s, surface; SLE, systemic lupus erythematosus; MZ, marginal zone; WT, wild type; MOMA, metallophilic macrophage.