p300 protein acetyltransferase activity suppresses systemic lupus erythematosus-like autoimmune disease in mice.
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.
Forster
Nicole
N
Institute of Molecular Biology and Tumor Research, University of Marburg, Marburg, Germany.
Gallinat
Sven
S
Jablonska
Jadwiga
J
Weiss
Siegfried
S
Elsässer
Hans-Peter
HP
Lutz
Werner
W
D000107:Acetylation; D000818:Animals; D016175:B-Lymphocyte Subsets / Q000201:enzymology / Q000473:pathology; D018797:Cell Cycle Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D050881:E1A-Associated p300 Protein / Q000378:metabolism*; D005260:Female; D051548:Histone Acetyltransferases / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D008180:Lupus Erythematosus, Systemic / Q000201:enzymology* / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D019463:Mice, Inbred MRL lpr; D017354:Point Mutation; D017634:Self Tolerance / Q000235:genetics; D014157:Transcription Factors / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor
D018797:Cell Cycle Proteins; D050881:E1A-Associated p300 Protein; D051548:Histone Acetyltransferases; D014157:Transcription Factors; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor; C494361:Ep300 protein, mouse