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Elevated expression of the Brn-3a and Brn-3b transcription factors in systemic lupus erythematosus correlates with antibodies to Brn-3 and overexpression of Hsp90

Ripley, BJM; Rahman, AA; Isenberg, DA; Latchman, DS; (2005) Elevated expression of the Brn-3a and Brn-3b transcription factors in systemic lupus erythematosus correlates with antibodies to Brn-3 and overexpression of Hsp90. ARTHRITIS RHEUM , 52 (4) 1171 - 1179. 10.1002/art.21000.

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Abstract

Objective. Important developmental and antiapoptotic roles have been described for the Brn-3 family of transcription factors in mammalian cells. Following a report of pathogenic autoantibody-inducing T cell reactivity to the Brn-3 transcription factors in murine lupus, we undertook this study to investigate serum levels of antibodies to Brn-3 and levels of expression of Brn-3 in peripheral blood mononuclear cells (PBMCs) of patients with systemic lupus erythematosus (SLE).Methods. Serum and PBMC samples were obtained from 87 SLE patients and 30 normal control subjects. Serum antibodies to the Brn-3a and Brn-3b transcription factors were measured by enzyme-linked immunosorbent assay. Levels of Brn-3a and Brn-3b messenger RNA (mRNA) in PBMCs were measured by reverse transcription and real-time quantitative polymerase chain reaction.Results. Elevated serum levels of antibodies to Brn-3a and Brn-3b were found in 43% and 32%, respectively, of SLE patients. This elevation paralleled enhanced expression of Brn-3a and Brn-3b in PBMCs of 44% and 31%, respectively, of SLE patients. Furtherniore. we observed a significant correlation (P = 0.002) between elevated levels of anti-Brn-3b antibodies and elevated levels of Brn-3b mRNA in individual patients. A preliminary analysis of possible target genes for Brn-3a and Brn-3b revealed a significant correlation (P = 0.01) between the level of Brn-3a mRNA and the level of Hsp90 protein (90-kd heat-shock protein, which is over expressed in SLE) in PBMCs of SLE patients. In addition, we observed that overexpression of Brn-3a and Brn-3b in cultured cells enhanced expression of Hsp90 protein and transcription of Hsp90 promoter-reporter constructs. Finally, we observed an association between elevated levels of Brn-3a mRNA and active SLE (P 0.002).Conclusion. Expression of both Brn-3a and Brn-3b was found to be enhanced in SLE, and this correlated with enhanced levels of autoantibodies to these proteins and with the previously reported overexpression of Hsp90, which was shown to be a novel gene regulated by Brn-3a and Brn-3b. The overexpression of Brn-3a correlated with active disease, suggesting that it may play a role in the disease process via its targeting by the immune system and its ability to induce the expression of specific genes.

Type: Article
Title: Elevated expression of the Brn-3a and Brn-3b transcription factors in systemic lupus erythematosus correlates with antibodies to Brn-3 and overexpression of Hsp90
DOI: 10.1002/art.21000
Keywords: POU-DOMAIN FACTORS, SHOCK-PROTEIN, REVISED CRITERIA, GENE-EXPRESSION, CANCER CELLS, IN-VIVO, FAMILY, NEURONS, BINDING, AUTOANTIBODIES
UCL classification: UCL > Office of the President and Provost
UCL > School of Life and Medical Sciences
UCL > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > School of Life and Medical Sciences > Faculty of Medical Sciences > Medicine (Division of) > Inflammation
UCL > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute of Child Health > ICH - General Administration > ICH - Directors Office
URI: http://discovery.ucl.ac.uk/id/eprint/40235
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