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* Research Unit EA2216 Immunology and Pathology, IFR148 ScInBioS, Université de Brest and Université Européenne de Bretagne;
CHU Brest, Hôpital Morvan and Hôpital de la Cavale Blanche, Brest, France;
William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom
B lymphocytes from patients with systemic lupus erythematosus (SLE) are characterized by reduced expression levels of membrane CD5. Recent studies from our laboratory have revealed that the level of membrane CD5 is determined by the relative level of two alternative CD5 isoforms; CD5-E1A, which is expressed on the membrane, and CD5-E1B, which is retained in the cytoplasm. Using bisulfite sequencing and methylation-sensitive endonuclease assays we show that the promoter for the alternative CD5-E1B isoform is demethylated in B cells from patients with SLE but not in healthy controls. We go on to show that differential methylation is more pronounced following BCR engagement. As a result of this demethylation, CD5-E1B mRNA is transcribed at the expense of CD5-E1A mRNA transcription. We provide further evidence that production of high IL-6 levels by SLE B cells abrogates the ability of SLE B cells to induce DNA methyl transferase (DNMT1) and then to methylate DNA, an effect that is reversed in the presence of a blocking Ab to the IL-6 receptor. The pattern of demethylation of CpG islands in the CD5-E1B promoter in SLE B cells is similar to those in B cells from healthy controls stimulated in the presence of IL-6, or treated with the methylation inhibitor PD98059. The study reveals that engagement of the BCR with constitutive IL-6 down-regulates the level of membrane CD5, which negatively regulates BCR signaling, in SLE B cells. This altered signaling could, in turn, promote the activation and expansion of autoreactive B cells in SLE patients.
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1 This work was supported by grants from the Conseil Regional de Bretagne, the Conseil Général du Finistère, and the French Ministry for Education and Research.
2 S.G. and C.L.D. contributed equally to the work.
3 Address correspondence and reprint requests to Prof. Pierre Youinou, Laboratory of Immunology, Brest University Medical School Hospital, BP824, F-29609, Brest, France. E-mail address: youinou{at}univ-brest.fr
4 Abbreviations used in this paper: SLE, systemic lupus erythematosus; ChIP, chromatin immunoprecipitation; DNMT, DNA methyl transferase; HERV, human endogenous retrovirus; HC, healthy control; MBD, methyl-CpG-binding domain protein; LTR, long terminal repeat; SLEDAI, SLE disease activity index.
5 The online version of this article contains supplemental material.
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