title: Interleukin-6 is responsible for aberrant B-cell receptor-mediated regulation of RAG expression in systemic lupus erythematosus.
abstract: Defective regulation of secondary immunoglobulin V(D)J gene rearrangement promotes the production of autoantibodies in systemic lupus erythematosus (SLE). It remains unclear, however, whether the regulation of the recombination-activating genes RAG1 and RAG2 is effective in SLE. RAG1 and RAG2 messenger RNA expression was analysed before and after in vitro activation of sorted CD19(+) CD5(-) B cells with anti-immunoglobulin M antibodies, in 20 SLE patients and 17 healthy controls. The expression of CDK2 and p27(Kip1) regulators of the RAG2 protein, were examined. The levels of interleukin-6 (IL-6) and its influence on RAG regulation were also evaluated in vitro. SLE patients had increased frequency of RAG-positive B cells. B-cell receptor (BCR) engagement induced a shift in the frequency of kappa- and lambda-positive cells, associated with a persistence of RAG messenger RNA and the maintenance of RAG2 protein within the nucleus. While expression of the RAG2-negative regulator CDK2 was normal, the positive regulator p27(Kip1) was up-regulated and enhanced by BCR engagement. This effect was the result of the aberrant production of IL-6 by SLE B cells. Furthermore, IL-6 receptor blockade led to a reduction in p27(Kip1) expression, and allowed the translocation of RAG2 from the nucleus to the cytoplasm. Our study indicates that aberrant production of IL-6 contributes to the inability of SLE B cells to terminate RAG protein production. Therefore, we hypothesize that because of constitutive IL-6 signalling in association with BCR engagement, SLE B cells would become prone to secondary immunoglobulin gene rearrangements and autoantibody production.
authors.affiliation: EA Immunologie et Pathologie, Brest University Medical School, Brest, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Hillion
authors.forename: Soizic
authors.initials: S
authors.lastname: Garaud
authors.forename: Valérie
authors.initials: V
authors.lastname: Devauchelle
authors.forename: Anne
authors.initials: A
authors.lastname: Bordron
authors.forename: Christian
authors.initials: C
authors.lastname: Berthou
authors.forename: Pierre
authors.initials: P
authors.lastname: Youinou
authors.forename: Christophe
authors.initials: C
authors.lastname: Jamin
mesh_terms: D000888:Antibodies, Anti-Idiotypic / Q000276:immunology; D016175:B-Lymphocyte Subsets / Q000276:immunology*; D002478:Cells, Cultured; D050760:Cyclin-Dependent Kinase Inhibitor p27; D004268:DNA-Binding Proteins / Q000096:biosynthesis* / Q000235:genetics; D005786:Gene Expression Regulation / Q000276:immunology; D015322:Gene Rearrangement, B-Lymphocyte / Q000276:immunology; D018398:Homeodomain Proteins / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D007075:Immunoglobulin M / Q000276:immunology; D015850:Interleukin-6 / Q000276:immunology*; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008180:Lupus Erythematosus, Systemic / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology; D009687:Nuclear Proteins / Q000096:biosynthesis* / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods
chemical_list: D000888:Antibodies, Anti-Idiotypic; C436291:CDKN1B protein, human; D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; D007075:Immunoglobulin M; D015850:Interleukin-6; D047908:Intracellular Signaling Peptides and Proteins; D009687:Nuclear Proteins; C499311:RAG2 protein, human; D012333:RNA, Messenger; C064658:RAG-1 protein; D050760:Cyclin-Dependent Kinase Inhibitor p27