title: Interferon-beta increases BAFF levels in multiple sclerosis: implications for B cell autoimmunity.
abstract: B cells are increasingly recognized as major players in multiple sclerosis pathogenesis. The BAFF/APRIL system is crucial for B cell homoeostasis and may drive B cell-dependent autoimmunity. We asked whether this system is affected by Interferon (IFN)-beta therapy. We analysed transcription of the ligands (BAFF, APRIL, TWE-PRIL) and the corresponding receptors (BAFF-R, TACI and BCMA) by TaqMan-PCR ex vivo in whole blood and in immune cell subsets purified from IFN-beta-treated multiple sclerosis patients. Serum BAFF concentrations were determined by ELISA. This cross-sectional study involved 107 donors. IFN-beta therapy strongly induced BAFF transcription proportionally to the IFN-beta biomarker MxA in monocytes and granulocytes in vivo. BAFF serum concentrations were elevated in IFN-beta-treated multiple sclerosis patients to a similar level as observed in SLE patients. In cultured PBMC, neutrophils, fibroblasts and astrocytes, BAFF was induced by IFN-beta concentrations similar to those reached in vivo in treated multiple sclerosis patients. BAFF turned out to be the main regulated element of the BAFF/APRIL system. In untreated multiple sclerosis patients, there was no BAFF increase as compared to healthy controls. Our study reveals a complex situation. We show that IFN-beta therapy induces a potent B cell survival factor, BAFF. However, B cell depletion would be desirable at least in some multiple sclerosis patients. The systemic induction of BAFF by IFN-beta therapy may facilitate the production of various autoantibodies and of IFN-neutralizing antibodies. Individual MS/NMO patients who have major B cell involvement may benefit less than others from IFN-beta therapy, thus explaining interindividual differences of the therapeutic response.
authors.affiliation: Department of Neuroimmunology, Max Planck Institute of Neurobiology, Am Klopferspitz 18, 82152 Martinsried, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Krumbholz
authors.forename: H
authors.initials: H
authors.lastname: Faber
authors.forename: F
authors.initials: F
authors.lastname: Steinmeyer
authors.forename: L-A
authors.initials: LA
authors.lastname: Hoffmann
authors.forename: T
authors.initials: T
authors.lastname: Kümpfel
authors.forename: H
authors.initials: H
authors.lastname: Pellkofer
authors.forename: T
authors.initials: T
authors.lastname: Derfuss
authors.forename: C
authors.initials: C
authors.lastname: Ionescu
authors.forename: M
authors.initials: M
authors.lastname: Starck
authors.forename: C
authors.initials: C
authors.lastname: Hafner
authors.forename: R
authors.initials: R
authors.lastname: Hohlfeld
authors.forename: E
authors.initials: E
authors.lastname: Meinl
mesh_terms: D000328:Adult; D015551:Autoimmunity; D053264:B-Cell Activating Factor / Q000097:blood / Q000378:metabolism*; D053265:B-Cell Activation Factor Receptor / Q000378:metabolism; D001402:B-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D016022:Case-Control Studies; D002478:Cells, Cultured; D003430:Cross-Sectional Studies; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005260:Female; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D016899:Interferon-beta / Q000032:analysis / Q000627:therapeutic use*; D008297:Male; D009103:Multiple Sclerosis / Q000188:drug therapy* / Q000276:immunology; D053300:Tumor Necrosis Factor Ligand Superfamily Member 13 / Q000378:metabolism
chemical_list: D053264:B-Cell Activating Factor; D053265:B-Cell Activation Factor Receptor; D053300:Tumor Necrosis Factor Ligand Superfamily Member 13; D016899:Interferon-beta