title: Myelin Basic Protein-Induced Production of Tumor Necrosis Factor-α and Interleukin-6, and Presentation of the Immunodominant Peptide MBP85-99 by B Cells from Patients with Relapsing-Remitting Multiple Sclerosis.
abstract: B cells are involved in driving relapsing-remitting multiple sclerosis (RRMS), as demonstrated by the positive effect of therapeutic B-cell depletion. Aside from producing antibodies, B cells are efficient antigen-presenting and cytokine-secreting cells. Diverse polyclonal stimuli have been used to study cytokine production by B cells, but here we used the physiologically relevant self-antigen myelin basic protein (MBP) to stimulate B cells from untreated patients with RRMS and healthy donors. Moreover, we took advantage of the unique ability of the monoclonal antibody MK16 to recognize the immunodominant peptide MBP85-99 presented on HLA-DR15, and used it as a probe to directly study B-cell presentation of self-antigenic peptide. The proportions of B cells producing TNF-α or IL-6 after stimulation with MBP were higher in RRMS patients than in healthy donors, indicating a pro-inflammatory profile for self-reactive patient B cells. In contrast, polyclonal stimulation with PMA + ionomycin and MBP revealed no difference in cytokine profile between B cells from RRMS patients and healthy donors. Expanded disability status scale (EDSS) as well as multiple sclerosis severity score (MSSS) correlated with reduced ability of B cells to produce IL-10 after stimulation with MBP, indicative of diminished B-cell immune regulatory function in patients with the most severe disease. Moreover, EDSS correlated positively with the frequencies of TNF-α, IL-6 and IL-10 producing B cells after polyclonal stimulation. Patient-derived, IL-10-producing B cells presented MBP85-99 poorly, as did IL-6-producing B cells, particulary in the healthy donor group. B cells from MS patients thus present antigen to T cells in a pro-inflammatory context. These findings contribute to understanding the therapeutic effects of B-cell depletion in human autoimmune diseases, including MS.
authors.affiliation: Institute for Inflammation Research, Center for Rheumatology and Spine Diseases, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark.
authors.forename: Claus H
authors.initials: CH
authors.lastname: Nielsen
authors.affiliation: Department of Neurology, Copenhagen University Hospital Rigshospitalet, Danish Multiple Sclerosis Center, Copenhagen, Denmark.
authors.forename: Lars
authors.initials: L
authors.lastname: Börnsen
authors.affiliation: Department of Neurology, Copenhagen University Hospital Rigshospitalet, Danish Multiple Sclerosis Center, Copenhagen, Denmark.
authors.forename: Finn
authors.initials: F
authors.lastname: Sellebjerg
authors.affiliation: Institute for Inflammation Research, Center for Rheumatology and Spine Diseases, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark.
authors.forename: Marie K
authors.initials: MK
authors.lastname: Brimnes
mesh_terms: D000328:Adult; D001324:Autoantigens / Q000378:metabolism; D001402:B-Lymphocytes / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism; D005260:Female; D059810:HLA-DR Serological Subtypes / Q000378:metabolism; D006801:Humans; D007249:Inflammation; D016753:Interleukin-10 / Q000378:metabolism; D015850:Interleukin-6 / Q000096:biosynthesis*; D007963:Leukocytes, Mononuclear / Q000166:cytology; D008297:Male; D008875:Middle Aged; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000097:blood* / Q000503:physiopathology; D004676:Myelin Basic Protein / Q000378:metabolism*; D010446:Peptide Fragments / Q000378:metabolism*; D012720:Severity of Illness Index; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*
chemical_list: D001324:Autoantigens; D016207:Cytokines; D059810:HLA-DR Serological Subtypes; C106559:HLA-DR15 antigen; C508609:IL10 protein, human; C508600:IL6 protein, human; D015850:Interleukin-6; D004676:Myelin Basic Protein; D010446:Peptide Fragments; D014409:Tumor Necrosis Factor-alpha; C107908:myelin basic protein 85-99; D016753:Interleukin-10