title: Serum BAFF and APRIL Levels, T-Lymphocyte Subsets, and Immunoglobulins after B-Cell Depletion Using the Monoclonal Anti-CD20 Antibody Rituximab in Myalgic Encephalopathy/Chronic Fatigue Syndrome.
abstract: Myalgic Encephalopathy/Chronic Fatigue Syndrome (ME/CFS) is a disease of unknown etiology. We have previously suggested clinical benefit from B-cell depletion using the monoclonal anti-CD20 antibody rituximab in a randomized and placebo-controlled study. Prolonged responses were then demonstrated in an open-label phase-II study with maintenance rituximab treatment. Using blood samples from patients in the previous two clinical trials, we investigated quantitative changes in T-lymphocyte subsets, in immunoglobulins, and in serum levels of two B-cell regulating cytokines during follow-up. B-lymphocyte activating factor of the tumor necrosis family (BAFF) in baseline serum samples was elevated in 70 ME/CFS patients as compared to 56 healthy controls (p = 0.011). There were no significant differences in baseline serum BAFF levels between patients with mild, moderate, or severe ME/CFS, or between responders and non-responders to rituximab. A proliferation-inducing ligand (APRIL) serum levels were not significantly different in ME/CFS patients compared to healthy controls at baseline, and no changes in serum levels were seen during follow-up. Immunophenotyping of peripheral blood T-lymphocyte subsets and T-cell activation markers at multiple time points during follow-up showed no significant differences over time, between rituximab and placebo groups, or between responders and non-responders to rituximab. Baseline serum IgG levels were significantly lower in patients with subsequent response after rituximab therapy compared to non-responders (p = 0.03). In the maintenance study, slight but significant reductions in mean serum immunoglobulin levels were observed at 24 months compared to baseline; IgG 10.6-9.5 g/L, IgA 1.8-1.5 g/L, and IgM 0.97-0.70 g/L. Although no functional assays were performed, the lack of significant associations of T- and NK-cell subset numbers with B-cell depletion, as well as the lack of associations to clinical responses, suggest that B-cell regulatory effects on T-cell or NK-cell subsets are not the main mechanisms for the observed improvements in ME/CFS symptoms observed in the two previous trials. The modest increase in serum BAFF levels at baseline may indicate an activated B-lymphocyte system in a subgroup of ME/CFS patients.
authors.affiliation: Department of Oncology and Medical Physics, Haukeland University Hospital, Bergen, Norway.
authors.forename: Sigrid
authors.initials: S
authors.lastname: Lunde
authors.affiliation: Department of Immunology and Transfusion Medicine, Haukeland University Hospital, Bergen, Norway.|Department of Clinical Science, University of Bergen, Haukeland University Hospital, Bergen, Norway.
authors.forename: Einar K
authors.initials: EK
authors.lastname: Kristoffersen
authors.affiliation: Department of Oncology and Medical Physics, Haukeland University Hospital, Bergen, Norway.|Department of Clinical Medicine, University of Bergen, Haukeland University Hospital, Bergen, Norway.
authors.forename: Dipak
authors.initials: D
authors.lastname: Sapkota
authors.affiliation: Department of Oncology and Medical Physics, Haukeland University Hospital, Bergen, Norway.
authors.forename: Kristin
authors.initials: K
authors.lastname: Risa
authors.affiliation: Department of Oncology and Medical Physics, Haukeland University Hospital, Bergen, Norway.|Department of Clinical Science, University of Bergen, Haukeland University Hospital, Bergen, Norway.
authors.forename: Olav
authors.initials: O
authors.lastname: Dahl
authors.affiliation: Department of Oncology and Medical Physics, Haukeland University Hospital, Bergen, Norway.|Department of Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway.
authors.forename: Ove
authors.initials: O
authors.lastname: Bruland
authors.affiliation: Department of Oncology and Medical Physics, Haukeland University Hospital, Bergen, Norway.|Department of Clinical Science, University of Bergen, Haukeland University Hospital, Bergen, Norway.
authors.forename: Olav
authors.initials: O
authors.lastname: Mella
authors.affiliation: Department of Oncology and Medical Physics, Haukeland University Hospital, Bergen, Norway.
authors.forename: Øystein
authors.initials: Ø
authors.lastname: Fluge
mesh_terms: D000328:Adult; D053264:B-Cell Activating Factor / Q000097:blood*; D001402:B-Lymphocytes / Q000276:immunology; D016022:Case-Control Studies; D004268:DNA-Binding Proteins / Q000097:blood*; D015673:Fatigue Syndrome, Chronic / Q000097:blood / Q000188:drug therapy* / Q000276:immunology; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007136:Immunoglobulins / Q000097:blood*; D007155:Immunologic Factors / Q000627:therapeutic use*; D008297:Male; D000069283:Rituximab / Q000627:therapeutic use*; D016176:T-Lymphocyte Subsets / Q000187:drug effects*; D014157:Transcription Factors / Q000097:blood*
chemical_list: D053264:B-Cell Activating Factor; D004268:DNA-Binding Proteins; D007136:Immunoglobulins; D007155:Immunologic Factors; C118660:PDS5B protein, human; C505719:TNFSF13B protein, human; D014157:Transcription Factors; D000069283:Rituximab