title: Altered Natural Killer Cell Subsets in Seropositive Arthralgia and Early Rheumatoid Arthritis Are Associated with Autoantibody Status.
abstract: The role of natural killer (NK) cells in the immunopathogenesis of rheumatoid arthritis (RA) is unclear. Therefore, numerical and functional alterations of CD56(dim) and CD56(bright) NK cells in the early stages of RA development were studied.
  
  
  
  Whole blood samples from newly diagnosed, treatment-naive, seropositive (SP) and seronegative (SN) patients with RA (SP RA, n = 45 and SN RA, n = 12), patients with SP arthralgia (n = 30), and healthy controls (HC, n = 41) were assessed for numbers and frequencies of T cells, B cells, and NK cells. SP status was defined as positive for anticyclic citrullinated peptide antibodies (anti-CCP) and/or rheumatoid factor (RF). Peripheral blood mononuclear cells were used for further analysis of NK cell phenotype and function.
  
  
  
  Total NK cell numbers were decreased in SP RA and SP arthralgia but not in SN RA. Also, NK cells from SP RA showed a decreased potency for interferon-γ (IFN-γ) production. A selective decrease of CD56(dim), but not CD56(bright), NK cells in SP RA and SP arthralgia was observed. This prompted investigation of CD16 (FcγRIIIa) triggering in NK cell apoptosis and cytokine expression. In vitro, CD16 triggering induced apoptosis of CD56(dim) but not CD56(bright) NK cells from HC. This apoptosis was augmented by adding interleukin 2 (IL-2). Also, CD16 triggering in the presence of IL-2 stimulated IFN-γ and tumor necrosis factor-α expression by CD56(dim) NK cells.
  
  
  
  The decline of CD56(dim) NK cells in SP arthralgia and SP RA and the in vitro apoptosis of CD56(dim) NK cells upon CD16 triggering suggest a functional role of immunoglobulin G-containing autoantibody (anti-CCP and/or RF)-immune complexes in this process. Moreover, CD16-triggered cytokine production by CD56(dim) NK cells may contribute to systemic inflammation as seen in SP arthralgia and SP RA.
authors.affiliation: From the Department of Rheumatology and Clinical Immunology, and the Department of Laboratory Medicine, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.P. Chalan, PhD, Department of Rheumatology and Clinical Immunology, University of Groningen; J. Bijzet, BS, Department of Rheumatology and Clinical Immunology, University of Groningen; E. Brouwer, MD, PhD, Department of Rheumatology and Clinical Immunology, University of Groningen; A.M. Boots, Prof., Department of Rheumatology and Clinical Immunology, University of Groningen; B.J. Kroesen, PhD, Department of Laboratory Medicine, University of Groningen.
authors.forename: Paulina
authors.initials: P
authors.lastname: Chalan
authors.affiliation: From the Department of Rheumatology and Clinical Immunology, and the Department of Laboratory Medicine, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.P. Chalan, PhD, Department of Rheumatology and Clinical Immunology, University of Groningen; J. Bijzet, BS, Department of Rheumatology and Clinical Immunology, University of Groningen; E. Brouwer, MD, PhD, Department of Rheumatology and Clinical Immunology, University of Groningen; A.M. Boots, Prof., Department of Rheumatology and Clinical Immunology, University of Groningen; B.J. Kroesen, PhD, Department of Laboratory Medicine, University of Groningen.
authors.forename: Johan
authors.initials: J
authors.lastname: Bijzet
authors.affiliation: From the Department of Rheumatology and Clinical Immunology, and the Department of Laboratory Medicine, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.P. Chalan, PhD, Department of Rheumatology and Clinical Immunology, University of Groningen; J. Bijzet, BS, Department of Rheumatology and Clinical Immunology, University of Groningen; E. Brouwer, MD, PhD, Department of Rheumatology and Clinical Immunology, University of Groningen; A.M. Boots, Prof., Department of Rheumatology and Clinical Immunology, University of Groningen; B.J. Kroesen, PhD, Department of Laboratory Medicine, University of Groningen.
authors.forename: Bart-Jan
authors.initials: BJ
authors.lastname: Kroesen
authors.affiliation: From the Department of Rheumatology and Clinical Immunology, and the Department of Laboratory Medicine, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.P. Chalan, PhD, Department of Rheumatology and Clinical Immunology, University of Groningen; J. Bijzet, BS, Department of Rheumatology and Clinical Immunology, University of Groningen; E. Brouwer, MD, PhD, Department of Rheumatology and Clinical Immunology, University of Groningen; A.M. Boots, Prof., Department of Rheumatology and Clinical Immunology, University of Groningen; B.J. Kroesen, PhD, Department of Laboratory Medicine, University of Groningen. m.boots@umcg.nl.
authors.forename: Annemieke M H
authors.initials: AM
authors.lastname: Boots
authors.affiliation: From the Department of Rheumatology and Clinical Immunology, and the Department of Laboratory Medicine, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.P. Chalan, PhD, Department of Rheumatology and Clinical Immunology, University of Groningen; J. Bijzet, BS, Department of Rheumatology and Clinical Immunology, University of Groningen; E. Brouwer, MD, PhD, Department of Rheumatology and Clinical Immunology, University of Groningen; A.M. Boots, Prof., Department of Rheumatology and Clinical Immunology, University of Groningen; B.J. Kroesen, PhD, Department of Laboratory Medicine, University of Groningen.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Brouwer
mesh_terms: D000328:Adult; D000368:Aged; D018771:Arthralgia / Q000276:immunology* / Q000378:metabolism; D001172:Arthritis, Rheumatoid / Q000276:immunology* / Q000378:metabolism; D001323:Autoantibodies / Q000276:immunology*; D002097:C-Reactive Protein / Q000378:metabolism; D019002:CD56 Antigen / Q000378:metabolism; D005260:Female; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000276:immunology / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D012217:Rheumatoid Factor / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D001323:Autoantibodies; D019002:CD56 Antigen; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D002097:C-Reactive Protein; D012217:Rheumatoid Factor
keywords: ARTHRALGIA; AUTOANTIBODIES; NATURAL KILLER CELLS; RHEUMATOID ARTHRITIS; RHEUMATOID FACTOR