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Arthritis Rheum. 2008 Sep;58(9):2700-11. doi: 10.1002/art.23760.

Natural killer cell degeneration exacerbates experimental arthritis in mice via enhanced interleukin-17 production.

Author information

1
Department of Pathology, Center of Infection and Immunology, University of Hong Kong, Hong Kong, China.

Abstract

OBJECTIVE:

An altered phenotype and dysfunction of natural killer (NK) cells have been observed in patients with rheumatoid arthritis. The aim of this study was to determine whether dysregulated NK cells contribute to the pathogenesis of experimental arthritis.

METHODS:

For initiation of collagen-induced arthritis (CIA), DBA/1J mice were immunized with type II collagen in Freund's adjuvant. Control mice were immunized with adjuvant alone. NK cells from the blood, spleens, and bone marrow of immunized mice were analyzed by flow cytometry. Levels of interleukin-17 (IL-17) secretion and autoantibody production were measured by enzyme-linked immunosorbent assays. Immunized mice in which NK cells were depleted by anti-asialo G(M1) antibody treatment were assessed for the development of CIA. Moreover, sorting-purified NK cells from both mice with CIA and control mice were analyzed for cytokine gene expression.

RESULTS:

We observed markedly reduced frequencies of NK cells in the blood and spleens of mice with CIA compared with the frequencies in adjuvant-treated control mice. Upon NK cell depletion, immunized mice displayed an early onset of arthritis with more severe clinical symptoms, which correlated with increased plasma cell generation and autoantibody production. Moreover, a substantially increased number of IL-17-secreting cells in synovial tissue and more pronounced joint damage were observed. Freshly isolated NK cells from mice with CIA showed markedly reduced expression of interferon-gamma (IFNgamma). Furthermore, coculture of normal NK cells and CD4+ T cells revealed that NK cells strongly suppressed production of Th17 cells via their IFNgamma production.

CONCLUSION:

These results suggest that NK cells play a protective role in the development of experimental arthritis, an effect that is possibly mediated by suppressing Th17 cell generation via IFNgamma production.

PMID:
18759269
DOI:
10.1002/art.23760
[Indexed for MEDLINE]
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