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Increased FcRII expression and aberrant tumour necrosis factor production by mature dendritic cells from patients with active rheumatoid arthritis

T R D J Radstake¹, A B Blom¹, A W Slöetjes¹, E O F van Gorselen¹, G J Pesman², L Engelen³, R Torensma³, W B van den Berg¹, C G Figdor³, P L E M van Lent¹, G J Adema³, P Barrera¹

¹ Department of Rheumatology, University Medical Centre, Nijmegen, The Netherlands
² Department of Experimental and Chemical Endocrinology, University Medical Centre, Nijmegen, The Netherlands
³ Tumour Immunology Laboratory, University Medical Centre, Nijmegen, The Netherlands

Correspondence to:
Correspondence to:
Dr T R D J Radstake
Department of Rheumatology, University Medical Centre Nijmegen, Geertgroote plein 8, 6500 HB Nijmegen, The Netherlands; T.radstake{at}reuma.umcn.nl

Objectives: To investigate potential differences in phenotype and behaviour of immature (iDC) and mature dendritic cells (mDC) from patients with RA and healthy subjects.

Methods: iDC and mDC were derived from blood monocytes of patients with RA and healthy controls following standardised protocols. FACS was used to analyse expression of FcRI, II, and III and molecules to characterise DC. Discrimination between FcRIIa and FcRIIb was achieved by RT-PCR. Immunohistochemistry was performed on synovial biopsy specimens of three patients with RA and three healthy controls. TNF production by iDC and mDC upon FcR dependent stimulation was compared between patients with RA and controls by ELISA.

Results: iDC from patients with active RA but not from patients with inactive RA or healthy controls markedly up regulated FcRII. mDC from patients with active RA also lacked the physiological down regulation of FcRII that occurs upon maturation in both control groups. RT-PCR analysis confirmed the increased expression of FcRII in RA—especially marked for FcRIIb. FcR dependent stimulation of DC using antigen-IgG immune complexes (IC) significantly increased TNF production by DC from healthy subjects, but significantly decreased TNF by DC from patients with RA. Overlapping expression patterns between FcRII and DC-LAMP in the synovial tissue of patients with RA imply that in vivo, also, mature DC express increased levels of FcRIIb.

Conclusion: The presence and altered characteristics of DC during active RA suggest that DC help to modulate autoimmunity in RA. Further studies should elucidate the role of local factors in altering the function of DC in RA and in increasing expression of FcRII.

Abbreviations: DAS28, 28 joint disease activity score; DC, dendritic cells; ELISA, enzyme linked immunosorbent assay; FACS, fluorescence activated cell sorter; FcR, Fc gamma receptor; GAPDH, glyceraldehyde 3-phosphate dehydrogenase; HAGGs, heat aggregated gamma immunoglobulins; IC, immune complexes; IL, interleukin; LPS, lipopolysaccharide; MFI, mean fluorescence intensity; MHC, major histocompatibility complex; PBMC, peripheral blood mononuclear cell; RA, rheumatoid arthritis; RT-PCR, reverse transcriptase-polymerase chain reaction; TNF, tumour necrosis factor

Keywords: dendritic cells; autoimmunity; Fc gamma receptor; rheumatoid arthritis; tumour necrosis factor

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