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. 2004 Dec;63(12):1556–1563. doi: 10.1136/ard.2003.016550

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

T Radstake 1, A Blom 1, A Sloetjes 1, E O F van Gorselen 1, G Pesman 1, L Engelen 1, R Torensma 1, W B van den Berg 1, C Figdor 1, P L E M van Lent 1, G Adema 1, P Barrera 1
PMCID: PMC1754865  PMID: 15547078

Abstract

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 FcγRI, II, and III and molecules to characterise DC. Discrimination between FcγRIIa and FcγRIIb was achieved by RT-PCR. Immunohistochemistry was performed on synovial biopsy specimens of three patients with RA and three healthy controls. TNFα production by iDC and mDC upon FcγR 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 FcγRII. mDC from patients with active RA also lacked the physiological down regulation of FcγRII that occurs upon maturation in both control groups. RT-PCR analysis confirmed the increased expression of FcγRII in RA—especially marked for FcγRIIb. FcγR dependent stimulation of DC using antigen-IgG immune complexes (IC) significantly increased TNFα production by DC from healthy subjects, but significantly decreased TNFα by DC from patients with RA. Overlapping expression patterns between FcγRII and DC-LAMP in the synovial tissue of patients with RA imply that in vivo, also, mature DC express increased levels of FcγRIIb.

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 FcγRII.

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Figure 1.

Figure 1

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 FcγRI, II, and III expression on iDC and mDC from patients with RA and healthy subjects. (A) FACS analysis of the indicated markers (solid line) or isotype controls (dotted line) of DC within the life gate. Numbers within the histograms represent the mean fluorescence of the marker corrected for isotype values. Each graph displays data from one representative donor. (B) Averaged mean expression of the indicated markers from the whole group of healthy donors (n = 32) and patients with RA (n = 31) of both iDC and mDC.

Figure 2.

Figure 2

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 Expression of FcγRI, II, and III on mDC and monocytes from patients with RA and healthy subjects using double staining techniques. (A) MFI of the FcγR subtypes (solid line) and isotype control (dotted line) on mDC (CD83, FcγR double positive cells) and monocytes (CD14, FcγR double positive cells) within the life gate by using double staining FACS analysis. The mean fluorescence is indicated within the histogram. (B) Averaged mean expression of the indicated markers on mDC and monocytes from the whole group of healthy donors (n = 9, n = 10) and patients with RA (n = 13, n = 10), respectively. Of note, only CD83, FcγR and CD14, FcγR double positive cells are shown.

Figure 3.

Figure 3

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 FcγRI, II, and III expression by iDC and influence of RA disease activity. (A) FACS analysis of FcγR subtypes (solid line) and isotype control (dotted line) on iDC from a healthy donor, a patient with active RA, and a patient with RA in remission. The numbers within the histograms indicate the mean fluorescence. Each histogram displays one representative person. (B) Averaged mean expression of CD64, CD32, and CD16 (FcγRI, II, and III, respectively) on iDC from healthy donors (n = 10), patients with RA in remission (n = 6), and patients with RA with active disease (n = 8).

Figure 4.

Figure 4

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 mRNA expression of FcγRIIa and FcγRIIb by iDC and mDC from patients with RA and healthy controls. The bars represent the median level of FcγRII mRNA analysed with PCR techniques, corrected for the expression of the housekeeping gene GAPDH. Eight patients with active RA, six patients with RA in remission (n = 6), and 10 healthy donors (n = 10) were studied.

Figure 5.

Figure 5

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 (A) TNFα production by iDC and mDC. TNFα production (pg/ml) by iDC (n = 21) and mDC (n = 21) from patients with RA (RA DC) and DC from healthy controls (n = 18) (C DC). Full maturation was achieved by adding LPS on day 6. (B) TNFα production by mDC after stimulation with anti-IgG complexes (HAGGs). TNFα production of mDC with and without HAGGs stimulation from patients with RA (n = 10, B) and from healthy subjects (n = 8, C). Full maturation was achieved by adding LPS on day 6.

Figure 6.

Figure 6

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 Co-expression of FcγRII and CD83 in synovial tissue. (A) and (B) show immunostaining of RA synovial tissue with CD32 and DC-LAMP, respectively. Immunostaining with the same set of markers is shown for synovial tissue of a healthy control (HC), respectively.

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