Activatory Fc Gamma Receptor IV Plays a Crucial Role in Pathogenesis of Experimental Immune Complex Mediated Chronic Arthritis

Irene Di Ceglie¹, Arjen Blom¹, Sjef Verbeek², Peter van der Kraan³, Wim van den Berg¹ and Peter L. van Lent¹, ¹Experimental Rheumatology, Experimental Rheumatology, Radboud University, Nijmegen, Netherlands, ²Human Genetic, Human Genetic, Leiden University Medical Center, Leiden, Netherlands, ³Experimental Rheumatology, Radboud University, Nijmegen, Netherlands

Meeting: 2014 ACR/ARHP Annual Meeting

Keywords: Fc receptors and rheumatoid arthritis (RA)

Session Information

Title: Rheumatoid Arthritis - Animal Models

Session Type: Abstract Submissions (ACR)

Background/Purpose

Rheumatoid arthritis is characterized by Immune complex dependent chronic joint inflammation and severe cartilage and bone destruction. Earlier we found that in the absence of activatory FcγRI and III, joint destruction during the early murine phase of antigen-induced arthritis (AIA) was protected (1) but the role of FcγRIV has not yet been elucidated.

Methods

AIA was induced by injection of mBSA into the knee joint of FcγRI,II,III ^-/-, FcγI,II,III,IV^-/-and wild type (WT) control mice previously immunized with mBSA/CFA. Histology of total knee joints was taken at day 7 and 21 after arthritis induction. Joint inflammation was scored using an arbitrary scale. Cartilage damage was measured as proteoglycan (PG) depletion. Bone destruction was determined using an arbitrary score. mBSA antibody titers were determined using ELISA.

Results

Both KO strains showed antibody titers against mBSA comparable to immunized control mice. In the early phase of AIA (day 7), joint inflammation was significantly higher in FcγRI,II,III^-/-(infiltrate 47% and exudate 107% higher) when compared to WT controls. In FcγRI,II,III,IV^-/-however, although comparable antibody titers, inflammation was significantly lower (infiltrate 30% and exudate 46% lower) than in WT controls. Early cartilage destruction was protected in both strains reflected by significantly lower PG depletion (34% and 20% lower respectively) when compared to their WT controls.

During the chronic phase at day 21, joint inflammation in FcγI/II/III^-/- was still significantly higher (infiltrate 450% and exudate 170% higher) when compared to WT controls. Protection of cartilage damage seen in early AIA was lost and PG depletion significantly increased in FcγRI,II,III ^-/-by 260 %. Bone erosion also increased by 150%. These results suggest that FcγRI and III regulate destruction in the early phase whereas FcγRIV may be more important in chronic stages of arthritis.

In line with this we found that joint inflammation in FcγRI,II,III,IV ^-/-was much lower when compared with FcγI/II/III^-/- and remained at the same level as their WT controls, implying an active role of FcγRIV in inflammation during the chronic phase. The amount of PG depletion in FcγRI,II,III,IV ^-/-was comparable to that observed in WT. In contrast erosion of cartilage matrix but also bone were found to be significantly lower when compared to WT controls (76% and 34% lower respectively).

Conclusion

Activatory FcγRIV is crucial in regulating joint inflammation during acute and chronic phase of AIA and became crucial in mediating cartilage and bone destruction during the chronic phase of the disease.

Disclosure:

I. Di Ceglie,
None;

A. Blom,
None;

S. Verbeek,
None;

P. van der Kraan,
None;

W. van den Berg,
None;

P. L. van Lent,
None.

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