Joint inflammation and chondrocyte death become independent of Fcγ receptor type III by local overexpression of interferon‐γ during immune complex–mediated arthritis

Nabbe, Karin C.; Boross, Péter; Holthuysen, A.E.M.; Slöetjes, A.; Kolls, Jay K.; Verbeek, Sjef; Lent, P.L.E.M. van; Berg, Wim B. van den

doi:10.1002/art.20874

Cited by 13 publications

(7 citation statements)

References 42 publications

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“…In the early phase of CIA, cartilage destruction correlated with the level of inflammation, which was predominantly dependent on Fc␥RIII (Fig. 2), confirming results from studies in other arthritis models (13,18). The prominent role of the low affinity Fc␥RIII can be explained by its 1) broad expression pattern (macrophages, neutrophils, mast cells, NK cells, and NKT cells); 2) relatively high basal expression level; and 3) broad specificity for IgG (IgG1 Ͼ IgG2a Ͼ IgG2b).…”

Section: Discussionsupporting

confidence: 84%

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Destructive Arthritis in the Absence of Both FcγRI and FcγRIII

Boross

Lent²,

Martín-Ramírez

et al. 2008

The Journal of Immunology

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Fc receptors for IgG (FcγR) have been implicated in the development of arthritis. However, the precise contribution of the individual FcγR to joint pathology is unclear. In this study, the role of the different FcγR was assessed both in an active and in a passive mouse model of arthritis by analyzing disease development in double and triple knockout (KO) offspring from crosses of FcγRI KO, FcγRIII KO, FcγRI/III double KO, or FcR γ-chain KO with the FcγRII KO on C57BL6 background, which is susceptible for collagen-induced arthritis (CIA). In the active CIA model, onset was significantly delayed in the absence of FcγRIII, whereas incidence and maximum severity were significantly decreased in FcγRI/II/III triple KO but not in FcγRII/III double KO and FcγRI/II double KO mice as compared with FcγRII KO animals. Remarkably, fully destructive CIA developed in FcγRI/II/III triple KO mice. In contrast, FcR γ/FcγRII double KO mice were resistant to CIA. These findings were confirmed with the passive KRN serum-induced arthritis model. These results indicate that all activating FcγR play a role in the development of arthritis, mainly in the downstream effector phase. FcγRIII is critically required for early arthritis onset, and FcγRI can substantially contribute to arthritis pathology. Importantly, FcγRI and FcγRIII were together dispensable for the development of destructive arthritis but the FcR γ-chain was not, suggesting a role for another FcR γ-chain associated receptor, most likely FcγRIV. In addition, FcγRII plays a negative regulatory role in both the central and effector phase of arthritis.

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Section: Discussionsupporting

confidence: 84%

“…It has been shown that activation of infiltrating or resident cells in the joint leads to severe cartilage destruction, such as matrix metalloproteinase-induced damage or chondrocyte death (17). Activating Fc␥R have been implicated in this process in the Ag-induced arthritis (AIA) model (13,18).…”

mentioning

confidence: 99%

Destructive Arthritis in the Absence of Both FcγRI and FcγRIII

Boross

Lent²,

Martín-Ramírez

et al. 2008

The Journal of Immunology

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“…In FcγRIII KO mice IFNγ-most likely through increasing FcγRI expression on resident macrophages in the joint-is able to bypass FcγRIII requirement for inflammation during ICA. This study also proves that both FcγRI and FcγRIII can contribute to MMP-mediated destruction of cartilage [70].…”

Section: Immune Complex-mediated Arthritismentioning

confidence: 53%

“…FcγRI expression during AIA is upregulated by T cell derived IFNγ, hence, late cartilage destruction becomes entirely FcγRI-dependent. Artificially induced local overexpression of IFNγ by adenovirus expression vectors in the knee during ICA results in elevated chondrocyte death in wild-type and FcγRIII KO mice, but not in FcγRI KO mice [69,70]. However, MMP-induced proteoglycan damage is elevated in FcγRI KO mice as well, indicating that FcγRIII-when upregulated by IFNγ-is able to mediate this process [69].…”

Section: Immune Complex-mediated Arthritismentioning

confidence: 88%

The complex role of Fcγ receptors in the pathology of arthritis

Boross

Verbeek

2006

Springer Semin Immun

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Autoantibodies of the IgG class and the immune complexes they form are central players in the pathology of rheumatoid arthritis (RA). Receptors for the Fc part of IgG, FcgammaR constitute one of the main effector mechanisms through which IgG immune complexes exert their action. The different members of the FcgammaR family exhibit extensive structural homology leading to redundancy in ligand specificity and signal transduction. Moreover, the initiation of effector mechanisms by IgG immune complexes can also be mediated by the complement system. This strong redundancy and high degree of complexity hampers a direct in vivo analysis of antibody effector pathways. Over the last decade, mice deficient for different combinations of FcgammaR have been generated by gene targeting. These knockout mice provide excellent tools to define the specific contribution of the different FcgammaR to IgG effector pathways in well-established in vivo mouse models for arthritis. This review will discuss the results of the studies that analyze the role of the different members of the FcgammaR family in murine arthritis models and their implications for our understanding of the human disease.

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“…2) or Con A (data not shown), suggesting that the elevated T cell IFN-g release in mice lacking CD1d-dependent NKTs was not due to a general higher activation status of T cells in these mice. Even though IFN-g has recently been implicated as a regulatory cytokine in arthritis (52), others have shown that IFN-g worsens CIA and is important for cartilage destruction during immune complex-mediated arthritis (53,54).…”

Section: B6mentioning

confidence: 99%

CD1d-Dependent NKT Cells Play a Protective Role in Acute and Chronic Arthritis Models by Ameliorating Antigen-Specific Th1 Responses

Teige

Bockermann

Hasan

et al. 2010

The Journal of Immunology

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A protective and anti-inflammatory role for CD1d-dependent NKT cells (NKTs) has been reported in experimental and human autoimmune diseases. However, their role in arthritis has been unclear, with conflicting reports of CD1d-dependent NKTs acting both as regulatory and disease-promoting cells in arthritis. These differing modes of action might be due to genetic differences of inbred mice and incomplete backcrossing of gene-modified mice. We therefore put special emphasis on controlling the genetic backgrounds of the mice used. Additionally, we used two different murine arthritis models, Ag-induced arthritis (AIA) and collagen-induced arthritis (CIA), to evaluate acute and chronic arthritis in CD1d knockout mice and mice depleted of NK1.1+ cells. CD1d-deficient mice developed more severe AIA compared with wild-type littermates, with a higher degree of inflammation and proteoglycan depletion. Chronic arthritis in CIA was also worse in the absence of CD1d-dependent NKTs. Elevated levels of Ag-specific IFN-γ production accompanied these findings rather than changes in IL-17α. Depletion of NK1.1+ cells supported these findings in AIA and CIA. This report provides support for CD1d-dependent NKTs being suppressor cells in acute and chronic arthritis, likely via inhibition of arthritogenic Th1 cells. These results make CD1d-dependent NKTs an attractive target for therapeutic intervention.

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Joint inflammation and chondrocyte death become independent of Fcγ receptor type III by local overexpression of interferon‐γ during immune complex–mediated arthritis

Cited by 13 publications

References 42 publications

Destructive Arthritis in the Absence of Both FcγRI and FcγRIII

Destructive Arthritis in the Absence of Both FcγRI and FcγRIII

The complex role of Fcγ receptors in the pathology of arthritis

CD1d-Dependent NKT Cells Play a Protective Role in Acute and Chronic Arthritis Models by Ameliorating Antigen-Specific Th1 Responses

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