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Regular Article |
RI and FcRIII and Inhibitory FcRII in Inflammation and Cartilage Destruction during Experimental Antigen-Induced Arthritis
From the Department of Rheumatology,*
University Medical
Centre, Nijmegen; and the Department of Human and Clinical
Genetics,
University Medical Centre, Leiden,
The Netherlands
IgG-containing immune complexes, which are found in most RA
joints, communicate with hematopoietic cells using three
classes of Fc receptors(Fc
RI, -II, -III). In a
previous study we found that if a chronic T-cell-mediated
antigen-induced arthritis (AIA) was elicited in knee joints of FcR
-chain-deficient mice that lack functional FcRI and
FcRIII, joint inflammation was comparable but severe
cartilage destruction was absent. We now examined the individual role
of the stimulatory FcRI and FcRIII and inhibitory FcRII in
inflammation and functional cartilage damage in knee joints with AIA
using FcRI-, FcRII-, and FcRIII-deficient
mice. Three weeks after immunization with the antigen-methylated bovine
serum albumin (BSA), cellular (T-cell responses as
measured by lymphocyte proliferation) immunity raised against mBSA was
comparable in all groups examined. Humoral (total IgG,
IgG1, IgG2a, and IgG2b levels) immunity against mBSA
was comparable in FcRI-/- and FcRIII-/- but higher in
FcRII-/- if compared to controls. Joint swelling as measured by
99mTc uptake at days 1, 3, and 7 was
similar in FcRI-/- and FcRIII-/- mice and significantly
higher in FcRII-/-. Chronic inflammation and cartilage damage
(depletion of proteoglycans, metalloproteinase (MMP)-induced
neoepitopes, and matrix erosion) was studied histologically in
total knee joint sections stained with hematoxylin or safranin-O.
Histologically, at day 7 after AIA induction, exudate
and infiltrate in the knee joint was similar in FcRI-/- and
FcRIII-/- and significantly higher (230% and 340%) in
FcRII-/- mice if compared to controls. Aggrecan breakdown in
cartilage caused by MMPs and, which is related to severe
irreversible cartilage erosion, was further studied by
immunolocalization of MMP-mediated neoepitopes (VDIPEN) and image
analysis. MMP-induced neoepitopes determined in various cartilage
layers (tibia and femur) were primarily inhibited in FcRI-/- (79
to 87% and 87 to 88%, respectively) and comparable in
FcRIII-/-. VDIPEN neoepitopes were much higher (82 to 122% and
200 to 250%, respectively) in FcRII-/- mice. Initial
depletion of proteoglycans was similar (60 to 100%) in all groups. In
the chronic phase, cartilage matrix erosion in the lateral and
medial tibia was significantly elevated in FcRII-/- (222% and
186%, respectively) but not in FcRI-/- or FcRIII-/-
mice. These results suggest that during T-cell-mediated AIA,
FcRI and FcRIII act in concert in acute and chronic inflammation
whereas FcRI is the dominant FcR involved in severe cartilage
destruction. FcRII is a crucial inhibiting factor in acute and
chronic inflammation and cartilage erosion.
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