Role of activatory FcγRI and FcγRIII and inhibitory FcγRII in inflammation and cartilage destruction during experimental antigen-induced arthritis

PLEM Van Lent, K Nabbe, AB Blom… - The American journal of …, 2001 - Elsevier
PLEM Van Lent, K Nabbe, AB Blom, AEM Holthuysen, A Sloetjes, LBA Van De Putte…
The American journal of pathology, 2001Elsevier
IgG-containing immune complexes, which are found in most RA joints, communicate with
hematopoietic cells using three classes of Fc receptors (FcγRI,-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 γ-chain-deficient mice that lack functional FcγRI and FcγRIII, joint inflammation
was comparable but severe cartilage destruction was absent. We now examined the
individual role of the stimulatory FcγRI and FcγRIII and inhibitory FcγRII in inflammation and …
IgG-containing immune complexes, which are found in most RA joints, communicate with hematopoietic cells using three classes of Fc receptors(FcγRI, -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 γ-chain-deficient mice that lack functional FcγRI and FcγRIII, joint inflammation was comparable but severe cartilage destruction was absent. We now examined the individual role of the stimulatory FcγRI and FcγRIII and inhibitory FcγRII in inflammation and functional cartilage damage in knee joints with AIA using FcγRI-, FcγRII-, and FcγRIII-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 FcγRI−/− and FcγRIII−/− but higher in FcγRII−/− if compared to controls. Joint swelling as measured by99mTc uptake at days 1, 3, and 7 was similar in FcγRI−/− and FcγRIII−/− mice and significantly higher in FcγRII−/−. 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 FcγRI−/− and FcγRIII−/− and significantly higher (230% and 340%) in FcγRII−/− 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 FcγRI−/− (79 to 87% and 87 to 88%, respectively) and comparable in FcγRIII−/−. VDIPEN neoepitopes were much higher (82 to 122% and 200 to 250%, respectively) in FcγRII−/− 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 FcγRII−/− (222% and 186%, respectively) but not in FcγRI−/− or FcγRIII−/− mice. These results suggest that during T-cell-mediated AIA, FcγRI and FcγRIII act in concert in acute and chronic inflammation whereas FcγRI is the dominant FcR involved in severe cartilage destruction. FcγRII is a crucial inhibiting factor in acute and chronic inflammation and cartilage erosion.
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