| First Author | van Lent PL | Year | 2001 |
| Journal | Am J Pathol | Volume | 159 |
| Issue | 6 | Pages | 2309-20 |
| PubMed ID | 11733380 | Mgi Jnum | J:72937 |
| Mgi Id | MGI:2154019 | Doi | 10.1016/s0002-9440(10)63081-7 |
| Citation | Van Lent PL, et al. (2001) Role of Activatory FcgammaRI and FcgammaRIII and Inhibitory FcgammaRII in Inflammation and Cartilage Destruction during Experimental Antigen-Induced Arthritis. Am J Pathol 159(6):2309-20 |
| abstractText | IgG-containing immune complexes, which are found in most RA joints, communicate with hematopoietic cells using three classes of Fc receptors(FcgammaRI, -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 gamma-chain-deficient mice that lack functional FcgammaRI and FcgammaRIII, joint inflammation was comparable but severe cartilage destruction was absent. We now examined the individual role of the stimulatory FcgammaRI and FcgammaRIII and inhibitory FcgammaRII in inflammation and functional cartilage damage in knee joints with AIA using FcgammaRI-, FcgammaRII-, and FcgammaRIII-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 FcgammaRI-/- and FcgammaRIII-/- but higher in FcgammaRII-/- if compared to controls. Joint swelling as measured by (99m)Tc uptake at days 1, 3, and 7 was similar in FcgammaRI-/- and FcgammaRIII-/- mice and significantly higher in FcgammaRII-/-. 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 FcgammaRI-/- and FcgammaRIII-/- and significantly higher (230% and 340%) in FcgammaRII-/- 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 FcgammaRI-/- (79 to 87% and 87 to 88%, respectively) and comparable in FcgammaRIII-/-. VDIPEN neoepitopes were much higher (82 to 122% and 200 to 250%, respectively) in FcgammaRII-/- 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 FcgammaRII-/- (222% and 186%, respectively) but not in FcgammaRI-/- or FcgammaRIII-/- mice. These results suggest that during T-cell-mediated AIA, FcgammaRI and FcgammaRIII act in concert in acute and chronic inflammation whereas FcgammaRI is the dominant FcR involved in severe cartilage destruction. FcgammaRII is a crucial inhibiting factor in acute and chronic inflammation and cartilage erosion. |
